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Sample records for monosynaptic excitatory post-synaptic

  1. Dual effect of GABA on descending monosynaptic excitatory postsynaptic potential in frog lumbar motoneurons.

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    Ovsepian, S V; Vesselkin, N P

    2004-01-01

    Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked by stimulating ipsilateral ventrolateral column (VLC) in the thoracic section were recorded in lumbar motoneurons within the isolated spinal cord of the frog Rana ridibunda. Bath application of the selective GABAB receptor agonist (-)-baclofen (0.05 mM) caused a reduction in the peak amplitude of VLC EPSP. Baclofen did not cause any consistent change in the membrane potential or in the EPSP waveform within frog motoneurones. The selective GABA(B) receptor antagonist saclofen (0.1 mM) completely blocked the effect of (-)-baclofen on VLC EPSP. A decrease in VLC EPSP peak amplitude was also observed during GABA (0.5 mM) application. Unlike (-)-baclofen, inhibition of VLC EPSP induced by GABA was accompanied by a shortening of the EPSP time course and a reduction in membrane input resistance within lumbar motoneurons. The decrease in VLC EPSP peak amplitude induced by (-)-baclofen and GABA was accompanied by an increase in the paired-pulse facilitation. These data provide evidence for a dual pre- and postsynaptic GABAergic inhibition of the VLC monosynaptic EPSP in lumbar motoneurons within the frog spinal cord.

  2. Excitatory Post-Synaptic Potential Mimicked in Indium-Zinc-Oxide Synaptic Transistors Gated by Methyl Cellulose Solid Electrolyte

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    Guo, Liqiang; Wen, Juan; Ding, Jianning; Wan, Changjin; Cheng, Guanggui

    2016-12-01

    The excitatory postsynaptic potential (EPSP) of biological synapses is mimicked in indium-zinc-oxide synaptic transistors gated by methyl cellulose solid electrolyte. These synaptic transistors show excellent electrical performance at an operating voltage of 0.8 V, Ion/off ratio of 2.5 × 106, and mobility of 38.4 cm2/Vs. After this device is connected to a resistance of 4 MΩ in series, it exhibits excellent characteristics as an inverter. A threshold potential of 0.3 V is achieved by changing the gate pulse amplitude, width, or number, which is analogous to biological EPSP.

  3. Male-specific alteration in excitatory post-synaptic development and social interaction in pre-natal valproic acid exposure model of autism spectrum disorder.

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    Kim, Ki Chan; Kim, Pitna; Go, Hyo Sang; Choi, Chang Soon; Park, Jin Hee; Kim, Hee Jin; Jeon, Se Jin; Dela Pena, Ike Campomayor; Han, Seol-Heui; Cheong, Jae Hoon; Ryu, Jong Hoon; Shin, Chan Young

    2013-03-01

    Autism spectrum disorder (ASD) is a pervasive developmental disorder characterized by three main behavioral symptoms including social deficits, impaired communication, and stereotyped and repetitive behaviors. ASD prevalence shows gender bias to male. Prenatal exposure to valproic acid (VPA), a drug used in epilepsy and bipolar disorder, induces autistic symptoms in both human and rodents. As we reported previously, prenatally VPA-exposed animals at E12 showed impairment in social behavior without any overt reproductive toxicity. Social interactions were not significantly different between male and female rats in control condition. However, VPA-exposed male offspring showed significantly impaired social interaction while female offspring showed only marginal deficits in social interaction. Similar male inclination was observed in hyperactivity behavior induced by VPA. In addition to the ASD-like behavioral phenotype, prenatally VPA-exposed rat offspring shows crooked tail phenotype, which was not different between male and female groups. Both male and female rat showed reduced GABAergic neuronal marker GAD and increased glutamatergic neuronal marker vGluT1 expression. Interestingly, despite of the similar increased expression of vGluT1, post-synaptic marker proteins such as PSD-95 and α-CAMKII expression was significantly elevated only in male offspring. Electron microscopy showed increased number of post-synapse in male but not in female at 4 weeks of age. These results might suggest that the altered glutamatergic neuronal differentiation leads to deranged post-synaptic maturation only in male offspring prenatally exposed to VPA. Consistent with the increased post-synaptic compartment, VPA-exposed male rats showed higher sensitivity to electric shock than VPA-exposed female rats. These results suggest that prenatally VPA-exposed rats show the male preponderance of ASD-like behaviors including defective social interaction similar to human autistic patients, which

  4. Experimental hypothyroidism delays field excitatory post-synaptic potentials and disrupts hippocampal long-term potentiation in the dentate gyrus of hippocampal formation and Y-maze performance in adult rats.

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    Artis, A S; Bitiktas, S; Taşkın, E; Dolu, N; Liman, N; Suer, C

    2012-03-01

    Manipulations of thyroid hormones have been shown to influence learning and memory. Although a large body of literature is available on the effect of thyroid hormone deficiency on learning and memory functions during the developmental stage, electrophysiological and behavioural findings, particularly on propylthiouracil administration to adult normothyroid animals, are not satisfactory. The experiments in the present study were carried out on 12 adult male Wistar rats aged 6-7 months. Hypothyroidism was induced by administering 6-n-propyl-2-thiouracil in their drinking water for 21 days at a concentration of 0.05%. The spatial learning performance of hypothyroid and control rats was studied on a Y-maze. The rats were then placed in a stereotaxic frame under urethane anaesthesia. A bipolar tungsten electrode was used to stimulate the medial perforant path. A glass micropipette was inserted into the granule cell layer of the ipsilateral dentate gyrus to record field excitatory post-synaptic potentials. After a 15-min baseline recording of field potentials, long-term potentiation was induced by four sets of tetanic trains. The propylthiouracil-treated rats showed a significantly attenuated input-output (I/O) relationship when population spike (PS) amplitudes and field excitatory post-synaptic potentials (fEPSP) were compared. fEPSP and PS latencies were found to be longer in the hypothyroid group than in the control group. The PS amplitude and fEPSP slope potentiations in the hypothyroid rats were not statistically different from those in the control rats, except for the field EPSP slope measured in the post-tetanic and maintenance phases. The hypothyroid rats also showed lower thyroxine levels and poor performance in the spatial memory task. The present study provides in vivo evidence for the action of propylthiouracil leading to impaired synaptic plasticity, which might explain deficit in spatial memory tasks in adult hypothyroid rats.

  5. Dissecting molecular architecture of post-synaptic density at excitatory synapses: An Editorial Highlight for 'Hierarchical organization and genetically separable subfamilies of PSD95 postsynaptic supercomplexes' on page 504.

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    Chen, Jinjun; Pan, Hui-Lin

    2017-08-01

    This Editorial highlights a study by Frank and colleagues (2017) in the current issue of Journal of Neurochemistry. The authors report the genetic composition and stoichiometry of endogenous subfamilies of PSD95-containing supercomplexes in the mouse brain using an innovative strategy of combining gene-tagging knock-in, targeted mutations, and quantitative biochemical assays. Their findings shed new light on our understanding of the genetic hierarchy required for the assembly of distinct supercomplex subfamilies at excitatory synapses in the brain. © 2017 International Society for Neurochemistry.

  6. Spike Train Auto-Structure Impacts Post-Synaptic Firing and Timing-Based Plasticity

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    Scheller, Bertram; Castellano, Marta; Vicente, Raul; Pipa, Gordon

    2011-01-01

    Cortical neurons are typically driven by several thousand synapses. The precise spatiotemporal pattern formed by these inputs can modulate the response of a post-synaptic cell. In this work, we explore how the temporal structure of pre-synaptic inhibitory and excitatory inputs impact the post-synaptic firing of a conductance-based integrate and fire neuron. Both the excitatory and inhibitory input was modeled by renewal gamma processes with varying shape factors for modeling regular and temporally random Poisson activity. We demonstrate that the temporal structure of mutually independent inputs affects the post-synaptic firing, while the strength of the effect depends on the firing rates of both the excitatory and inhibitory inputs. In a second step, we explore the effect of temporal structure of mutually independent inputs on a simple version of Hebbian learning, i.e., hard bound spike-timing-dependent plasticity. We explore both the equilibrium weight distribution and the speed of the transient weight dynamics for different mutually independent gamma processes. We find that both the equilibrium distribution of the synaptic weights and the speed of synaptic changes are modulated by the temporal structure of the input. Finally, we highlight that the sensitivity of both the post-synaptic firing as well as the spike-timing-dependent plasticity on the auto-structure of the input of a neuron could be used to modulate the learning rate of synaptic modification. PMID:22203800

  7. The backbone of the post-synaptic density originated in a unicellular ancestor of choanoflagellates and metazoans

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    Manuel Michaël

    2010-02-01

    Full Text Available Abstract Background Comparative genomics of the early diverging metazoan lineages and of their unicellular sister-groups opens new window to reconstructing the genetic changes which preceded or accompanied the evolution of multicellular body plans. A recent analysis found that the genome of the nerve-less sponges encodes the homologues of most vertebrate post-synaptic proteins. In vertebrate excitatory synapses, these proteins assemble to form the post-synaptic density, a complex molecular platform linking membrane receptors, components of their signalling pathways, and the cytoskeleton. Newly available genomes from Monosiga brevicollis (a member of Choanoflagellata, the closest unicellular relatives of animals and Trichoplax adhaerens (a member of Placozoa: besides sponges, the only nerve-less metazoans offer an opportunity to refine our understanding of post-synaptic protein evolution. Results Searches for orthologous proteins and reconstruction of gene gains/losses based on the taxon phylogeny indicate that post-synaptic proteins originated in two main steps. The backbone scaffold proteins (Shank, Homer, DLG and some of their partners were acquired in a unicellular ancestor of choanoflagellates and metazoans. A substantial additional set appeared in an exclusive ancestor of the Metazoa. The placozoan genome contains most post-synaptic genes but lacks some of them. Notably, the master-scaffold protein Shank might have been lost secondarily in the placozoan lineage. Conclusions The time of origination of most post-synaptic proteins was not concomitant with the acquisition of synapses or neural-like cells. The backbone of the scaffold emerged in a unicellular context and was probably not involved in cell-cell communication. Based on the reconstructed protein composition and potential interactions, its ancestral function could have been to link calcium signalling and cytoskeleton regulation. The complex later became integrated into the evolving

  8. Myosin IIb activity and phosphorylation status determines dendritic spine and post-synaptic density morphology.

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    Jennifer L Hodges

    Full Text Available Dendritic spines in hippocampal neurons mature from a filopodia-like precursor into a mushroom-shape with an enlarged post-synaptic density (PSD and serve as the primary post-synaptic location of the excitatory neurotransmission that underlies learning and memory. Using myosin II regulatory mutants, inhibitors, and knockdowns, we show that non-muscle myosin IIB (MIIB activity determines where spines form and whether they persist as filopodia-like spine precursors or mature into a mushroom-shape. MIIB also determines PSD size, morphology, and placement in the spine. Local inactivation of MIIB leads to the formation of filopodia-like spine protrusions from the dendritic shaft. However, di-phosphorylation of the regulatory light chain on residues Thr18 and Ser19 by Rho kinase is required for spine maturation. Inhibition of MIIB activity or a mono-phosphomimetic mutant of RLC similarly prevented maturation even in the presence of NMDA receptor activation. Expression of an actin cross-linking, non-contractile mutant, MIIB R709C, showed that maturation into a mushroom-shape requires contractile activity. Loss of MIIB also leads to an elongated PSD morphology that is no longer restricted to the spine tip; whereas increased MIIB activity, specifically through RLC-T18, S19 di-phosphorylation, increases PSD area. These observations support a model whereby myosin II inactivation forms filopodia-like protrusions that only mature once NMDA receptor activation increases RLC di-phosphorylation to stimulate MIIB contractility, resulting in mushroom-shaped spines with an enlarged PSD.

  9. α-Actinin-2 mediates spine morphology and assembly of the post-synaptic density in hippocampal neurons.

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    Jennifer L Hodges

    Full Text Available Dendritic spines are micron-sized protrusions that constitute the primary post-synaptic sites of excitatory neurotransmission in the brain. Spines mature from a filopodia-like protrusion into a mushroom-shaped morphology with a post-synaptic density (PSD at its tip. Modulation of the actin cytoskeleton drives these morphological changes as well as the spine dynamics that underlie learning and memory. Several PSD molecules respond to glutamate receptor activation and relay signals to the underlying actin cytoskeleton to regulate the structural changes in spine and PSD morphology. α-Actinin-2 is an actin filament cross-linker, which localizes to dendritic spines, enriched within the post-synaptic density, and implicated in actin organization. We show that loss of α-actinin-2 in rat hippocampal neurons creates an increased density of immature, filopodia-like protrusions that fail to mature into a mushroom-shaped spine during development. α-Actinin-2 knockdown also prevents the recruitment and stabilization of the PSD in the spine, resulting in failure of synapse formation, and an inability to structurally respond to chemical stimulation of the N-methyl-D-aspartate (NMDA-type glutamate receptor. The Ca2+-insensitive EF-hand motif in α-actinin-2 is necessary for the molecule's function in regulating spine morphology and PSD assembly, since exchanging it for the similar but Ca2+-sensitive domain from α-actinin-4, another α-actinin isoform, inhibits its function. Furthermore, when the Ca2+-insensitive domain from α-actinin-2 is inserted into α-actinin-4 and expressed in neurons, it creates mature spines. These observations support a model whereby α-actinin-2, partially through its Ca2+-insensitive EF-hand motif, nucleates PSD formation via F-actin organization and modulates spine maturation to mediate synaptogenesis.

  10. Monosynaptic functional connectivity in cerebral cortex during wakefulness and under graded levels of anesthesia

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    Jeannette A Vizuete

    2012-10-01

    Full Text Available The balance between excitation and inhibition is considered to be of significant importance for neural computation and cognitive function. Excitatory and inhibitory functional connectivity in intact cortical neuronal networks in wakefulness and graded levels of anesthesia has not been systematically investigated. We compared monosynaptic excitatory and inhibitory spike transmission probabilities using pairwise cross-correlogram analysis. Spikes were measured at 64 sites in the visual cortex of rats with chronically implanted microelectrode arrays during wakefulness and three levels of anesthesia produced by desflurane. Anesthesia decreased the number of active units, the number of functional connections, and the strength of excitatory connections. Connection probability (number of connections per number of active unit pairs was unaffected until the deepest anesthesia level, at which a significant increase in the excitatory to inhibitory ratio of connection probabilities was observed. The results suggest that the excitatory-inhibitory balance is altered at an anesthetic depth associated with unconsciousness.

  11. Predicting protein-protein interactions in the post synaptic density.

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    Bar-shira, Ossnat; Chechik, Gal

    2013-09-01

    The post synaptic density (PSD) is a specialization of the cytoskeleton at the synaptic junction, composed of hundreds of different proteins. Characterizing the protein components of the PSD and their interactions can help elucidate the mechanism of long-term changes in synaptic plasticity, which underlie learning and memory. Unfortunately, our knowledge of the proteome and interactome of the PSD is still partial and noisy. In this study we describe a computational framework to improve the reconstruction of the PSD network. The approach is based on learning the characteristics of PSD protein interactions from a set of trusted interactions, expanding this set with data collected from large scale repositories, and then predicting novel interaction with proteins that are suspected to reside in the PSD. Using this method we obtained thirty predicted interactions, with more than half of which having supporting evidence in the literature. We discuss in details two of these new interactions, Lrrtm1 with PSD-95 and Src with Capg. The first may take part in a mechanism underlying glutamatergic dysfunction in schizophrenia. The second suggests an alternative mechanism to regulate dendritic spines maturation.

  12. PET measures of pre- and post-synaptic cardiac beta adrenergic function

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    Link, Jeanne M.; Stratton, John R.; Levy, Wayne; Poole, Jeanne E.; Shoner, Steven C.; Stuetzle, Werner; Caldwell, James H. E-mail: jcald@u.washington.edu

    2003-11-01

    Positron Emission Tomography was used to measure global and regional cardiac {beta}-adrenergic function in 19 normal subjects and 9 congestive heart failure patients. [{sup 11}C]-meta-hydroxyephedrine was used to image norepinephrine transporter function as an indicator of pre-synaptic function and [{sup 11}C]-CGP12177 was used to measure cell surface {beta}-receptor density as an indicator of post-synaptic function. Pre-synaptic, but not post-synaptic, function was significantly different between normals and CHF patients. Pre-synaptic function was well matched to post-synaptic function in the normal hearts but significantly different and poorly matched in the CHF patients studied. This imaging technique can help us understand regional sympathetic function in cardiac disease.

  13. Betahistine produces post-synaptic inhibition of the excitability of the primary afferent neurons in the vestibular endorgans.

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    Soto, E; Chávez, H; Valli, P; Benvenuti, C; Vega, R

    2001-01-01

    Betahistine has been used to treat several vestibular disorders of both central and peripheral origin. The objective of this work was to study the action of betahistine in the vestibular endorgans. Experiments were done in wild larval axolotl (Ambystoma tigrinum). Multiunit extracellular recordings were obtained from the semicircular canal nerve using a suction electrode. Betahistine (10 microM to 10 mM; n = 32) inhibited the basal spike discharge of the vestibular afferent neurons with an IC50 of 600 microM. To define the site of action of betahistine, its interactions with the nitric oxide synthase inhibitor NG-nitro-L-arginine (3 microM) and with the cholinergic antagonists atropine (10 microM; n = 3) and d-tubocurarine (10 microM; n = 3) were studied. The action of betahistine when co-administered with these drugs was the same as that in control experiments, indicating that its effects did not include nitric oxide production or the activation of cholinergic receptors. In contrast, 0.01-1 mM betahistine reduced the excitatory action of kainic acid (10 microM; n = 6) and quiscualic acid (1 microM; n = 13). These results indicate that the action of betahistine on the spike discharge of afferent neurons seems to be due to a post-synaptic inhibitory action on the primary afferent neuron response to the hair cell neurotransmitter.

  14. A post-synaptic scaffold at the origin of the animal kingdom.

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    Onur Sakarya

    Full Text Available BACKGROUND: The evolution of complex sub-cellular structures such as the synapse requires the assembly of multiple proteins, each conferring added functionality to the integrated structure. Tracking the early evolution of synapses has not been possible without genomic information from the earliest branching animals. As the closest extant relatives to the Eumetazoa, Porifera (sponges represent a pivotal group for understanding the evolution of nervous systems, because sponges lack neurons with clearly recognizable synapses, in contrast to eumetazoan animals. METHODOLOGY/PRINCIPAL FINDINGS: We show that the genome of the demosponge Amphimedon queenslandica possesses a nearly complete set of post-synaptic protein homologs whose conserved interaction motifs suggest assembly into a complex structure. In the critical synaptic scaffold gene, dlg, residues that make hydrogen bonds and van der Waals interactions with the PDZ ligand are 100% conserved between sponge and human, as is the motif organization of the scaffolds. Expression in Amphimedon of multiple post-synaptic gene homologs in larval flask cells further supports the existence of an assembled structure. Among the few post-synaptic genes absent from Amphimedon, but present in Eumetazoa, are receptor genes including the entire ionotropic glutamate receptor family. CONCLUSIONS/SIGNIFICANCE: Highly conserved protein interaction motifs and co-expression in sponges of multiple proteins whose homologs interact in eumetazoan synapses indicate that a complex protein scaffold was present at the origin of animals, perhaps predating nervous systems. A relatively small number of crucial innovations to this pre-existing structure may represent the founding changes that led to a post-synaptic element.

  15. Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts.

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    Emanuele, Marco; Esposito, Alessandro; Camerini, Serena; Antonucci, Flavia; Ferrara, Silvia; Seghezza, Silvia; Catelani, Tiziano; Crescenzi, Marco; Marotta, Roberto; Canale, Claudio; Matteoli, Michela; Menna, Elisabetta; Chieregatti, Evelina

    2016-05-01

    Alpha-synuclein (αSyn) interferes with multiple steps of synaptic activity at pre-and post-synaptic terminals, however the mechanism/s by which αSyn alters neurotransmitter release and synaptic potentiation is unclear. By atomic force microscopy we show that human αSyn, when incubated with reconstituted membrane bilayer, induces lipid rafts' fragmentation. As a consequence, ion channels and receptors are displaced from lipid rafts with consequent changes in their activity. The enhanced calcium entry leads to acute mobilization of synaptic vesicles, and exhaustion of neurotransmission at later stages. At the post-synaptic terminal, an acute increase in glutamatergic transmission, with increased density of PSD-95 puncta, is followed by disruption of the interaction between N-methyl-d-aspartate receptor (NMDAR) and PSD-95 with ensuing decrease of long term potentiation. While cholesterol loading prevents the acute effect of αSyn at the presynapse; inhibition of casein kinase 2, which appears activated by reduction of cholesterol, restores the correct localization and clustering of NMDARs.

  16. Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts

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    Marco Emanuele

    2016-05-01

    Full Text Available Alpha-synuclein (αSyn interferes with multiple steps of synaptic activity at pre-and post-synaptic terminals, however the mechanism/s by which αSyn alters neurotransmitter release and synaptic potentiation is unclear. By atomic force microscopy we show that human αSyn, when incubated with reconstituted membrane bilayer, induces lipid rafts' fragmentation. As a consequence, ion channels and receptors are displaced from lipid rafts with consequent changes in their activity. The enhanced calcium entry leads to acute mobilization of synaptic vesicles, and exhaustion of neurotransmission at later stages. At the post-synaptic terminal, an acute increase in glutamatergic transmission, with increased density of PSD-95 puncta, is followed by disruption of the interaction between N-methyl-d-aspartate receptor (NMDAR and PSD-95 with ensuing decrease of long term potentiation. While cholesterol loading prevents the acute effect of αSyn at the presynapse; inhibition of casein kinase 2, which appears activated by reduction of cholesterol, restores the correct localization and clustering of NMDARs.

  17. The importance of the excitatory amino acid transporter 3 (EAAT3)

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    E. Bjørn-Yoshimoto, Walden; Underhill, Suzanne M.

    2016-01-01

    Abstract The neuronal excitatory amino acid transporter 3 (EAAT3) is fairly ubiquitously expressed in the brain, though it does not necessarily maintain the same function everywhere. It is important in maintaining low local concentrations of glutamate, where its predominant post-synaptic localiza......Abstract The neuronal excitatory amino acid transporter 3 (EAAT3) is fairly ubiquitously expressed in the brain, though it does not necessarily maintain the same function everywhere. It is important in maintaining low local concentrations of glutamate, where its predominant post...

  18. Effects of stimulation of group I afferents from flexor muscles on heterosynaptic facilitation of monosynaptic reflexes produced by Ia and descending inputs: a test for presynaptic inhibition.

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    Rudomin, P; Jiménez, I; Enriquez, M

    1991-01-01

    1. In the chloralose anesthetized cat, conditioning stimulation of group I flexor afferents depresses the monosynaptic potentials generated by Ia afferents in single spinal motoneurons or in populations of motoneurons without affecting the monosynaptic potentials produced by stimulation of descending fibers in the ipsilateral ventromedial fasciculus (VMF). 2. Heterosynaptic facilitation of monosynaptic reflexes was used to test changes in the presynaptic effectiveness of excitatory inputs with direct connections with motoneurons. We found that the heterosynaptic facilitation of Ia origin was reduced by conditioning stimulation of group I afferents from flexors, without affecting the heterosynaptic facilitation produced by stimulation of the VMF. 3. These results confirm and expand previous observations showing that the synaptic effectiveness of descending fibers synapsing with motoneurons is not subjected to a presynaptic control mechanism of the type acting on Ia fiber terminals, and provide further basis for the use of changes in heterosynaptic facilitation of monosynaptic reflexes of Ia origin as an estimate of changes in presynaptic inhibition of Ia fibers (Hultborn et al. 1987a).

  19. Valproic acid mediates the synaptic excitatory/inhibitory balance through astrocytes--a preliminary study.

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    Wang, Chao-Chuan; Chen, Po See; Hsu, Chien-Wen; Wu, Shou-Jung; Lin, Chieh-Ting; Gean, Po Wu

    2012-04-27

    Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for the treatment of epilepsy and bipolar disorder. However, the underlying therapeutic mechanisms of the treatment of each disease remain unclear. Recently, the anti-epileptic effect of VPA has been found to lead to modulation of the synaptic excitatory/inhibitory balance. In addition, the therapeutic action of VPA has been linked to its effect on astrocytes by regulating gene expression at the molecular level, perhaps through an epigenetic mechanism as a histone deacetylase (HDAC) inhibitor. To provide insight into the mechanisms underlying the actions of VPA, this study investigated whether the synaptic excitatory/inhibitory (E/I) balance could be mediated by VPA through astrocytes. First, using the primary rat neuronal, astroglial, and neuro-glial mixed culture systems, we demonstrated that VPA treatment could regulate the mRNA levels of two post-synaptic cell adhesion molecules(neuroligin-1 and neuregulin-1) and two extracellular matrices (neuronal pentraxin-1and thrombospondin-3) in primary rat astrocyte cultures in a time- and concentration-dependent manner. Moreover, the up-regulation effect of VPA was noted in astrocytes, but not in neurons. In addition, these regulatory effects could be mimicked by sodium butyrate, a HDAC inhibitor, but not by lithium or two other glycogen synthase kinase-3 beta inhibitors. With the known role of these four proteins in regulating the synaptic E/I balance, we further demonstrated that VPA increased excitatory post-synaptic protein (postsynaptic density 95) and inhibitory post-synaptic protein (Gephyrin) in cortical neuro-glial mixed cultures. Our results suggested that VPA might affect the synaptic excitatory/inhibitory balance through its effect on astrocytes. This work provides the basis for future evaluation of the role of astroglial cell adhesion molecules and the extracellular matrix on the control of excitatory and

  20. Dystrophin and utrophin influence fiber type composition and post-synaptic membrane structure.

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    Rafael, J A; Townsend, E R; Squire, S E; Potter, A C; Chamberlain, J S; Davies, K E

    2000-05-22

    The X-linked muscle wasting disease Duchenne muscular dystrophy is caused by the lack of dystrophin in muscle. Protein structure predictions, patient mutations, in vitro binding studies and transgenic and knockout mice suggest that dystrophin plays a mechanical role in skeletal muscle, linking the subsarcolemmal cytoskeleton with the extracellular matrix through its direct interaction with the dystrophin-associated protein complex (DAPC). Although a signaling role for dystrophin has been postulated, definitive data have been lacking. To identify potential non-mechanical roles of dystrophin, we tested the ability of various truncated dystrophin transgenes to prevent any of the skeletal muscle abnormalities associated with the double knockout mouse deficient for both dystrophin and the dystrophin-related protein utrophin. We show that restoration of the DAPC with Dp71 does not prevent the structural abnormalities of the post-synaptic membrane or the abnormal oxidative properties of utrophin/dystrophin-deficient muscle. In marked contrast, a dystrophin protein lacking the cysteine-rich domain, which is unable to prevent dystrophy in the mdx mouse, is able to ameliorate these abnormalities in utrophin/dystrophin-deficient mice. These experiments provide the first direct evidence that in addition to a mechanical role and relocalization of the DAPC, dystrophin and utrophin are able to alter both structural and biochemical properties of skeletal muscle. In addition, these mice provide unique insights into skeletal muscle fiber type composition.

  1. GABAA receptors: post-synaptic co-localization and cross-talk with other receptors

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    Amulya Nidhi Shrivastava

    2011-06-01

    Full Text Available γ-aminobutyric acid type A receptors (GABAARs are the major inhibitory neurotransmitter receptors in the central nervous system (CNS, and importantly contribute to the functional regulation of the nervous system. Several studies in the last few decades have convincingly shown that GABA can be co-localized with other neurotransmitters in the same synapse, and can be co-released with these neurotransmitters either from the same vesicles or from different vesicle pools. The co-released transmitters may act on post-synaptically co-localized receptors resulting in a simultaneous activation of both receptors. Most of the studies investigating such co-activation observed a reduced efficacy of GABA for activating GABAARs and thus, a reduced inhibition of the postsynaptic neuron. Similarly, in several cases activation of GABAARs has been reported to suppress the response of the associated receptors. Such a receptor cross-talk is either mediated via a direct coupling between the two receptors or via the activation of intracellular signaling pathways and is used for fine tuning of inhibition in the nervous system. Recently, it was demonstrated that a direct interaction of different receptors might already occur in intracellular compartments and might also be used to specifically target the receptors to the cell membrane. In this article, we provide an overview on such cross-talks between GABAARs and several other neurotransmitter receptors and briefly discuss their possible physiological and clinical importance.

  2. Absence of synergy for monosynaptic Group I inputs between abdominal and internal intercostal motoneurons.

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    Ford, T W; Meehan, C F; Kirkwood, P A

    2014-09-01

    Internal intercostal and abdominal motoneurons are strongly coactivated during expiration. We investigated whether that synergy was paralleled by synergistic Group I reflex excitation. Intracellular recordings were made from motoneurons of the internal intercostal nerve of T8 in anesthetized cats, and the specificity of the monosynaptic connections from afferents in each of the two main branches of this nerve was investigated. Motoneurons were shown by antidromic excitation to innervate three muscle groups: external abdominal oblique [EO; innervated by the lateral branch (Lat)], the region of the internal intercostal muscle proximal to the branch point (IIm), and muscles innervated from the distal remainder (Dist). Strong specificity was observed, only 2 of 54 motoneurons showing excitatory postsynaptic potentials (EPSPs) from both Lat and Dist. No EO motoneurons showed an EPSP from Dist, and no IIm motoneurons showed one from Lat. Expiratory Dist motoneurons fell into two groups. Those with Dist EPSPs and none from Lat (group A) were assumed to innervate distal internal intercostal muscle. Those with Lat EPSPs (group B) were assumed to innervate abdominal muscle (transversus abdominis or rectus abdominis). Inspiratory Dist motoneurons (assumed to innervate interchondral muscle) showed Dist EPSPs. Stimulation of dorsal ramus nerves gave EPSPs in 12 instances, 9 being in group B Dist motoneurons. The complete absence of heteronymous monosynaptic Group I reflex excitation between muscles that are synergistically activated in expiration leads us to conclude that such connections from muscle spindle afferents of the thoracic nerves have little role in controlling expiratory movements but, where present, support other motor acts. Copyright © 2014 the American Physiological Society.

  3. Monosynaptic Ia projections from intrinsic hand muscles to forearm motoneurones in humans

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    Marchand-Pauvert, V; Nicolas, G; Pierrot-Deseilligny, E

    2000-01-01

    Heteronymous Ia excitatory projections from intrinsic hand muscles to human forearm motoneurones (MNs) were investigated. Changes in firing probability of single motor units (MUs) in the flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), flexor digitorum superficialis (FDS), extensor carpi radialis (ECR), extensor carpi ulnaris (ECU) and extensor digitorum communis (EDC) were studied after electrical stimuli were applied to the median and ulnar nerve at wrist level and to the corresponding homonymous nerve at elbow level.Homonymous facilitation, occurring at the same latency as the H reflex, and therefore attributed to monosynaptic Ia EPSPs, was found in all the sampled units. In many MUs an early facilitation was also evoked by heteronymous low-threshold afferents from intrinsic hand muscles. The low threshold (between 0.5 and 0.6 times motor threshold (MT)) and the inability of a pure cutaneous stimulation to reproduce this effect indicate that it is due to stimulation of group I muscle afferents.Evidence for a similar central delay (monosynaptic) in heteronymous as in homonymous pathways was accepted when the difference in latencies of the homonymous and heteronymous peaks did not differ from the estimated supplementary afferent conduction time from wrist to elbow level by more than 0.5 ms (conduction velocity in the fastest Ia afferents between wrist and elbow levels being equal to 69 m s−1).A statistically significant heteronymous monosynaptic Ia excitation from intrinsic hand muscles supplied by both median and ulnar nerves was found in MUs belonging to all forearm motor nuclei tested (although not in ECU MUs after ulnar stimulation). It was, however, more often found in flexors than in extensors, in wrist than in finger muscles and in muscles operating in the radial than in the ulnar side.It is argued that the connections of Ia afferents from intrinsic hand muscles to forearm MNs, which are stronger and more widely distributed than in the cat, might

  4. Pre- and post-synaptic sympathetic function in human hibernating myocardium

    Energy Technology Data Exchange (ETDEWEB)

    John, Anna S.; Pepper, John R.; Dreyfus, Gilles D.; Pennell, Dudley J. [Imperial College, Hammersmith Hospital, National Heart and Lung Institute, London (United Kingdom); Mongillo, Marco; Khan, Muhammad T. [Imperial College, Hammersmith Hospital, Medical Research Council Clinical Sciences Centre, London (United Kingdom); Depre, Christophe [University of Medicine and Dentistry New Jersey, Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, New Jersey, NJ (United States); University of Medicine and Dentistry New Jersey, Cardiovascular Research Institute, Department of Medicine, New Jersey, NJ (United States); Rimoldi, Ornella E. [Imperial College, Hammersmith Hospital, National Heart and Lung Institute, London (United Kingdom); Imperial College, Hammersmith Hospital, Medical Research Council Clinical Sciences Centre, London (United Kingdom); New York Medical College, Cardiovascular Research Institute, Department of Medicine, Valhalla, NY (United States); Camici, Paolo G. [Imperial College, Hammersmith Hospital, National Heart and Lung Institute, London (United Kingdom); Imperial College, Hammersmith Hospital, Medical Research Council Clinical Sciences Centre, London (United Kingdom)

    2007-12-15

    Impaired pre-synaptic noradrenaline uptake-1 mechanism has been reported in a swine model of hibernating myocardium (HM). To ascertain whether adrenergic neuroeffector abnormalities are present in human HM, we combined functional measurements in vivo using cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) to assess pre- and post-synaptic sympathetic function. Twelve patients with coronary artery disease and chronic left ventricular (LV) dysfunction underwent CMR at baseline and 6 months after bypass for assessment of regional and global LV function and identification of segments with reversible dysfunction. Before surgery, myocardial noradrenaline uptake-1 ([{sup 11}C]meta-hydroxy-ephedrine; HED) and {beta}-adrenoceptor ({beta}-AR) density ([{sup 11}C]CGP-12177) were measured with PET. Patient PET data were compared with those in 18 healthy controls. The volume of distribution (V{sub d}) of HED in HM (47.95{+-}28.05 ml/g) and infarcted myocardium (42.69{+-}25.76 ml/g) was significantly reduced compared with controls (66.09{+-}14.48 ml/g). The V{sub d} of HED in normal myocardium (49.93{+-}20.48 ml/g) of patients was also lower than that in controls and the difference was close to statistical significance (p=0.06). Myocardial {beta}-AR density was significantly lower in HM (5.49{+-}2.35 pmol/g), infarcted (4.82{+-}2.61 pmol/g) and normal (5.86{+-}1.81 pmol/g) segments of patients compared with healthy controls (8.61{+-}1.32 pmol/g). Noradrenaline uptake-1 mechanism and {beta}-AR density are reduced in the myocardium of patients with chronic LV dysfunction and evidence of HM. The increased sympathetic activity to the heart in these patients is a generalised rather than regional phenomenon which is likely to contribute to the remodelling process of the whole LV rather than playing a causative role in HM. (orig.)

  5. Effects of excitatory amino acid antagonists on evoked and spontaneous excitatory potentials in guinea-pig hippocampus.

    Science.gov (United States)

    Cotman, C W; Flatman, J A; Ganong, A H; Perkins, M N

    1986-09-01

    Evoked and spontaneous excitatory post-synaptic potentials (e.p.s.p.s) at the mossy fibre input to CA3 pyramidal neurones were recorded intracellularly in slices from the guinea-pig hippocampus. The effects of several amino acid antagonists on these responses were examined. L-2-amino-4-phosphonobutyrate (L-AP4), L-serine-O-phosphate (L-SOP), kynurenate, and N-(p-bromobenzoyl)piperazine-2,3-dicarboxylate (pBB-PzDA) reduced the amplitude of evoked mossy fibre e.p.s.p.s without affecting membrane potential or input resistance. Antagonism of mossy fibre spontaneous miniature e.p.s.p.s (m.e.p.s.p.s) by these compounds fell into two groups. L-AP4 and L-SOP applied at concentrations that blocked evoked e.p.s.p.s did not affect amplitude distributions of spontaneous m.e.p.s.p.s. Kynurenate and pBB-PzDA significantly affected the amplitude distributions and reduced the mean amplitude of spontaneous m.e.p.s.p.s. These results are consistent with a presynaptic site of action for L-AP4 and L-SOP and a post-synaptic site of action for kynurenate and pBB-PzDA as antagonists of e.p.s.p.s at the guinea-pig mossy fibre-CA3 pyramidal neurone synapse.

  6. Effects of excitatory amino acid antagonists on evoked and spontaneous excitatory potentials in guinea-pig hippocampus.

    Science.gov (United States)

    Cotman, C W; Flatman, J A; Ganong, A H; Perkins, M N

    1986-01-01

    Evoked and spontaneous excitatory post-synaptic potentials (e.p.s.p.s) at the mossy fibre input to CA3 pyramidal neurones were recorded intracellularly in slices from the guinea-pig hippocampus. The effects of several amino acid antagonists on these responses were examined. L-2-amino-4-phosphonobutyrate (L-AP4), L-serine-O-phosphate (L-SOP), kynurenate, and N-(p-bromobenzoyl)piperazine-2,3-dicarboxylate (pBB-PzDA) reduced the amplitude of evoked mossy fibre e.p.s.p.s without affecting membrane potential or input resistance. Antagonism of mossy fibre spontaneous miniature e.p.s.p.s (m.e.p.s.p.s) by these compounds fell into two groups. L-AP4 and L-SOP applied at concentrations that blocked evoked e.p.s.p.s did not affect amplitude distributions of spontaneous m.e.p.s.p.s. Kynurenate and pBB-PzDA significantly affected the amplitude distributions and reduced the mean amplitude of spontaneous m.e.p.s.p.s. These results are consistent with a presynaptic site of action for L-AP4 and L-SOP and a post-synaptic site of action for kynurenate and pBB-PzDA as antagonists of e.p.s.p.s at the guinea-pig mossy fibre-CA3 pyramidal neurone synapse. PMID:3795109

  7. Tonically Active α5GABAA Receptors Reduce Motoneuron Excitability and Decrease the Monosynaptic Reflex

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    Martha Canto-Bustos

    2017-09-01

    Full Text Available Motoneurons, the final common path of the Central Nervous System (CNS, are under a complex control of its excitability in order to precisely translate the interneuronal pattern of activity into skeletal muscle contraction and relaxation. To fulfill this relevant function, motoneurons are provided with a vast repertoire of receptors and channels, including the extrasynaptic GABAA receptors which have been poorly investigated. Here, we confirmed that extrasynaptic α5 subunit-containing GABAA receptors localize with choline acetyltransferase (ChAT positive cells, suggesting that these receptors are expressed in turtle motoneurons as previously reported in rodents. In these cells, α5GABAA receptors are activated by ambient GABA, producing a tonic shunt that reduces motoneurons’ membrane resistance and affects their action potential firing properties. In addition, α5GABAA receptors shunted the synaptic excitatory inputs depressing the monosynaptic reflex (MSR induced by activation of primary afferents. Therefore, our results suggest that α5GABAA receptors may play a relevant physiological role in motor control.

  8. Fluctuations of excitability in the monosynaptic reflex pathway to lumbar motoneurons in the cat.

    Science.gov (United States)

    Gossard, J P; Floeter, M K; Kawai, Y; Burke, R E; Chang, T; Schiff, S J

    1994-09-01

    1. It is well known that the amplitude of successive monosynaptic reflexes (MSR), elicited by afferent stimuli of constant strength, fluctuate from trial to trial. Previous evidence suggests that such excitability fluctuations within the motor pool can be introduced either pre- and/or postsynaptically. Using unanesthetized decerebrate or decerebrate/spinal cats, we attempted to evaluate the relative importance of pre- and postsynaptic mechanisms to MSR variability and the potential contribution of changes in the identities of responding motoneurons to such variability. 2. Comparisons between the MSR amplitude, measured in a severed ventral root, and the probability of firing of up to three individual motoneurons in fine filaments teased from the same root, confirmed that both correlated and uncorrelated fluctuations of motoneuron excitability are involved in MSR variability. Linear regression analysis from concurrent intracellular recordings from homonymous motoneurons showed that the MSR fluctuations were correlated with the variations in membrane potential baseline, as well as with the fluctuations in the monosynaptic excitatory postsynaptic potential peak amplitude. In all 11 cases tested, the former correlation was stronger than the latter. 3. Stimulation of the caudal cutaneous sural nerve (CCS) was used to alter the postsynaptic potential background on which triceps surae (GS) MSRs were generated. The interval chosen between CCS conditioning and the GS stimulation excluded the involvement of presynaptic inhibition. When conditioned by preceding CCS stimulation, GS population MSRs generally (8/9 cases tested) increased in amplitude without much change in their overall variance. However, the individual motoneurons that contributed to the population responses did show changes in both relative excitability and in the uncorrelated component of their response variance. About half of the concurrently recorded motoneurons (6/13) showed a decrease in relative

  9. Improved Monosynaptic Neural Circuit Tracing Using Engineered Rabies Virus Glycoproteins

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    Euiseok J. Kim

    2016-04-01

    Full Text Available Monosynaptic rabies virus tracing is a unique and powerful tool used to identify neurons making direct presynaptic connections onto neurons of interest across the entire nervous system. Current methods utilize complementation of glycoprotein gene-deleted rabies of the SAD B19 strain with its glycoprotein, B19G, to mediate retrograde transsynaptic spread across a single synaptic step. In most conditions, this method labels only a fraction of input neurons and would thus benefit from improved efficiency of transsynaptic spread. Here, we report newly engineered glycoprotein variants to improve transsynaptic efficiency. Among them, oG (optimized glycoprotein is a codon-optimized version of a chimeric glycoprotein consisting of the transmembrane/cytoplasmic domain of B19G and the extracellular domain of rabies Pasteur virus strain glycoprotein. We demonstrate that oG increases the tracing efficiency for long-distance input neurons up to 20-fold compared to B19G. oG-mediated rabies tracing will therefore allow identification and study of more complete monosynaptic input neural networks.

  10. Distributed and Mixed Information in Monosynaptic Inputs to Dopamine Neurons.

    Science.gov (United States)

    Tian, Ju; Huang, Ryan; Cohen, Jeremiah Y; Osakada, Fumitaka; Kobak, Dmitry; Machens, Christian K; Callaway, Edward M; Uchida, Naoshige; Watabe-Uchida, Mitsuko

    2016-09-21

    Dopamine neurons encode the difference between actual and predicted reward, or reward prediction error (RPE). Although many models have been proposed to account for this computation, it has been difficult to test these models experimentally. Here we established an awake electrophysiological recording system, combined with rabies virus and optogenetic cell-type identification, to characterize the firing patterns of monosynaptic inputs to dopamine neurons while mice performed classical conditioning tasks. We found that each variable required to compute RPE, including actual and predicted reward, was distributed in input neurons in multiple brain areas. Further, many input neurons across brain areas signaled combinations of these variables. These results demonstrate that even simple arithmetic computations such as RPE are not localized in specific brain areas but, rather, distributed across multiple nodes in a brain-wide network. Our systematic method to examine both activity and connectivity revealed unexpected redundancy for a simple computation in the brain.

  11. Differential effects of (-)-baclofen on Ia and descending monosynaptic EPSPs.

    Science.gov (United States)

    Jiménez, I; Rudomin, P; Enriquez, M

    1991-01-01

    1. In cats anesthetized with alpha-chloralose, population synaptic responses of motoneurons produced by stimulation of group I afferents were recorded from ventral roots with a sucrose gap or extracellularly from the motor pool. These responses were depressed, and often abolished, following the intravenous injection of 1-3 mg/kg of (-)-baclofen, a presumed GABAb agonist. 2. The monosynaptic population responses of motoneurons produced by stimulation of the ipsilateral ventromedial funiculus (VMF), the bulbar reticular formation or the vestibular nucleus, were also depressed following the administration of (-)-baclofen, but to a lesser degree than responses produced by stimulation of group I fibers. 3. Depression of the synaptic actions of Ia and of descending fibers following the administration of (-)-baclofen occurred without significant changes in the presynaptic volley recorded from the cord dorsum. However, in 3/4 experiments the intraspinally recorded Ia terminal potential was reduced following the injection of (-)-baclofen. The VMF terminal potentials were also depressed, but to a lesser degree. 4. Intracellular recordings from spinal motoneurons indicate that the (-)-baclofen-induced depression of the monosynaptic Ia- and VMF-EPSPs occurred without important changes in the time course of EPSP decay. This suggests that with the amounts used, postsynaptic changes were not contributing significantly to the EPSP depression. 5. It is suggested that (-)-baclofen depresses synaptic transmission probably by activation of GABAb receptors located at the intraspinal terminations of Ia and descending fibers. The lower sensitivity of VMF actions to (-)-baclofen would be accounted for by a relatively low density of baclofen receptors in descending fiber terminals.

  12. Monosynaptic convergence of somatic and visceral C-fiber afferents on projection and local circuit neurons in lamina I: a substrate for referred pain.

    Science.gov (United States)

    Luz, Liliana L; Fernandes, Elisabete C; Sivado, Miklos; Kokai, Eva; Szucs, Peter; Safronov, Boris V

    2015-10-01

    Referred pain is a phenomenon of feeling pain at a site other than the site of the painful stimulus origin. It arises from a pathological mixing of nociceptive processing pathways for visceral and somatic inputs. Despite numerous studies based on unit recordings from spinal and supraspinal neurons, the exact mechanism and site of this mixing within the central nervous system are not known. Here, we selectively recorded from lamina I neurons, using a visually guided patch-clamp technique, in thoracic spinal cord preparation with preserved intercostal (somatic) and splanchnic (visceral) nerves. We show that somatic and visceral C fibers converge monosynaptically onto a group of lamina I neurons, which includes both projection and local circuit neurons. Other groups of lamina I neurons received inputs from either somatic or visceral afferents. We have also identified a population of lamina I local circuit neurons showing overall inhibitory responses upon stimulation of both nerves. Thus, the present data allow us to draw two major conclusions. First, lamina I of the spinal cord is the first site in the central nervous system where somatic and visceral pathways directly converge onto individual projection and local circuit neurons. Second, the mechanism of somatovisceral convergence is complex and based on functional integration of monosynaptic and polysynaptic excitatory as well as inhibitory inputs in specific groups of neurons. This complex pattern of convergence provides a substrate for alterations in the balance between visceral and somatic inputs causing referred pain.

  13. The post-synaptic density of human postmortem brain tissues: an experimental study paradigm for neuropsychiatric illnesses.

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    Chang-Gyu Hahn

    Full Text Available Recent molecular genetics studies have suggested various trans-synaptic processes for pathophysiologic mechanisms of neuropsychiatric illnesses. Examination of pre- and post-synaptic scaffolds in the brains of patients would greatly aid further investigation, yet such an approach in human postmortem tissue has yet to be tested. We have examined three methods using density gradient based purification of synaptosomes followed by detergent extraction (Method 1 and the pH based differential extraction of synaptic membranes (Methods 2 and 3. All three methods separated fractions from human postmortem brains that were highly enriched in typical PSD proteins, almost to the exclusion of pre-synaptic proteins. We examined these fractions using electron microscopy (EM and verified the integrity of the synaptic membrane and PSD fractions derived from human postmortem brain tissues. We analyzed protein composition of the PSD fractions using two dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS and observed known PSD proteins by mass spectrometry. Immunoprecipitation and immunoblot studies revealed that expected protein-protein interactions and certain posttranscriptional modulations were maintained in PSD fractions. Our results demonstrate that PSD fractions can be isolated from human postmortem brain tissues with a reasonable degree of integrity. This approach may foster novel postmortem brain research paradigms in which the stoichiometry and protein composition of specific microdomains are examined.

  14. Brain region specific pre-synaptic and post-synaptic degeneration are early components of neuropathology in prion disease.

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    Zuzana Šišková

    Full Text Available Synaptic abnormalities, one of the key features of prion disease pathogenesis, gives rise to functional deficits and contributes to the devastating clinical outcome. The synaptic compartment is the first to succumb in several neurodegenerative diseases linked with protein misfolding but the mechanisms underpinning this are poorly defined. In our current study we document that a focal intrahippocampal injection of the mouse-adapted 22L scrapie strain produces a complex, region-specific pathology in the brain. Our findings reveal that early synaptic changes in the stratum radiatum of the hippocampus, identical to those observed with the ME7 strain, occur when 22L strain is introduced into the hippocampus. The pathology was defined by degenerating Type I pre-synaptic elements progressively enveloped by the post-synaptic density of the dendritic spine. In contrast, the pathology in the cerebellum suggested that dendritic disintegration rather than pre-synaptic abnormalities dominate the early degenerative changes associated with the Purkinje cells. Indeed, both of the major synaptic inputs into the cerebellum, which arise from the parallel and climbing fibers, remained intact even at late stage disease. Immunolabeling with pathway selective antibodies reinforced these findings. These observations demonstrate that neuronal vulnerability to pathological protein misfolding is strongly dependent on the structure and function of the target neurons.

  15. Inflammation unmasks gabapentin's effect on Aδ-fiber evoked excitatory postsynaptic currents in substantia gelatinosa neurons of rat spinal cord

    Institute of Scientific and Technical Information of China (English)

    刘智良; 徐如祥; 杨鲲

    2003-01-01

    ObjectiveTo study the analgesic mechanism of gabapentin, an anticonvulsant, during antinociceptive clinical treatment. MethodsWhole-cell voltage-clamp recordings were taken from adult rat spinal cord slices to investigate the effect of gabapentin on primary afferent Aδ-fiber evokedexcitatory postsynaptic currents (EPSCs) to substantia gelatinosa (SG) neurons in normal and inflamed (established by plantar injection of carrageenan) rats. Results Gabapentin (5-20 μmol/L for 5 min) depressed dorsal root Aδ fiber evoked polysynaptic, but not monosynaptic EPSCs to SG experiencing inflammation by about 25ptic or monosynaptic EPSCs in normal rats. Gabapentin failed to block a glutamate receptor subtype, N-methyl-D-aspartate (NMDA), -induced slow excitatory currents on SG neurons.ConclusionsInflammation, at least in part, unmasks the gabapentin depression on nociception transmission in the dorsal horn, and this depression is not due to the blockade of postsynaptic NMDA receptor.

  16. 17beta-Estradiol reduces excitatory postsynaptic potential (EPSP) amplitude in rat basolateral amygdala neurons.

    Science.gov (United States)

    Womble, Mark D; Andrew, James A; Crook, Joseph J

    2002-10-11

    We examined the actions of estrogen on excitatory synaptic transmission in the basolateral amygdala (BLA), a brain region involved in learning, emotions, and the effects of stress. Intracellular recordings of monosynaptic excitatory postsynaptic potentials (EPSPs) were obtained from BLA neurons in a slice preparation. Bath application of 17beta-estradiol (2 micro M) reduced EPSP amplitude by an average of 77%. This reduction was readily reversed by washing with control saline and was not mimicked by the inactive isomer 17 alpha-estradiol. Other passive and active properties of BLA neurons were unaffected by 17beta-estradiol. The observed EPSP reduction is in sharp contrast to the potentiation of EPSPs by estrogen observed in other brain regions.

  17. Monosynaptic glutamatergic activation of locus coeruleus and other lower brainstem noradrenergic neurons by the C1 cells in mice.

    Science.gov (United States)

    Holloway, Benjamin B; Stornetta, Ruth L; Bochorishvili, Genrieta; Erisir, Alev; Viar, Kenneth E; Guyenet, Patrice G

    2013-11-27

    The C1 neurons, located in the rostral ventrolateral medulla (VLM), are activated by pain, hypotension, hypoglycemia, hypoxia, and infection, as well as by psychological stress. Prior work has highlighted the ability of these neurons to increase sympathetic tone, hence peripheral catecholamine release, probably via their direct excitatory projections to sympathetic preganglionic neurons. In this study, we use channelrhodopsin-2 (ChR2) optogenetics to test whether the C1 cells are also capable of broadly activating the brain's noradrenergic system. We selectively expressed ChR2(H134R) in rostral VLM catecholaminergic neurons by injecting Cre-dependent adeno-associated viral vectors into the brain of adult dopamine-β-hydroxylase (DβH)(Cre/0) mice. Most ChR2-expressing VLM neurons (75%) were immunoreactive for phenylethanolamine N-methyl transferease, thus were C1 cells, and most of the ChR2-positive axonal varicosities were immunoreactive for vesicular glutamate transporter-2 (78%). We produced light microscopic evidence that the axons of rostral VLM (RVLM) catecholaminergic neurons contact locus coeruleus, A1, and A2 noradrenergic neurons, and ultrastructural evidence that these contacts represent asymmetric synapses. Using optogenetics in tissue slices, we show that RVLM catecholaminergic neurons activate the locus coeruleus as well as A1 and A2 noradrenergic neurons monosynaptically by releasing glutamate. In conclusion, activation of RVLM catecholaminergic neurons, predominantly C1 cells, by somatic or psychological stresses has the potential to increase the firing of both peripheral and central noradrenergic neurons.

  18. Spindle activity and monosynaptic reflex excitability during foreperiod.

    Science.gov (United States)

    Gerilovsky, L; Struppler, A; Altmann, H; Velho, F

    1983-11-01

    Healthy volunteers were instructed to perform an isometric plantar foot flexion as quickly as possible after a foreperiod (FP) of 1000 msec defined by two clicks (warning signal (WS) and response signal (RS). In 6 volunteers the H reflex was evoked in triceps surae muscle and recorded by surface electrodes (stimulus intensity 30% of maximum). The H reflex was elicited at WS and RS as well as during FP at intervals of 100 msec. H reflex amplitudes were taken as a sign of monosynaptic reflex excitability (MSRE). Amplitudes during FP were compared with the average control values at rest. Relaxation of lower limb muscles before and during FP was controlled by EMG. MSRE was increased in the first part of FP with a maximum at 300 msec after WS and decreased in the second part, with a minimum at 800 msec after WS. In a second series of experiments, in 10 volunteers, single fiber activity from primary muscle spindle afferents was recorded with tungsten electrodes from deep peroneal nerve (6 records) and from tibial nerve (3 records). The activity of primary spindle afferents before and during the FP was calculated by instantaneous discharge frequency and histograms of spike distribution. The EMG was taken from sural triceps and anterior tibial muscles with needle electrodes; a mechanogram of tendon deflection was taken by an appropriate strain gauge. In 5 primary afferents without spontaneous activity at rest and during FP, discharge started with a delay of 10-15 msec after the onset of EMG activity during the motor reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Reassessment of Non-Monosynaptic Excitation from the Motor Cortex to Motoneurons in Single Motor Units of the Human Biceps Brachii.

    Science.gov (United States)

    Nakajima, Tsuyoshi; Tazoe, Toshiki; Sakamoto, Masanori; Endoh, Takashi; Shibuya, Satoshi; Elias, Leonardo A; Mezzarane, Rinaldo A; Komiyama, Tomoyoshi; Ohki, Yukari

    2017-01-01

    Corticospinal excitation is mediated by polysynaptic pathways in several vertebrates, including dexterous monkeys. However, indirect non-monosynaptic excitation has not been clearly observed following transcranial electrical stimulation (TES) or cervicomedullary stimulation (CMS) in humans. The present study evaluated indirect motor pathways in normal human subjects by recording the activities of single motor units (MUs) in the biceps brachii (BB) muscle. The pyramidal tract was stimulated with weak TES, CMS, and transcranial magnetic stimulation (TMS) contralateral to the recording side. During tasks involving weak co-contraction of the BB and hand muscles, all stimulation methods activated MUs with short latencies. Peristimulus time histograms (PSTHs) showed that responses with similar durations were induced by TES (1.9 ± 1.4 ms) and CMS (2.0 ± 1.4 ms), and these responses often showed multiple peaks with the PSTH peak having a long duration (65.3% and 44.9%, respectively). Such long-duration excitatory responses with multiple peaks were rarely observed in the finger muscles following TES or in the BB following stimulation of the Ia fibers. The responses obtained with TES were compared in the same 14 BB MUs during the co-contraction and isolated BB contraction tasks. Eleven and three units, respectively, exhibited activation with multiple peaks during the two tasks. In order to determine the dispersion effects on the axon conduction velocities (CVs) and synaptic noise, a simulation study that was comparable to the TES experiments was performed with a biologically plausible neuromuscular model. When the model included the monosynaptic-pyramidal tract, multiple peaks were obtained in about 34.5% of the motoneurons (MNs). The experimental and simulation results indicated the existence of task-dependent disparate inputs from the pyramidal tract to the MNs of the upper limb. These results suggested that intercalated interneurons are present in the spinal cord and

  20. Reassessment of Non-Monosynaptic Excitation from the Motor Cortex to Motoneurons in Single Motor Units of the Human Biceps Brachii

    Science.gov (United States)

    Nakajima, Tsuyoshi; Tazoe, Toshiki; Sakamoto, Masanori; Endoh, Takashi; Shibuya, Satoshi; Elias, Leonardo A.; Mezzarane, Rinaldo A.; Komiyama, Tomoyoshi; Ohki, Yukari

    2017-01-01

    Corticospinal excitation is mediated by polysynaptic pathways in several vertebrates, including dexterous monkeys. However, indirect non-monosynaptic excitation has not been clearly observed following transcranial electrical stimulation (TES) or cervicomedullary stimulation (CMS) in humans. The present study evaluated indirect motor pathways in normal human subjects by recording the activities of single motor units (MUs) in the biceps brachii (BB) muscle. The pyramidal tract was stimulated with weak TES, CMS, and transcranial magnetic stimulation (TMS) contralateral to the recording side. During tasks involving weak co-contraction of the BB and hand muscles, all stimulation methods activated MUs with short latencies. Peristimulus time histograms (PSTHs) showed that responses with similar durations were induced by TES (1.9 ± 1.4 ms) and CMS (2.0 ± 1.4 ms), and these responses often showed multiple peaks with the PSTH peak having a long duration (65.3% and 44.9%, respectively). Such long-duration excitatory responses with multiple peaks were rarely observed in the finger muscles following TES or in the BB following stimulation of the Ia fibers. The responses obtained with TES were compared in the same 14 BB MUs during the co-contraction and isolated BB contraction tasks. Eleven and three units, respectively, exhibited activation with multiple peaks during the two tasks. In order to determine the dispersion effects on the axon conduction velocities (CVs) and synaptic noise, a simulation study that was comparable to the TES experiments was performed with a biologically plausible neuromuscular model. When the model included the monosynaptic-pyramidal tract, multiple peaks were obtained in about 34.5% of the motoneurons (MNs). The experimental and simulation results indicated the existence of task-dependent disparate inputs from the pyramidal tract to the MNs of the upper limb. These results suggested that intercalated interneurons are present in the spinal cord and

  1. Monosynaptic Glutamatergic Activation of Locus Coeruleus and Other Lower Brainstem Noradrenergic Neurons by the C1 Cells in Mice

    Science.gov (United States)

    Holloway, Benjamin B.; Stornetta, Ruth L.; Bochorishvili, Genrieta; Erisir, Alev; Viar, Kenneth E.

    2013-01-01

    The C1 neurons, located in the rostral ventrolateral medulla (VLM), are activated by pain, hypotension, hypoglycemia, hypoxia, and infection, as well as by psychological stress. Prior work has highlighted the ability of these neurons to increase sympathetic tone, hence peripheral catecholamine release, probably via their direct excitatory projections to sympathetic preganglionic neurons. In this study, we use channelrhodopsin-2 (ChR2) optogenetics to test whether the C1 cells are also capable of broadly activating the brain's noradrenergic system. We selectively expressed ChR2(H134R) in rostral VLM catecholaminergic neurons by injecting Cre-dependent adeno-associated viral vectors into the brain of adult dopamine-β-hydroxylase (DβH)Cre/0 mice. Most ChR2-expressing VLM neurons (75%) were immunoreactive for phenylethanolamine N-methyl transferease, thus were C1 cells, and most of the ChR2-positive axonal varicosities were immunoreactive for vesicular glutamate transporter-2 (78%). We produced light microscopic evidence that the axons of rostral VLM (RVLM) catecholaminergic neurons contact locus coeruleus, A1, and A2 noradrenergic neurons, and ultrastructural evidence that these contacts represent asymmetric synapses. Using optogenetics in tissue slices, we show that RVLM catecholaminergic neurons activate the locus coeruleus as well as A1 and A2 noradrenergic neurons monosynaptically by releasing glutamate. In conclusion, activation of RVLM catecholaminergic neurons, predominantly C1 cells, by somatic or psychological stresses has the potential to increase the firing of both peripheral and central noradrenergic neurons. PMID:24285886

  2. Asymmetric excitatory synaptic dynamics underlie interaural time difference processing in the auditory system.

    Directory of Open Access Journals (Sweden)

    Pablo E Jercog

    Full Text Available Low-frequency sound localization depends on the neural computation of interaural time differences (ITD and relies on neurons in the auditory brain stem that integrate synaptic inputs delivered by the ipsi- and contralateral auditory pathways that start at the two ears. The first auditory neurons that respond selectively to ITD are found in the medial superior olivary nucleus (MSO. We identified a new mechanism for ITD coding using a brain slice preparation that preserves the binaural inputs to the MSO. There was an internal latency difference for the two excitatory pathways that would, if left uncompensated, position the ITD response function too far outside the physiological range to be useful for estimating ITD. We demonstrate, and support using a biophysically based computational model, that a bilateral asymmetry in excitatory post-synaptic potential (EPSP slopes provides a robust compensatory delay mechanism due to differential activation of low threshold potassium conductance on these inputs and permits MSO neurons to encode physiological ITDs. We suggest, more generally, that the dependence of spike probability on rate of depolarization, as in these auditory neurons, provides a mechanism for temporal order discrimination between EPSPs.

  3. PSPs and ERPs: applying the dynamics of post-synaptic potentials to individual units in simulation of temporally extended Event-Related Potential reading data.

    Science.gov (United States)

    Laszlo, Sarah; Armstrong, Blair C

    2014-05-01

    The Parallel Distributed Processing (PDP) framework is built on neural-style computation, and is thus well-suited for simulating the neural implementation of cognition. However, relatively little cognitive modeling work has concerned neural measures, instead focusing on behavior. Here, we extend a PDP model of reading-related components in the Event-Related Potential (ERP) to simulation of the N400 repetition effect. We accomplish this by incorporating the dynamics of cortical post-synaptic potentials--the source of the ERP signal--into the model. Simulations demonstrate that application of these dynamics is critical for model elicitation of repetition effects in the time and frequency domains. We conclude that by advancing a neurocomputational understanding of repetition effects, we are able to posit an interpretation of their source that is both explicitly specified and mechanistically different from the well-accepted cognitive one.

  4. Activation of brainstem serotoninergic pathways decreases homosynaptic depression of monosynaptic responses of frog spinal motoneurons.

    Science.gov (United States)

    Cardona, A; Rudomin, P

    1983-12-05

    In the isolated neuraxis of the frog, low frequency stimulation (0.5-2 Hz) of the lateral columns produces monosynaptic responses in the ventral roots which are depressed with an exponential time course. Serotonin (10 mumol/liter) added to the bath, or stimulation of the brain-stem midline raphe nuclei, but not of the lateral reticular formation, reduced the magnitude of the low frequency depression of the responses. The above actions were abolished by methysergide (1 mumol/liter), a specific antagonist of serotonin. These observations show that the magnitude of the homosynaptic depression of monosynaptic responses of motoneurons can be controlled by descending serotonergic mechanisms. This action is considered to be an important component of the arousal behavior mediated by the brain-stem raphe nuclei.

  5. Monosynaptic connections between primary afferents and giant neurons in the turtle spinal dorsal horn

    DEFF Research Database (Denmark)

    Fernández, A; Radmilovich, M; Russo, R E

    1996-01-01

    This paper reports the occurrence of monosynaptic connections between dorsal root afferents and a distinct cell type-the giant neuron-deep in the dorsal horn of the turtle spinal cord. Light microscope studies combining Nissl stain and transganglionic HRP-labeling of the primary afferents have...... revealed the occurrence of axosomatic and axodendritic contacts between labeled boutons and giant neurons. The synaptic nature of these contacts has been confirmed by use of electron microscope procedures involving the partial three-dimensional reconstruction of identified giant neurons. Intracellular...... recording in spinal cord slices provided functional evidence indicating the monosynaptic connections between dorsal root afferents and giant neurons. The recorded neurons were morphologically identified by means of biocytin injection and with avidin conjugates. Electrical stimulation of the ipsilateral...

  6. Requirement for Dicer in Maintenance of Monosynaptic Sensory-Motor Circuits in the Spinal Cord.

    Science.gov (United States)

    Imai, Fumiyasu; Chen, Xiaoting; Weirauch, Matthew T; Yoshida, Yutaka

    2016-11-22

    In contrast to our knowledge of mechanisms governing circuit formation, our understanding of how neural circuits are maintained is limited. Here, we show that Dicer, an RNaseIII protein required for processing microRNAs (miRNAs), is essential for maintenance of the spinal monosynaptic stretch reflex circuit in which group Ia proprioceptive sensory neurons form direct connections with motor neurons. In postnatal mice lacking Dicer in proprioceptor sensory neurons, there are no obvious defects in specificity or formation of monosynaptic sensory-motor connections. However, these circuits degrade through synapse loss and retraction of proprioceptive axonal projections from the ventral spinal cord. Peripheral terminals are also impaired without retracting from muscle targets. Interestingly, despite these central and peripheral axonal defects, proprioceptive neurons survive in the absence of Dicer-processed miRNAs. These findings reveal that Dicer, through its production of mature miRNAs, plays a key role in the maintenance of monosynaptic sensory-motor circuits.

  7. High concentrations of divalent cations isolate monosynaptic inputs from local circuits in the auditory midbrain

    Directory of Open Access Journals (Sweden)

    Shobhana eSivaramakrishnan

    2013-10-01

    Full Text Available Hierarchical processing of sensory information occurs at multiple levels between the peripheral and central pathway. Different extents of convergence and divergence in top down and bottom up projections makes it difficult to separate the various components activated by a sensory input. In particular, hierarchical processing at sub-cortical levels is little understood. Here we have developed a method to isolate extrinsic inputs to the inferior colliculus (IC, a nucleus in the midbrain region of the auditory system, with extensive ascending and descending convergence. By applying a high concentration of divalent cations (HiDi locally within the IC, we isolate a HiDi-sensitive from a HiDi-insensitive component of responses evoked by afferent input in brain slices and in vivo during a sound stimulus. Our results suggest that the HiDi sensitive component is a monosynaptic input to the IC, while the HiDi-insensitive component is a local polysynaptic circuit. Monosynaptic inputs have short latencies, rapid rise times and underlie first spike latencies. Local inputs have variable delays and evoke long-lasting excitation. In vivo, local circuits have variable onset times and temporal profiles. Our results suggest that high concentrations of divalent cations should prove to be a widely useful method of isolating extrinsic monosynaptic inputs from local circuits in vivo.

  8. Model-free reconstruction of excitatory neuronal connectivity from calcium imaging signals.

    Directory of Open Access Journals (Sweden)

    Olav Stetter

    Full Text Available A systematic assessment of global neural network connectivity through direct electrophysiological assays has remained technically infeasible, even in simpler systems like dissociated neuronal cultures. We introduce an improved algorithmic approach based on Transfer Entropy to reconstruct structural connectivity from network activity monitored through calcium imaging. We focus in this study on the inference of excitatory synaptic links. Based on information theory, our method requires no prior assumptions on the statistics of neuronal firing and neuronal connections. The performance of our algorithm is benchmarked on surrogate time series of calcium fluorescence generated by the simulated dynamics of a network with known ground-truth topology. We find that the functional network topology revealed by Transfer Entropy depends qualitatively on the time-dependent dynamic state of the network (bursting or non-bursting. Thus by conditioning with respect to the global mean activity, we improve the performance of our method. This allows us to focus the analysis to specific dynamical regimes of the network in which the inferred functional connectivity is shaped by monosynaptic excitatory connections, rather than by collective synchrony. Our method can discriminate between actual causal influences between neurons and spurious non-causal correlations due to light scattering artifacts, which inherently affect the quality of fluorescence imaging. Compared to other reconstruction strategies such as cross-correlation or Granger Causality methods, our method based on improved Transfer Entropy is remarkably more accurate. In particular, it provides a good estimation of the excitatory network clustering coefficient, allowing for discrimination between weakly and strongly clustered topologies. Finally, we demonstrate the applicability of our method to analyses of real recordings of in vitro disinhibited cortical cultures where we suggest that excitatory connections

  9. Model-Free Reconstruction of Excitatory Neuronal Connectivity from Calcium Imaging Signals

    Science.gov (United States)

    Stetter, Olav; Battaglia, Demian; Soriano, Jordi; Geisel, Theo

    2012-01-01

    A systematic assessment of global neural network connectivity through direct electrophysiological assays has remained technically infeasible, even in simpler systems like dissociated neuronal cultures. We introduce an improved algorithmic approach based on Transfer Entropy to reconstruct structural connectivity from network activity monitored through calcium imaging. We focus in this study on the inference of excitatory synaptic links. Based on information theory, our method requires no prior assumptions on the statistics of neuronal firing and neuronal connections. The performance of our algorithm is benchmarked on surrogate time series of calcium fluorescence generated by the simulated dynamics of a network with known ground-truth topology. We find that the functional network topology revealed by Transfer Entropy depends qualitatively on the time-dependent dynamic state of the network (bursting or non-bursting). Thus by conditioning with respect to the global mean activity, we improve the performance of our method. This allows us to focus the analysis to specific dynamical regimes of the network in which the inferred functional connectivity is shaped by monosynaptic excitatory connections, rather than by collective synchrony. Our method can discriminate between actual causal influences between neurons and spurious non-causal correlations due to light scattering artifacts, which inherently affect the quality of fluorescence imaging. Compared to other reconstruction strategies such as cross-correlation or Granger Causality methods, our method based on improved Transfer Entropy is remarkably more accurate. In particular, it provides a good estimation of the excitatory network clustering coefficient, allowing for discrimination between weakly and strongly clustered topologies. Finally, we demonstrate the applicability of our method to analyses of real recordings of in vitro disinhibited cortical cultures where we suggest that excitatory connections are characterized

  10. Orexin-A modulates excitatory synaptic transmission and neuronal excitability in the spinal cord substantia gelatinosa.

    Science.gov (United States)

    Jeon, Younghoon; Park, Ki Bum; Pervin, Rokeya; Kim, Tae Wan; Youn, Dong-ho

    2015-09-14

    Although intrathecal orexin-A has been known to be antinociceptive in various pain models, the role of orexin-A in antinociception is not well characterized. In the present study, we examined whether orexin-A modulates primary afferent fiber-mediated or spontaneous excitatory synaptic transmission using transverse spinal cord slices with attached dorsal root. Bath-application of orexin-A (100nM) reduced the amplitude of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation of Aδ- or C-primary afferent fibers. The magnitude of reduction was much larger for EPSCs evoked by polysynaptic C-fibers than polysynaptic Aδ-fibers, whereas it was similar in EPSCs evoked by monosynaptic Aδ- or C-fibers. SB674042, an orexin-1 receptor antagonist, but not EMPA, an orexin-2 receptor antagonist, significantly inhibited the orexin-A-induced reduction in EPSC amplitude from mono- or polysynaptic Aδ-fibers, as well as from mono- or polysynaptic C-fibers. Furthermore, orexin-A significantly increased the frequency of spontaneous EPSCs but not the amplitude. This increase was almost completely blocked by both SB674042 and EMPA. On the other hand, orexin-A produced membrane oscillations and inward currents in the SG neurons that were partially or completely inhibited by SB674042 or EMPA, respectively. Thus, this study suggests that the spinal actions of orexin-A underlie orexin-A-induced antinociceptive effects via different subtypes of orexin receptors.

  11. Olfactory receptor signaling is regulated by the post-synaptic density 95, Drosophila discs large, zona-occludens 1 (PDZ) scaffold multi-PDZ domain protein 1.

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2009-12-01

    The unique ability of mammals to detect and discriminate between thousands of different odorant molecules is governed by the diverse array of olfactory receptors expressed by olfactory sensory neurons in the nasal epithelium. Olfactory receptors consist of seven transmembrane domain G protein-coupled receptors and comprise the largest gene superfamily in the mammalian genome. We found that approximately 30% of olfactory receptors possess a classical post-synaptic density 95, Drosophila discs large, zona-occludens 1 (PDZ) domain binding motif in their C-termini. PDZ domains have been established as sites for protein-protein interaction and play a central role in organizing diverse cell signaling assemblies. In the present study, we show that multi-PDZ domain protein 1 (MUPP1) is expressed in the apical compartment of olfactory sensory neurons. Furthermore, on heterologous co-expression with olfactory sensory neurons, MUPP1 was shown to translocate to the plasma membrane. We found direct interaction of PDZ domains 1 + 2 of MUPP1 with the C-terminus of olfactory receptors in vitro. Moreover, the odorant-elicited calcium response of OR2AG1 showed a prolonged decay in MUPP1 small interfering RNA-treated cells. We have therefore elucidated the first building blocks of the putative \\'olfactosome\\

  12. Specificity of Monosynaptic Sensory-Motor Connections Imposed by Repellent Sema3E-PlexinD1 Signaling

    Directory of Open Access Journals (Sweden)

    Kaori Fukuhara

    2013-11-01

    Full Text Available In mammalian spinal cord, group Ia proprioceptive afferents form selective monosynaptic connections with a select group of motor pool targets. The extent to which sensory recognition of motor neurons contributes to the selectivity of sensory-motor connections remains unclear. We show here that proprioceptive sensory afferents that express PlexinD1 avoid forming monosynaptic connections with neurons in Sema3E+ motor pools yet are able to form direct connections with neurons in Sema3Eoff motor pools. Anatomical and electrophysiological analysis of mice in which Sema3E-PlexinD1 signaling has been deregulated or inactivated genetically reveals that repellent signaling underlies aspects of the specificity of monosynaptic sensory-motor connectivity in these reflex arcs. A semaphorin-based system of motor neuron recognition and repulsion therefore contributes to the formation of specific sensory-motor connections in mammalian spinal cord.

  13. Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat.

    Science.gov (United States)

    Brown, P Leon; Shepard, Paul D

    2016-09-01

    The lateral habenula, a phylogenetically conserved epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the lateral habenula also directly targets dopamine neurons within the ventral tegmental area, suggesting that opposing actions may result from increased lateral habenula activity. In the present study, we tested the effect of habenular efferent stimulation on dopamine and nondopamine neurons in the ventral tegmental area of Sprague-Dawley rats using a parasagittal brain slice preparation. Single pulse stimulation of the fasciculus retroflexus excited 48% of dopamine neurons and 51% of nondopamine neurons in the ventral tegmental area of rat pups. These proportions were not altered by excision of the rostromedial tegmental nucleus and were evident in both cortical- and striatal-projecting dopamine neurons. Glutamate receptor antagonists blocked this excitation, and fasciculus retroflexus stimulation elicited evoked excitatory postsynaptic potentials with a nearly constant onset latency, indicative of a monosynaptic, glutamatergic connection. Comparison of responses in rat pups and young adults showed no significant difference in the proportion of neurons excited by fasciculus retroflexus stimulation. Our data indicate that the well-known, indirect inhibitory effect of lateral habenula activation on midbrain dopamine neurons is complemented by a significant, direct excitatory effect. This pathway may contribute to the role of midbrain dopamine neurons in processing aversive stimuli and salience.

  14. Dopaminergic Modulation of Excitatory Transmission in the Anterior Cingulate Cortex of Adult Mice

    Science.gov (United States)

    Darvish-Ghane, Soroush; Yamanaka, Manabu

    2016-01-01

    Dopamine (DA) possesses potent neuromodulatory properties in the central nervous system. In the anterior cingulate cortex, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) are key ion channels in mediating nerve injury induced long-term potentiation (LTP) and chronic pain phenotype. In the present study, we reported the effects of DA on glutamate mediated excitatory post-synaptic currents (EPSCs) in pyramidal neurons of layer II/III of the ACC in adult mice. Bath application of DA (50 μM) caused a significant, rapid and reversible inhibition of evoked EPSCs (eEPSC). This inhibitory effect is dose-related and was absent in lower concentration of DA (5 μM). Furthermore, selective postsynaptic application of GDP-β-S (1.6 mM) in the internal solution completely abolished the inhibitory effects of DA (50 μM). We also investigated modulation of spontaneous EPSCs (sEPSCs) and TTX sensitive, miniature EPSCs (mEPSCs) by DA. Our results indicated mixed effects of potentiation and inhibition of frequency and amplitude for sEPSCs and mEPSCs. Furthermore, high doses of SCH23390 (100 μM) and sulpiride (100 μM) revealed that, inhibition of eEPSCs is mediated by postsynaptic D2-receptors (D2R). Our finding posits a pre- and postsynaptic mode of pyramidal neuron EPSC modulation in mice ACC by DA. PMID:27317578

  15. Multiple effects of β-amyloid on single excitatory synaptic connections in the PFC

    Directory of Open Access Journals (Sweden)

    Yun eWang

    2013-09-01

    Full Text Available Prefrontal cortex (PFC is recognized as an AD-vulnerable region responsible for defects in cognitive functioning. Pyramidal cell (PC connections are typically facilitating (F or depressing (D in PFC. Excitatory post-synaptic potentials (EPSPs were recorded using patch-clamp from single connections in PFC slices of rats and ferrets in the presence of Aβ. Synaptic transmission was significantly enhanced or reduced depending on their intrinsic type (facilitating or depressing, A species (A40 or A42 and concentration (1-200 nM vs. 0.3 - 1M. Nanomolar Aβ40 and Aβ42 had opposite effects on F-connections, resulting in fewer or increased EPSP failure rates, strengthening or weakening EPSPs and enhancing or inhibiting short-term potentiation (STP: SA and PTP, respectively. High Aβ40 concentrations induced inhibition regardless of synaptic type. D-connections were inhibited regardless of Aβ species or concentration. The inhibition induced with bath application was hard to recover by washout, but a complete recovery was obtained with brief local application and prompt washout. Our data suggests that Aβ40 modulates facilitation and depression of synaptic activity. At higher levels, Aβ40 and Aβ42 may induce inhibition only, further irreversible toxicity once diffusely accumulated in the synaptic environment.

  16. EFFECT OF NEURAL MOBILIZATION ON MONOSYNAPTIC REFLEX – A PRE TEST POST TEST EXPERIMENTAL DESIGN

    Directory of Open Access Journals (Sweden)

    Vipin Kumar

    2013-08-01

    Full Text Available Background:Neural mobilization techniques leads tofacilitation of nerve gliding, reduction of nerve adher-ence, dispersion of noxious fluids, increased neural vascularity and improvement of axoplasmic flow.It haspronounced effects on monosynaptic H-reflex, which is an electrically induced reflex analogous to mechani-cally induced spinal stretch reflex. Thus, it is a reliable tool for the assessment of muscle tone through theexcitability of AMNs.Materials and Methods:The study was carried out with30 male and female subjects fromMMIPR, MM University Mullana. H-reflex was taken before and after neural mobilization.Results:Significanteffects on monosynaptic H-reflex were shown after neural mobilization with a mean difference of decrease inH-reflex latency (28.43±2.13 ms to 26.91±1.99 ms; t-value 13.24 and increase in H-reflex amplitude(4.27±2.18mv to 5.25±2.50 mv; t-value -5.13 and increase in H/M ratio (0.42±0.21 to 0.52±0.25; t-value -5.22.Conclusion:Neural mobilization has direct effect on nerve conduction as measured by electrophysiologicaltesting, thereby providing evidence to include neural mobilizations as an intervention in altered neurodynamicsof the peripheral nerves.

  17. Corticotropin releasing factor dose-dependently modulates excitatory synaptic transmission in the noradrenergic nucleus locus coeruleus.

    Science.gov (United States)

    Prouty, Eric W; Waterhouse, Barry D; Chandler, Daniel J

    2017-03-01

    The noradrenergic nucleus locus coeruleus (LC) is critically involved in the stress response and receives afferent input from a number of corticotropin releasing factor (CRF) containing structures. Several in vivo and in vitro studies in rat have shown that CRF robustly increases the firing rate of LC neurons in a dose-dependent manner. While it is known that these increases are dependent on CRF receptor subtype 1 and mediated by effects of cAMP intracellular signaling cascades on potassium conductance, the impact of CRF on synaptic transmission within LC has not been clarified. In the present study, we used whole-cell patch clamp electrophysiology to assess how varying concentrations of bath-applied CRF affect AMPA-receptor dependent spontaneous excitatory post-synaptic currents (sEPSCs). Compared to vehicle, 10, 25, and 100 nm CRF had no significant effects on any sEPSC parameters. Fifty nanomolar CRF, however, significantly increased sEPSC amplitude, half-width, and charge transfer, while these measures were significantly decreased by 200 nm CRF. These observations suggest that stress may differentially affect ongoing excitatory synaptic transmission in LC depending on how much CRF is released from presynaptic terminals. Combined with the well-documented effects of CRF on membrane properties and spontaneous LC discharge, these observations may help explain how stress and CRF release are able to modulate the signal to noise ratio of LC neurons. These findings have implications for how stress affects the fidelity of signal transmission and information flow through LC and how it might impact norepinephrine release in the CNS.

  18. On how correlations between excitatory and inhibitory synaptic inputs maximize the information rate of neuronal firing

    Directory of Open Access Journals (Sweden)

    Pavel Anatolyevich Puzerey

    2014-06-01

    Full Text Available Cortical neurons receive barrages of excitatory and inhibitory inputs which are not independent, as network structure and synaptic kinetics impose statistical correlations. Experiments in vitro and in vivo have demonstrated correlations between inhibitory and excitatory synaptic inputs in which inhibition lags behind excitation in cortical neurons. This delay arises in feed-forward inhibition circuits and ensures that coincident excitation and inhibition do not preclude neuronal firing. Conversely, inhibition that is too delayed broadens neuronal integration times, thereby diminishing spike-time precision and increasing the firing frequency. This led us to hypothesize that the correlation between excitatory and inhibitory synaptic inputs modulates the encoding of information of neural spike trains. We tested this hypothesis by investigating the effect of such correlations on the information rate (IR of spike trains using the Hodgkin-Huxley model in which both synaptic and membrane conductances are stochastic. We investigated two different synaptic input regimes: balanced synaptic conductances and balanced currents. Our results show that correlations arising from the synaptic kinetics, tau, and millisecond lags, delta, of inhibition relative to excitation strongly affect the IR of spike trains. In the regime of balanced synaptic currents, for short time lags (delta ~ 1 ms there is an optimal tau that maximizes the IR of the postsynaptic spike train. Given the short time scales for monosynaptic inhibitory lags and synaptic decay kinetics reported in cortical neurons under physiological contexts, we propose that feed-forward inhibition in cortical circuits is poised to maximize the rate of information transfer between cortical neurons. Our results also provide a possible explanation for how certain drugs and genetic mutations affecting the synaptic kinetics can deteriorate information processing in the brain.

  19. The Antidepressant-Like Effect of Fish Oil: Possible Role of Ventral Hippocampal 5-HT1A Post-synaptic Receptor.

    Science.gov (United States)

    Carabelli, Bruno; Delattre, Ana Marcia; Pudell, Claudia; Mori, Marco Aurélio; Suchecki, Deborah; Machado, Ricardo B; Venancio, Daniel Paulino; Piazzetta, Sílvia Regina; Hammerschmidt, Ivilim; Zanata, Sílvio M; Lima, Marcelo M S; Zanoveli, Janaína Menezes; Ferraz, Anete Curte

    2015-08-01

    The pathophysiology of depression is not completely understood; nonetheless, numerous studies point to serotonergic dysfunction as a possible cause. Supplementation with fish oil rich docosahexaenoic (DHA) and eicosapentaenoic acids (EPA) during critical periods of development produces antidepressant effects by increasing serotonergic neurotransmission, particularly in the hippocampus. In a previous study, the involvement of 5-HT1A receptors was demonstrated and we hypothesized that fish oil supplementation (from conception to weaning) alters the function of post-synaptic hippocampal 5-HT1A receptors. To test this hypothesis, female rats were supplemented with fish oil during habituation, mating, gestation, and lactation. The adult male offspring was maintained without supplementation until 3 months of age, when they were subjected to the modified forced swimming test (MFST) after infusion of vehicle or the selective 5-HT1A antagonist, WAY100635, and frequency of swimming, immobility, and climbing was recorded for 5 min. After the behavioral test, the hippocampi were obtained for quantification of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and for 5-HT1A receptor expression by Western blotting analysis. Fish oil-supplemented offspring displayed less depressive-like behaviors in the MFST reflected by decreased immobility and increased swimming and higher 5-HT hippocampal levels. Although there was no difference in the expression of hippocampal 5-HT1A receptors, intra-hippocampal infusion of a sub-effective dose of 8-OH-DPAT enhanced the antidepressant effect of fish oil in supplemented animals. In summary, the present findings suggest that the antidepressant-like effects of fish oil supplementation are likely related to increased hippocampal serotonergic neurotransmission and sensitization of hippocampal 5-HT1A receptors.

  20. Elevated potassium elicits recurrent surges of large GABAA-receptor-mediated post-synaptic currents in hippocampal CA3 pyramidal neurons.

    Science.gov (United States)

    Shin, Damian Seung-Ho; Yu, Wilson; Sutton, Alex; Calos, Megan; Carlen, Peter Louis

    2011-03-01

    Previously, we found that rat hippocampal CA3 interneurons become hyperactive with increasing concentrations of extracellular K(+) up to 10 mM. However, it is unclear how this enhanced interneuronal activity affects pyramidal neurons. Here we voltage-clamped rat hippocampal CA3 pyramidal neurons in vitro at 0 mV to isolate γ-aminobutyric acid (GABA)-activated inhibitory post-synaptic currents (IPSCs) and measured these in artificial cerebrospinal fluid (aCSF) and with 10 mM K(+) bath perfusion. In aCSF, small IPSCs were present with amplitudes of 0.053 ± 0.007 nA and a frequency of 0.27 ± 0.14 Hz. With 10 mM K(+) perfusion, IPSCs increased greatly in frequency and amplitude, culminating in surge events with peak amplitudes of 0.56 ± 0.08 nA, that appeared and disappeared cyclically with durations lasting 2.02 ± 0.37 min repeatedly, up to 10 times over a 30-min bath perfusion of elevated K(+). These large IPSCs were GABA(A)-receptor mediated and did not involve significant desensitization of this receptor. Perfusion of a GABA transporter inhibitor (NO-711), glutamate receptor inhibitors CNQX and APV, or a gap junctional blocker (carbenoxolone) prevented the resurgence of large IPSCs. Pressure ejected sucrose resulted in the abolishment of subsequent surges. No elevated K(+)-mediated surges were observed in CA3 interneurons from the stratum oriens layer. In conclusion, these cyclic large IPSC events observable in CA3 pyramidal neurons in 10 mM KCl may be due to transient GABA depletion from continuously active interneuronal afferents.

  1. Genetic rescue of CB1 receptors on medium spiny neurons prevents loss of excitatory striatal synapses but not motor impairment in HD mice.

    Science.gov (United States)

    Naydenov, Alipi V; Sepers, Marja D; Swinney, Katie; Raymond, Lynn A; Palmiter, Richard D; Stella, Nephi

    2014-11-01

    Huntington's disease (HD) is caused by an expanded polyglutamine repeat in huntingtin protein that disrupts synaptic function in specific neuronal populations and results in characteristic motor, cognitive and affective deficits. Histopathological hallmarks observed in both HD patients and genetic mouse models include the reduced expression of synaptic proteins, reduced medium spiny neuron (MSN) dendritic spine density and decreased frequency of spontaneous excitatory post-synaptic currents (sEPSCs). Early down-regulation of cannabinoid CB1 receptor expression on MSN (CB1(MSN)) is thought to participate in HD pathogenesis. Here we present a cell-specific genetic rescue of CB1(MSN) in R6/2 mice and report that treatment prevents the reduction of excitatory synaptic markers in the striatum (synaptophysin, vGLUT1 and vGLUT2), of dendritic spine density on MSNs and of MSN sEPSCs, but does not prevent motor impairment. We conclude that loss of excitatory striatal synapses in HD mice is controlled by CB1(MSN) and can be uncoupled from the motor phenotype.

  2. A new regime for highly robust gamma oscillation with co-exist of accurate and weak synchronization in excitatory-inhibitory networks.

    Science.gov (United States)

    Wang, Zhijie; Fan, Hong; Han, Fang

    2014-08-01

    A great number of biological experiments show that gamma oscillation occurs in many brain areas after the presentation of stimulus. The neural systems in these brain areas are highly heterogeneous. Specifically, the neurons and synapses in these neural systems are diversified; the external inputs and parameters of these neurons and synapses are heterogeneous. How the gamma oscillation generated in such highly heterogeneous networks remains a challenging problem. Aiming at this problem, a highly heterogeneous complex network model that takes account of many aspects of real neural circuits was constructed. The network model consists of excitatory neurons and fast spiking interneurons, has three types of synapses (GABAA, AMPA, and NMDA), and has highly heterogeneous external drive currents. We found a new regime for robust gamma oscillation, i.e. the oscillation in inhibitory neurons is rather accurate but the oscillation in excitatory neurons is weak, in such highly heterogeneous neural networks. We also found that the mechanism of the oscillation is a mixture of interneuron gamma (ING) and pyramidal-interneuron gamma (PING). We explained the mixture ING and PING mechanism in a consistent-way by a compound post-synaptic current, which has a slowly rising-excitatory stage and a sharp decreasing-inhibitory stage.

  3. Monosynaptic responses of ventral roots of spinal cord in experimental diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Rodinsky A.G.

    2014-03-01

    Full Text Available In intact rats and rats with experimental diabetes mellitus (DM threshold, chronaxia, latent period, duration and amplitude of monosynaptic discharges of ventral root, as well as refractory periods in response to its paired stimulation were analyzed. There as found out increase in the threshold of excitability by 2 times (p0,05. In the response to paired stimulation there was obtained a significant increase in the amplitude of action potential under experimental DM in the interval of 2-5 ms between stimulation. There was made a conclusion that in DM a decrease in excitability and conductivity of the spinal cord structures at the level of L5, occurred and a tendency to increase of ability to summation of excitation was seen.

  4. Absence of synergy for monosynaptic Group I inputs between abdominal and internal intercostal motoneurons

    DEFF Research Database (Denmark)

    Ford, T W; Meehan, Claire Francesca; Kirkwood, P A

    2014-01-01

    , and the specificity of the monosynaptic connections from afferents in each of the two main branches of this nerve was investigated. Motoneurons were shown by antidromic excitation to innervate three muscle groups: external abdominal oblique [EO; innervated by the lateral branch (Lat)], the region of the internal...... motoneurons showed one from Lat. Expiratory Dist motoneurons fell into two groups. Those with Dist EPSPs and none from Lat (group A) were assumed to innervate distal internal intercostal muscle. Those with Lat EPSPs (group B) were assumed to innervate abdominal muscle (transversus abdominis or rectus......Internal intercostal and abdominal motoneurons are strongly coactivated during expiration. We investigated whether that synergy was paralleled by synergistic Group I reflex excitation. Intracellular recordings were made from motoneurons of the internal intercostal nerve of T8 in anesthetized cats...

  5. Hippocampal CA1 lacunosum-moleculare interneurons: modulation of monosynaptic GABAergic IPSCs by presynaptic GABAB receptors.

    Science.gov (United States)

    Khazipov, R; Congar, P; Ben-Ari, Y

    1995-11-01

    1. Whole cell patch-clamp recordings were employed to characterize monosynaptic inhibitory postsynaptic currents (IPSCs) in morphologically and electrophysiologically identified interneurons located in the stratum lacunosum moleculare, or near the border of the stratum radiatum (LM interneurons), in the CA1 region of hippocampal slices taken from 3- to 4-wk-old rats. Monosynaptic IPSCs, evoked in the presence of glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20 microM) and D-2-amino-5-phosphopentanoate (APV; 50 microM) were biphasic. The gamma-aminobutyric acid-A (GABAA) receptor antagonist, bicuculline (20 microM), blocked the fast IPSC, and the slow IPSC was blocked by the GABAB receptor antagonist CGP35348 (500 microM). 2. Monosynaptic IPSCs were evoked by electrical stimulation in several distant regions including the stratum radiatum, the stratum oriens, the stratum lacunosum-moleculare, and the molecular layer of dentate gyrus, suggesting an extensive network of inhibitory interneurons in the hippocampus. In paired recordings of CA1 interneurons and pyramidal cells, IPSCs were evoked by electrical stimulation of most of these distal regions with the exception of the molecular layer of dentate gyrus, which evoked an IPSC only in LM interneurons. 3. Frequent (> 0.1 Hz) stimulation depressed the evoked IPSCs. With a paired-pulse protocol, the second IPSC was depressed and the maximal depression (40-50%) was observed with an interstimulus interval of 100-200 ms. 4. The GABAB receptor agonist baclofen (1 microM) reduced the amplitude of evoked IPSCs and the paired-pulse depression of the second IPSC. The GABAB receptor antagonist CGP35348 (0.5-1 mM) had no significant effect on the amplitude of isolated IPSCs. However, CGP35348 reduced but did not fully block paired-pulse depression, suggesting that this depression is partly due to the activation of presynaptic GABAB receptors. 5. The paired-pulse depression depended on the level of

  6. Activity-induced remodeling of olfactory bulb microcircuits revealed by monosynaptic tracing.

    Directory of Open Access Journals (Sweden)

    Benjamin R Arenkiel

    Full Text Available The continued addition of new neurons to mature olfactory circuits represents a remarkable mode of cellular and structural brain plasticity. However, the anatomical configuration of newly established circuits, the types and numbers of neurons that form new synaptic connections, and the effect of sensory experience on synaptic connectivity in the olfactory bulb remain poorly understood. Using in vivo electroporation and monosynaptic tracing, we show that postnatal-born granule cells form synaptic connections with centrifugal inputs and mitral/tufted cells in the mouse olfactory bulb. In addition, newly born granule cells receive extensive input from local inhibitory short axon cells, a poorly understood cell population. The connectivity of short axon cells shows clustered organization, and their synaptic input onto newborn granule cells dramatically and selectively expands with odor stimulation. Our findings suggest that sensory experience promotes the synaptic integration of new neurons into cell type-specific olfactory circuits.

  7. Organization of Monosynaptic Inputs to the Serotonin and Dopamine Neuromodulatory Systems

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    Sachie K. Ogawa

    2014-08-01

    Full Text Available Serotonin and dopamine are major neuromodulators. Here, we used a modified rabies virus to identify monosynaptic inputs to serotonin neurons in the dorsal and median raphe (DR and MR. We found that inputs to DR and MR serotonin neurons are spatially shifted in the forebrain, and MR serotonin neurons receive inputs from more medial structures. Then, we compared these data with inputs to dopamine neurons in the ventral tegmental area (VTA and substantia nigra pars compacta (SNc. We found that DR serotonin neurons receive inputs from a remarkably similar set of areas as VTA dopamine neurons apart from the striatum, which preferentially targets dopamine neurons. Our results suggest three major input streams: a medial stream regulates MR serotonin neurons, an intermediate stream regulates DR serotonin and VTA dopamine neurons, and a lateral stream regulates SNc dopamine neurons. These results provide fundamental organizational principles of afferent control for serotonin and dopamine.

  8. Pain-related increase of excitatory transmission and decrease of inhibitory transmission in the central nucleus of the amygdala are mediated by mGluR1

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    Neugebauer Volker

    2010-12-01

    Full Text Available Abstract Neuroplasticity in the central nucleus of the amygdala (CeA, particularly its latero-capsular division (CeLC, is an important contributor to the emotional-affective aspects of pain. Previous studies showed synaptic plasticity of excitatory transmission to the CeLC in different pain models, but pain-related changes of inhibitory transmission remain to be determined. The CeLC receives convergent excitatory inputs from the parabrachial nucleus in the brainstem and from the basolateral amygdala (BLA. In addition, feedforward inhibition of CeA neurons is driven by glutamatergic projections from the BLA area to a cluster of GABAergic neurons in the intercalated cell masses (ITC. Using patch-clamp in rat brain slices we measured monosynaptic excitatory postsynaptic currents (EPSCs and polysynaptic inhibitory currents (IPSCs that were evoked by electrical stimulation in the BLA. In brain slices from arthritic rats, input-output functions of excitatory synaptic transmission were enhanced whereas inhibitory synaptic transmission was decreased compared to control slices from normal untreated rats. A non-NMDA receptor antagonist (NBQX blocked the EPSCs and reduced the IPSCs, suggesting that non-NMDA receptors mediate excitatory transmission and also contribute to glutamate-driven feed-forward inhibition of CeLC neurons. IPSCs were blocked by a GABAA receptor antagonist (bicuculline. Bicuculline increased EPSCs under normal conditions but not in slices from arthritic rats, which indicates a loss of GABAergic control of excitatory transmission. A metabotropic glutamate receptor subtype 1 (mGluR1 antagonist (LY367385 reversed both the increase of excitatory transmission and the decrease of inhibitory transmission in the arthritis pain model but had no effect on basal synaptic transmission in control slices from normal rats. The inhibitory effect of LY367385 on excitatory transmission was blocked by bicuculline suggesting the involvement of a GABAergic

  9. Inhibitory effects of endomorphin-2 on excitatory synaptic transmission and the neuronal excitability of sacral parasympathetic preganglionic neurons in young rats

    Science.gov (United States)

    Chen, Ying-Biao; Huang, Fen-Sheng; Fen, Ban; Yin, Jun-Bin; Wang, Wei; Li, Yun-Qing

    2015-01-01

    The function of the urinary bladder is partly controlled by parasympathetic preganglionic neurons (PPNs) of the sacral parasympathetic nucleus (SPN). Our recent work demonstrated that endomorphin-2 (EM-2)-immunoreactive (IR) terminals form synapses with μ-opioid receptor (MOR)-expressing PPNs in the rat SPN. Here, we examined the effects of EM-2 on excitatory synaptic transmission and the neuronal excitability of the PPNs in young rats (24–30 days old) using a whole-cell patch-clamp approach. PPNs were identified by retrograde labeling with the fluorescent tracer tetramethylrhodamine-dextran (TMR). EM-2 (3 μM) markedly decreased both the amplitude and the frequency of the spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) of PPNs. EM-2 not only decreased the resting membrane potentials (RMPs) in 61.1% of the examined PPNs with half-maximal response at the concentration of 0.282 μM, but also increased the rheobase current and reduced the repetitive action potential firing of PPNs. Analysis of the current–voltage relationship revealed that the EM-2-induced current was reversed at −95 ± 2.5 mV and was suppressed by perfusion of the potassium channel blockers 4-aminopyridine (4-AP) or BaCl2 or by the addition of guanosine 5′-[β-thio]diphosphate trilithium salt (GDP-β-S) to the pipette solution, suggesting the involvement of the G-protein-coupled inwardly rectifying potassium (GIRK) channel. The above EM-2-invoked inhibitory effects were abolished by the MOR selective antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), indicating that the effects of EM-2 on PPNs were mediated by MOR via pre- and/or post-synaptic mechanisms. EM-2 activated pre- and post-synaptic MORs, inhibiting excitatory neurotransmitter release from the presynaptic terminals and decreasing the excitability of PPNs due to hyperpolarization of their membrane potentials, respectively. These inhibitory effects of EM-2 on PPNs at the spinal cord level may

  10. Association of potassium channel Kv3.4 subunits with pre- and post-synaptic structures in brainstem and spinal cord.

    Science.gov (United States)

    Brooke, R E; Atkinson, L; Batten, T F C; Deuchars, S A; Deuchars, J

    2004-01-01

    Voltage-gated K+ channels (Kv) are divided into eight subfamilies (Kv1-8) and play a major role in determining the excitability of neurones. Members of the Kv3 subfamily are highly abundant in the CNS, with each Kv3 gene (Kv3.1-Kv3.4) exhibiting a unique pattern of expression, although single neurones can express more than one subtype. Of the Kv3 subunits relatively little is known of the Kv3.4 subunit distribution in the nervous system, particularly in the brainstem and spinal cord of the rat. We performed immunohistochemistry to determine both the cellular and sub-cellular distribution of the Kv3.4 subunit in these areas. Kv3.4 subunit immunoreactivity (Kv3.4-IR) was widespread, with dense, punctate staining in many regions including the intermediolateral cell column (IML) and the dorsal vagal nucleus (DVN), nucleus ambiguus (NA) and nucleus tractus solitarius (NTS). In the ventral horn a presynaptic location was confirmed by co-localization of Kv3.4-IR with the synaptic vesicle protein, SV2 and also with the glutamate vesicle markers vesicular glutamate transporter (VGluT) 1, VGluT2 or the glycine transporter GlyT2, suggesting a role for the channel in both excitatory and inhibitory neurotransmission. Electron microscopy confirmed a presynaptic terminal location of Kv3.4-IR in the VH, IML, DVN, NA and NTS. Interestingly however, patches of Kv3.4-IR were also revealed postsynaptically in dendritic and somatic structures throughout these areas. This staining was striking due to its localization at synaptic junctions at terminals with morphological features consistent with excitatory functions, suggesting an association with the postsynaptic density. Therefore the pre and postsynaptic localization of Kv3.4-IR suggests a role both in the control of transmitter release and in regulating neuronal excitability.

  11. Synaptic activity slows vesicular replenishment at excitatory synapses of rat hippocampus.

    Science.gov (United States)

    Bui, Loc; Glavinović, Mladen I

    2013-04-01

    Short-term synaptic depression mainly reflects the depletion of the readily releasable pool (RRP) of quanta. Its dynamics, and especially the replenishment rate of the RRP, are still not well characterized in spite of decades of investigation. Main reason is that the vesicular storage and release system is treated as time-independent. If it is time-dependent all parameters thus estimated become problematic. Indeed the reports about how prolonged stimulation affects the dynamics are contradictory. To study this, we used patterned stimulation on the Schaeffer collateral fiber pathway and model-fitting of the excitatory post-synaptic currents (EPSC) recorded from CA1 neurons in rat hippocampal slices. The parameters of a vesicular storage and release model with two pools were estimated by minimizing the squared difference between the ESPC amplitudes and simulated model output. This yields the 'basic' parameters (release coupling, replenishment coupling and RRP size) that underlie the 'derived' and commonly used parameters (fractional release and replenishment rate). The fractional release increases when [Ca(++)]o is raised, whereas the replenishment rate is [Ca(++)]o independent. Fractional release rises because release coupling increases, and the RRP becomes less able to contain quanta. During prolonged stimulation, the fractional release remains generally unaltered, whereas the replenishment rate decreases down to ~10 % of its initial value with a decay time of ~15 s, and this decrease in the replenishment rate significantly contributes to synaptic depression. In conclusion, the fractional release is [Ca(++)]o-dependent and stimulation-independent, whereas the replenishment rate is [Ca(++)]o-independent and stimulation-dependent.

  12. An excitatory GABA loop operating in vivo

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    Guadalupe eAstorga

    2015-07-01

    Full Text Available While it has been proposed that the conventional inhibitory neurotransmitter GABA can be excitatory in the mammalian brain, much remains to be learned concerning the circumstances and the cellular mechanisms governing potential excitatory GABA action. Using a combination of optogenetics and two-photon calcium imaging in vivo, we find that activation of chloride-permeable GABAA receptors in parallel fibers of the cerebellar molecular layer of adult mice causes parallel fiber excitation. Stimulation of parallel fibers at submaximal stimulus intensities leads to GABA release from molecular layer interneurons, thus creating a positive feedback loop that enhances excitation near the center of an activated parallel fiber bundle. Our results imply that elevated chloride concentration can occur in specific intracellular compartments of mature mammalian neurons and suggest an excitatory role for GABAA receptors in the cerebellar cortex of adult mice.

  13. Periodic modulation of repetitively elicited monosynaptic reflexes of the human lumbosacral spinal cord.

    Science.gov (United States)

    Hofstoetter, Ursula S; Danner, Simon M; Freundl, Brigitta; Binder, Heinrich; Mayr, Winfried; Rattay, Frank; Minassian, Karen

    2015-07-01

    In individuals with motor-complete spinal cord injury, epidural stimulation of the lumbosacral spinal cord at 2 Hz evokes unmodulated reflexes in the lower limbs, while stimulation at 22-60 Hz can generate rhythmic burstlike activity. Here we elaborated on an output pattern emerging at transitional stimulation frequencies with consecutively elicited reflexes alternating between large and small. We analyzed responses concomitantly elicited in thigh and leg muscle groups bilaterally by epidural stimulation in eight motor-complete spinal cord-injured individuals. Periodic amplitude modulation of at least 20 successive responses occurred in 31.4% of all available data sets with stimulation frequency set at 5-26 Hz, with highest prevalence at 16 Hz. It could be evoked in a single muscle group only but was more strongly expressed and consistent when occurring in pairs of antagonists or in the same muscle group bilaterally. Latencies and waveforms of the modulated reflexes corresponded to those of the unmodulated, monosynaptic responses to 2-Hz stimulation. We suggest that the cyclical changes of reflex excitability resulted from the interaction of facilitatory and inhibitory mechanisms emerging after specific delays and with distinct durations, including postactivation depression, recurrent inhibition and facilitation, as well as reafferent feedback activation. The emergence of large responses within the patterns at a rate of 5.5/s or 8/s may further suggest the entrainment of spinal mechanisms as involved in clonus. The study demonstrates that the human lumbosacral spinal cord can organize a simple form of rhythmicity through the repetitive activation of spinal reflex circuits. Copyright © 2015 the American Physiological Society.

  14. gamma-Aminobutyric acid (GABA): a fast excitatory transmitter which may regulate the development of hippocampal neurones in early postnatal life.

    Science.gov (United States)

    Ben-Ari, Y; Tseeb, V; Raggozzino, D; Khazipov, R; Gaiarsa, J L

    1994-01-01

    The properties of neonatal GABAergic synapses were investigated in neurones of the hippocampal CA3 region. GABA, acting on GABAA receptors, provides most of the excitatory drive on immature CA3 pyramidal neurones at an early stage of development, whereas glutamatergic synapses (in particular, those mediated by AMPA receptors) are mostly quiescent. Thus, during the first postnatal week of life, bicuculline fully blocked spontaneous and evoked depolarising potentials, and GABAA receptor agonists depolarised CA3 pyramidal neurones. GABAA mediated currents also had a reduced sensitivity to benzodiazepines. In the presence of bicuculline, between P0 and P4, increasing the stimulus strength reveals an excitatory postsynaptic potential which is mostly mediated by NMDA receptors. During the same developmental period, pre- (but not post) synaptic GABAB inhibition is present. Intracellular injections of biocytin showed that the axonal network of the GABAergic interneurones is well developed at birth, whereas the pyramidal recurrent collaterals are only beginning to develop. Finally, chronic bicuculline treatment of hippocampal neurones in culture reduced the extent of neuritic arborisation, suggesting that GABA acts as a trophic factor in that period. In conclusion, it is suggested that during the first postnatal week of life, when excitatory inputs are still poorly developed, GABAA receptors provide the excitatory drive necessary for pyramidal cell outgrowth. Starting from the end of the first postnatal week of life, when excitatory inputs are well developed, GABA (acting on both GABAA and GABAB receptors) will hyperpolarise the CA3 pyramidal neurones and, as in the adult, will prevent excessive neuronal discharges. Our electrophysiological and morphological studies have shown that hippocampal GABAergic interneurones are in a unique position to modulate the development of CA3 pyramidal neurones. Developing neurones require a certain degree of membrane depolarisation, and a

  15. Post-synaptic density-95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines.

    Science.gov (United States)

    Akama, Keith T; Thompson, Louisa I; Milner, Teresa A; McEwen, Bruce S

    2013-03-01

    The estrogen 17β-estradiol (E2) modulates dendritic spine plasticity in the cornu ammonis 1 (CA1) region of the hippocampus, and GPR30 (G-protein coupled estrogen receptor 1 (GPER1)) is an estrogen-sensitive G-protein-coupled receptor (GPCR) that is expressed in the mammalian brain and in specific subregions that are responsive to E2, including the hippocampus. The subcellular localization of hippocampal GPR30, however, remains unclear. Here, we demonstrate that GPR30 immunoreactivity is detected in dendritic spines of rat CA1 hippocampal neurons in vivo and that GPR30 protein can be found in rat brain synaptosomes. GPR30 immunoreactivity is identified at the post-synaptic density (PSD) and in the adjacent peri-synaptic zone, and GPR30 can associate with the spine scaffolding protein PSD-95 both in vitro and in vivo. This PSD-95 binding capacity of GPR30 is specific and determined by the receptor C-terminal tail that is both necessary and sufficient for PSD-95 interaction. The interaction with PSD-95 functions to increase GPR30 protein levels residing at the plasma membrane surface. GPR30 associates with the N-terminal tandem pair of PDZ domains in PSD-95, suggesting that PSD-95 may be involved in clustering GPR30 with other receptors in the hippocampus. We demonstrate that GPR30 has the potential to associate with additional post-synaptic GPCRs, including the membrane progestin receptor, the corticotropin releasing hormone receptor, and the 5HT1a serotonin receptor. These data demonstrate that GPR30 is well positioned in the dendritic spine compartment to integrate E2 sensitivity directly onto multiple inputs on synaptic activity and might begin to provide a molecular explanation as to how E2 modulates dendritic spine plasticity.

  16. Post-synaptic Density-95 (PSD-95) Binding Capacity of G-protein-coupled Receptor 30 (GPR30), an Estrogen Receptor That Can Be Identified in Hippocampal Dendritic Spines*

    Science.gov (United States)

    Akama, Keith T.; Thompson, Louisa I.; Milner, Teresa A.; McEwen, Bruce S.

    2013-01-01

    The estrogen 17β-estradiol (E2) modulates dendritic spine plasticity in the cornu ammonis 1 (CA1) region of the hippocampus, and GPR30 (G-protein coupled estrogen receptor 1 (GPER1)) is an estrogen-sensitive G-protein-coupled receptor (GPCR) that is expressed in the mammalian brain and in specific subregions that are responsive to E2, including the hippocampus. The subcellular localization of hippocampal GPR30, however, remains unclear. Here, we demonstrate that GPR30 immunoreactivity is detected in dendritic spines of rat CA1 hippocampal neurons in vivo and that GPR30 protein can be found in rat brain synaptosomes. GPR30 immunoreactivity is identified at the post-synaptic density (PSD) and in the adjacent peri-synaptic zone, and GPR30 can associate with the spine scaffolding protein PSD-95 both in vitro and in vivo. This PSD-95 binding capacity of GPR30 is specific and determined by the receptor C-terminal tail that is both necessary and sufficient for PSD-95 interaction. The interaction with PSD-95 functions to increase GPR30 protein levels residing at the plasma membrane surface. GPR30 associates with the N-terminal tandem pair of PDZ domains in PSD-95, suggesting that PSD-95 may be involved in clustering GPR30 with other receptors in the hippocampus. We demonstrate that GPR30 has the potential to associate with additional post-synaptic GPCRs, including the membrane progestin receptor, the corticotropin releasing hormone receptor, and the 5HT1a serotonin receptor. These data demonstrate that GPR30 is well positioned in the dendritic spine compartment to integrate E2 sensitivity directly onto multiple inputs on synaptic activity and might begin to provide a molecular explanation as to how E2 modulates dendritic spine plasticity. PMID:23300088

  17. Purines released from astrocytes inhibit excitatory synaptic transmission in the ventral horn of the spinal cord

    Directory of Open Access Journals (Sweden)

    Eva Meier Carlsen

    2014-06-01

    Full Text Available Spinal neuronal networks are essential for motor function. They are involved in the integration of sensory inputs and the generation of rhythmic motor outputs. They continuously adapt their activity to the internal state of the organism and to the environment. This plasticity can be provided by different neuromodulators. These substances are usually thought of being released by dedicated neurons. However, in other networks from the central nervous system synaptic transmission is also modulated by transmitters released from astrocytes. The star-shaped glial cell responds to neurotransmitters by releasing gliotransmitters, which in turn modulate synaptic transmission. Here we investigated if astrocytes present in the ventral horn of the spinal cord modulate synaptic transmission. We evoked synaptic inputs in ventral horn neurons recorded in a slice preparation from the spinal cord of neonatal mice. Neurons responded to electrical stimulation by monosynaptic EPSCs. We used mice expressing the enhanced green fluorescent protein under the promoter of the glial fibrillary acidic protein to identify astrocytes. Chelating calcium with BAPTA in a single neighboring astrocyte increased the amplitude of synaptic currents. In contrast, when we selectively stimulated astrocytes by activating PAR-1 receptors with the peptide TFLLR, the amplitude of EPSCs evoked by a paired stimulation protocol was reduced. The paired-pulse ratio was increased, suggesting an inhibition occurring at the presynaptic side of synapses. In the presence of blockers for extracellular ectonucleotidases, TFLLR did not induce presynaptic inhibition. Puffing adenosine reproduced the effect of TFLLR and blocking adenosine A1 receptors with DPCPX prevented it. Altogether our results show that ventral horn astrocytes are responsible for a tonic and a phasic inhibition of excitatory synaptic transmission by releasing ATP, which gets converted into adenosine that binds to inhibitory

  18. Neuroinflammation and excitatory symptoms in bipolar disorder

    Directory of Open Access Journals (Sweden)

    Isabella Panaccione

    2015-01-01

    Full Text Available Neuroinflammation has been proposed as a strong biological factor underlying the development of neuropsychiatric diseases. A role for dysregulation of the immune system was initially suggested in depressive disorders and subsequently extended to other illnesses, including bipolar disorder (BD. Indeed, there is growing evidence confirming the presence of a generalized pro-inflammatory state in BD patients, involving alterations in cytokine, acute-phase proteins, and complement factor secretion, white blood cell differentiation, microglial activation, arachidonic acid signaling pathways, and increased oxidative stress markers. Medications commonly used to treat BD, such as lithium, antiepileptics and antipsychotics, show some immunoregulatory activity both in vitro and in vivo. The aim of our study was to review the role of different inflammatory mechanisms, specifically in the development of excitatory symptoms, via a systematic PubMed search of the literature. Despite the high variability of results among studies, we found evidence indicating specific alterations of the inflammatory response during manic and mixed states of BD. These findings may help to clarify some of the complex mechanisms underlying the development of excitatory symptoms and suggest a potential role for drugs targeting the inflammatory system as new therapeutic options.

  19. Zingerone enhances glutamatergic spontaneous excitatory transmission by activating TRPA1 but not TRPV1 channels in the adult rat substantia gelatinosa.

    Science.gov (United States)

    Yue, Hai-Yuan; Jiang, Chang-Yu; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-08-01

    Transient receptor potential (TRP) channels are thought to play a role in regulating nociceptive transmission to spinal substantia gelatinosa (SG) neurons. It remains to be unveiled whether the TRP channels in the central nervous system are different in property from those involved in receiving nociceptive stimuli in the peripheral nervous system. We examined the effect of the vanilloid compound zingerone, which activates TRPV1 channels in the cell body of a primary afferent neuron, on glutamatergic excitatory transmission in the SG neurons of adult rat spinal cord slices by using the whole cell patch-clamp technique. Bath-applied zingerone reversibly and concentration-dependently increased spontaneous excitatory postsynaptic current (EPSC) frequency. This effect was accompanied by an inward current at -70 mV that was resistant to glutamate receptor antagonists. These zingerone effects were repeated and persisted in Na(+)-channel blocker tetrodotoxin-, La(3+)-, or IP3-induced Ca(2+)-release inhibitor 2-aminoethoxydiphenyl borate-containing or Ca(2+)-free Krebs solution. Zingerone activity was resistant to the selective TRPV1 antagonist capsazepine but sensitive to the nonselective TRP antagonist ruthenium red, the TRPA1 antagonist HC-030031, and the Ca(2+)-induced Ca(2+)-release inhibitor dantrolene. TRPA1 agonist allyl isothiocyanate but not capsaicin inhibited the facilitatory effect of zingerone. On the other hand, zingerone reduced monosynaptically evoked EPSC amplitudes, as did TRPA1 agonists. Like allyl isothiocyanate, zingerone enhanced GABAergic spontaneous inhibitory transmission in a manner sensitive to tetrodotoxin. We conclude that zingerone presynaptically facilitates spontaneous excitatory transmission, probably through Ca(2+)-induced Ca(2+)-release mechanisms, and produces a membrane depolarization in SG neurons by activating TRPA1 but not TRPV1 channels.

  20. The evidence for nitric oxide synthase immunopositivity in the monosynaptic Ia-motoneuron pathway of the dog.

    Science.gov (United States)

    Marsala, Jozef; Lukácová, Nadezda; Sulla, Igor; Wohlfahrt, Peter; Marsala, Martin

    2005-09-01

    In this study, nitric oxide synthase immunohistochemistry supported by nicotinamide adenine dinucleotide phosphate diaphorase histochemistry was used to demonstrate the nitric oxide synthase immunoreactivity in the monosynaptic Ia-motoneuron pathway exemplified by structural components of the afferent limb of the soleus H-reflex in the dog. A noticeable number of medium-sized intensely nitric oxide synthase immunoreactive somata (1000-2000 microm(2) square area) and large intraganglionic nitric oxide synthase immunoreactive fibers, presumed to be Ia axons, was found in the L7 and S1 dorsal root ganglia. The existence of nitric oxide synthase immunoreactive fibers (6-8 microm in diameter, not counting the myelin sheath) was confirmed in L7 and S1 dorsal roots and in the medial bundle of both dorsal roots before entering the dorsal root entry zone. By virtue of the funicular organization of nitric oxide synthase immunoreactive fibers in the dorsal funiculus, the largest nitric oxide synthase immunoreactive fibers represent stem Ia axons located in the deep portion of the dorsal funiculus close to the dorsomedial margin of the dorsal horn. Upon entering the gray matter of L7 and S1 segments and passing through the medial half of the dorsal horn, tapered nitric oxide synthase immunoreactive collaterals of the stem Ia fibers pass through the deep layers of the dorsal horn and intermediate zone, and terminate in the group of homonymous motoneurons in L7 and S1 segments innervating the gastrocnemius-soleus muscles. Terminal fibers issued in the ventral horn intensely nitric oxide synthase immunoreactive terminals with long axis ranging from 0.7 to >or=15.1 microm presumed to be Ia bNOS-IR boutons. This finding is unique in that it focuses directly on nitric oxide synthase immunopositivity in the signalling transmitted by proprioceptive Ia fibers. Nitric oxide synthase immunoreactive boutons were found in the neuropil of Clarke's column of L4 segment, varying greatly in

  1. Asymmetry between excitatory and inhibitory learning.

    Science.gov (United States)

    Harris, Justin A; Patterson, Angela E; Andrew, Benjamin J; Kwok, Dorothy W S; Loy, Ignacio

    2016-10-01

    Five experiments investigated how learning about the added feature in a feature-positive discrimination or feature-negative discrimination is related to the change in reinforcement rate that the feature signals. Rats were trained in a magazine-approach paradigm with 2 concurrent discriminations between A versus AX and B versus BY. In 2 experiments (1 and 3), X and Y signaled an increase of 0.3 in the probability of reinforcement, from 0.1 to 0.4 (A vs. AX), or from 0.6 to 0.9 (B vs. BY). After extended training, each session included probe test trials in which X and Y were presented alone (Experiment 1) or in compound with another excitatory conditional stimulus (CS), C (Experiment 3). There was no difference in response rate between the 2 types of test trial (X vs. Y; XC vs. YC), consistent with the fact that X and Y signaled the same absolute change in reinforcement. In Experiments 2 and 4, X and Y signaled a decrease of 0.3 in the probability of reinforcement, from 0.4 to 0.1 (A vs. AX) or from 0.9 to 0.6 (B vs. BY). Test trials in which X or Y was presented with C showed that X had greater inhibitory strength than Y, consistent with the fact that X signaled a larger relative change in reinforcement. This was confirmed in Experiment 5, in which X and Y had the same inhibitory strength on test after training in which they signaled the same relative change in reinforcement but different absolute changes (0.3 to 0.1 for A vs. AX; 0.9 to 0.3 for B vs. BY). The results show that excitatory conditioning is linearly related to the increase in reinforcement rate, whereas inhibitory learning is not linearly related to the decrease in reinforcement rate. Implications of this for theories of associative learning are discussed. (PsycINFO Database Record

  2. Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb

    Science.gov (United States)

    Deshpande, Aditi; Bergami, Matteo; Ghanem, Alexander; Conzelmann, Karl-Klaus; Lepier, Alexandra; Götz, Magdalena; Berninger, Benedikt

    2013-01-01

    Identifying the connectome of adult-generated neurons is essential for understanding how the preexisting circuitry is refined by neurogenesis. Changes in the pattern of connectivity are likely to control the differentiation process of newly generated neurons and exert an important influence on their unique capacity to contribute to information processing. Using a monosynaptic rabies virus-based tracing technique, we studied the evolving presynaptic connectivity of adult-generated neurons in the dentate gyrus (DG) of the hippocampus and olfactory bulb (OB) during the first weeks of their life. In both neurogenic zones, adult-generated neurons first receive local connections from multiple types of GABAergic interneurons before long-range projections become established, such as those originating from cortical areas. Interestingly, despite fundamental similarities in the overall pattern of evolution of presynaptic connectivity, there were notable differences with regard to the development of cortical projections: although DG granule neuron input originating from the entorhinal cortex could be traced starting only from 3 to 5 wk on, newly generated neurons in the OB received input from the anterior olfactory nucleus and piriform cortex already by the second week. This early glutamatergic input onto newly generated interneurons in the OB was matched in time by the equally early innervations of DG granule neurons by glutamatergic mossy cells. The development of connectivity revealed by our study may suggest common principles for incorporating newly generated neurons into a preexisting circuit. PMID:23487772

  3. [The receptors involved in the excitatory effects of kynurenines].

    Science.gov (United States)

    Lapin, I P; Ryzhov, I V

    1989-01-01

    There is presented a brief review of the authors' and literature data on the excitatory and convulsant effects of kynurenines, mainly 1-kynurenine and quinolinic acid. Particular attention is given to the interactions of kynurenines with the excitatory and inhibitory amino acids, their receptors, benzodiazepine receptor complex, catecholamines, serotonin, acetylcholine. The following trends of studies on the neuroactivity of kynurenines seem to be promising: isolation of specific binding sites for the most active kynurenines--kynurenine, quinolinic and kynurenic acids, the interaction with other endogenous convulsants like beta-carbolines, endorphines, folates, etc., the search of the brain structures triggering or deferring the excitatory and convulsant effects of kynurenines.

  4. Excitatory amino acid transporters as potential drug targets

    DEFF Research Database (Denmark)

    Bunch, Lennart; Erichsen, Mette Navy; Jensen, Anders Asbjørn

    2009-01-01

    BACKGROUND: Excitatory amino acid transporters (EAATs) are transmembrane proteins responsible for the uptake of (S)-glutamate (Glu) from the synaptic cleft, thereby terminating the glutamatergic neurotransmitter signal. Today five subtypes have been identified. Except for EAAT2, their individual...

  5. Ultrastructural evidence for a direct excitatory pathway from the nucleus retroambiguus to lateral longissimus and quadratus lumborum motoneurons in the female golden hamster.

    Science.gov (United States)

    Gerrits, Peter O; Mouton, Leonora J; de Weerd, Henk; Georgiadis, Janniko R; Krukerink, Marco; Holstege, Gert

    2004-12-20

    During mating, the female golden hamster displays a stereotyped specific receptive posture, characterized by lordosis of the back, elevation of the tail, and extension of the legs. Muscles involved in this posture are thought to be iliopsoas, cutaneus trunci, lateral longissimus (LL), and quadratus lumborum (QL). Lesion studies in rats suggest that mating behavior is controlled by the mesencephalic periaqueductal gray (PAG). The PAG does not project directly to the motoneurons innervating the muscles involved in mating, but is thought to make use of the nucleus retroambiguus (NRA) as relay. The NRA is located ventrolaterally in the most caudal medulla, and projects directly to iliopsoas and cutaneus trunci motoneuronal cell groups. The question is whether this is also true for LL and QL muscles. Retrograde HRP tracing experiments revealed that LL and QL motoneurons are located medially in the ventral horn of the T12-L6 and T13-L4 segments, respectively. A subsequent ultrastructural study combined wheatgerm agglutinin-conjugated horseradish peroxidase injections in the NRA with cholera-toxin B-subunit injections in LL and QL muscles. The results revealed monosynaptic contacts between anterogradely labeled NRA-fiber terminals with retrogradely labeled dendrites of both LL and QL motoneurons. Almost all these terminals had asymmetrical synapses and contained spherical vesicles, suggesting an excitatory function of this NRA-motoneuronal pathway. These results correspond with the hypothesis that in hamster the PAG-NRA-motoneuronal projection not only involves motoneurons of iliopsoas and cutaneus trunci but also of LL and QL.

  6. Streptozotocin Inhibits Electrophysiological Determinants of Excitatory and Inhibitory Synaptic Transmission in CA1 Pyramidal Neurons of Rat Hippocampal Slices: Reduction of These Effects by Edaravone

    Directory of Open Access Journals (Sweden)

    Ting Ju

    2016-12-01

    Full Text Available Background: Streptozotocin (STZ has served as an agent to generate an Alzheimer's disease (AD model in rats, while edaravone (EDA, a novel free radical scavenger, has recently emerged as an effective treatment for use in vivo and vitro AD models. However, to date, these beneficial effects of EDA have only been clearly demonstrated within STZ-induced animal models of AD and in cell models of AD. A better understanding of the mechanisms of EDA may provide the opportunity for their clinical application in the treatment of AD. Therefore, the purpose of this study was to investigate the underlying mechanisms of STZ and EDA as assessed upon electrophysiological alterations in CA1 pyramidal neurons of rat hippocampal slices. Methods: Through measures of evoked excitatory postsynaptic currents (eEPSCs, AMPAR-mediated eEPSCs (eEPSCsAMPA, evoked inhibitory postsynaptic currents (eIPSCs, evoked excitatory postsynaptic current paired pulse ratio (eEPSC PPR and evoked inhibitory postsynaptic current paired pulse ratio (eIPSC PPR, it was possible to investigate mechanisms as related to the neurotoxicity of STZ and reductions in these effects by EDA. Results: Our results showed that STZ (1000 µM significantly inhibited peak amplitudes of eEPSCs, eEPSCsAMPA and eIPSCs, while EDA (1000 µM attenuated these STZ-induced changes at holding potentials ranging from -60mV to +40 mV for EPSCs and -60mV to +20 mV for IPSCs. Our work also indicated that mean eEPSC PPR were substantially altered by STZ, effects which were partially restored by EDA. In contrast, no significant effects upon eIPSC PPR were obtained in response to STZ and EDA. Conclusion: Our data suggest that STZ inhibits glutamatergic transmission involving pre-synaptic mechanisms and AMPAR, and that STZ inhibits GABAergic transmission by post-synaptic mechanisms within CA1 pyramidal neurons. These effects are attenuated by EDA.

  7. Effects of Ketamine on Neuronal Spontaneous Excitatory Postsynaptic Currents and Miniature Excitatory Postsynaptic Currents in the Somatosensory Cortex of Rats

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    Chengdong Yuan

    2016-07-01

    Full Text Available Background: Ketamine is a commonly used intravenous anesthetic which produces dissociation anesthesia, analgesia, and amnesia. The mechanism of ketamine-induced synaptic inhibition in high-level cortical areas is still unknown. We aimed to elucidate the effects of different concentrations of ketamine on the glutamatergic synaptic transmission of the neurons in the primary somatosensory cortex by using the whole-cell patch-clamp method. Methods: Sprague-Dawley rats (11–19 postnatal days, n=36 were used to obtain brain slices (300 μM. Spontaneous excitatory postsynaptic currents (data from 40 neurons were recorded at a command potential of -70 mV in the presence of bicuculline (a competitive antagonist of GABAA receptors, 30 μM and strychnine (glycine receptor antagonist, 30 μM. Miniature excitatory postsynaptic currents (data from 40 neurons were also recorded when 1 μM of tetrodotoxin was added into the artificial cerebrospinal fluid. We used GraphPad Prism5for statistical analysis. Significant differences in the mean amplitude and frequency were tested using the Student paired 2-tailed t test. Values of P<0.05 were considered significant. Results: Different concentrations of ketamine inhibited the frequency and amplitude of the spontaneous excitatory postsynaptic currents as well as the amplitude of the miniature excitatory postsynaptic currents in a concentration-dependent manner, but they exerted no significant effect on the frequency of the miniature excitatory postsynaptic currents. Conclusion: Ketamine inhibited the excitatory synaptic transmission of the neurons in the primary somatosensory cortex. The inhibition may have been mediated by a reduction in the sensitivity of the postsynaptic glutamatergic receptors.

  8. Excitatory response of rabbit myometrium to nitric oxide in vitro.

    Science.gov (United States)

    Nakanishi, H; Matsuoka, I; Ono, T; Okawa, T; Katahira, K; Nakahata, N

    1996-05-01

    Nitric oxide (NO) at high concentration (approx. 33 microM) produced a marked excitation: increase of tension development or increase in amplitude of spontaneous contraction, in 7 out of 8 rabbit nonpregnant myometrial strips. One case produced an inhibition: disappearance of spontaneous contraction. A latent period of several sec usually preceded the excitation. The response of the myometrium to NO approx. 33 microM associated with remarkable increase in tissue cyclic GMP levels. NO approx. 33 microM reduced an inhibition, in 1 out of 3 myometrial strips taken from ovariectomized rabbits. Two cases produced an excitatory. A precursor of NO, L-Arginine 100 microM or an inhibitor of NO synthase, NG-nitro-L-arginine 100 microM also produced a transient weak excitatory response. On the contrary, 8-bromo-cyclic GMP 100 microM produced an inhibition. The excitatory response to NO 33 microM was almost unaffected by pretreatment with indomethacin 10 microM, whereas the spontaneous motility was remarkably depressed. The contractile response of the isolated rabbit myometrium to electrical field stimulation was almost unaffected by the pretreatment with L-arginine 100 microM or NG-nitro-L-arginine 100 microM. The present findings may indicate that NO has inhibitory and excitatory components on the mechanical activity of the rabbit isolated myometrium.

  9. Irregular persistent activity induced by synaptic excitatory feedback

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    Francesca Barbieri

    2007-11-01

    Full Text Available Neurophysiological experiments on monkeys have reported highly irregular persistent activity during the performance of an oculomotor delayed-response task. These experiments show that during the delay period the coefficient of variation (CV of interspike intervals (ISI of prefrontal neurons is above 1, on average, and larger than during the fixation period. In the present paper, we show that this feature can be reproduced in a network in which persistent activity is induced by excitatory feedback, provided that (i the post-spike reset is close enough to threshold , (ii synaptic efficacies are a non-linear function of the pre-synaptic firing rate. Non-linearity between presynaptic rate and effective synaptic strength is implemented by a standard short-term depression mechanism (STD. First, we consider the simplest possible network with excitatory feedback: a fully connected homogeneous network of excitatory leaky integrate-and-fire neurons, using both numerical simulations and analytical techniques. The results are then confirmed in a network with selective excitatory neurons and inhibition. In both the cases there is a large range of values of the synaptic efficacies for which the statistics of firing of single cells is similar to experimental data.

  10. Method for recording spinal reflexes in mice: effects of thyrotropin-releasing hormone, DOI, tolperisone and baclofen on monosynaptic spinal reflex potentials.

    Science.gov (United States)

    Okada, H; Honda, M; Ono, H

    2001-05-01

    Mice were used to record the spinal reflex potentials and to examine the effects of some drugs upon them. In anesthetized mice, laminectomy was performed in the lumbo-sacral region, and monosynaptic reflex potential (MSR) and polysynaptic reflex potential were recorded from the L5 ventral root after stimulation of the L5 dorsal root. Thyrotropin-releasing hormone (TRH) and 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI) produced transient and long-lasting increases in the MSR amplitude, respectively. Tolperisone hydrochloride and baclofen produced transient and long-lasting MSR depressions, respectively. These results show that mice can be used to record spinal reflex potentials, and that it may be possible to study the spinal cord function of mutant and knockout mice using this method.

  11. EXCITATORY CONNECTIONS BETWEEN SPINAL MOTONEURONS IN THE ADULT RAT

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objectives. Dendro-dendritic and dendro-somatic projections are common between spinal motoneurons. We attempted to clarify whether there are functional connections through these projections.Methods. Motoneurons were antidromically stimulated by the muscle nerve and recorded intracellularly to examine the direct interaction between them, after the related dorsal roots had been cut.Results. Excitatory connections, demonstrated by depolarizing potentials in response to muscle nerve stimulation, were found between motoneurons innervating the same muscle or synergistic muscles, but never between motoneurons innervating antagonistic muscles. These potentials were finely graded in response to a series of increasing stimuli and resistant to high frequency (50Hz) stimulation.Conclusions.These results indicate that excitatory connections, with certain specificity of spatial and temporal distribution, occur in the spinal motoneurons. It is also suggested that electrical coupling should be involved in these connections and this mechanism should improve the excitability of the motoneurons in the same column.

  12. Sequential dynamics in the motif of excitatory coupled elements

    Science.gov (United States)

    Korotkov, Alexander G.; Kazakov, Alexey O.; Osipov, Grigory V.

    2015-11-01

    In this article a new model of motif (small ensemble) of neuron-like elements is proposed. It is built with the use of the generalized Lotka-Volterra model with excitatory couplings. The main motivation for this work comes from the problems of neuroscience where excitatory couplings are proved to be the predominant type of interaction between neurons of the brain. In this paper it is shown that there are two modes depending on the type of coupling between the elements: the mode with a stable heteroclinic cycle and the mode with a stable limit cycle. Our second goal is to examine the chaotic dynamics of the generalized three-dimensional Lotka-Volterra model.

  13. Excitatory GABA in rodent developing neocortex in vitro.

    Science.gov (United States)

    Rheims, Sylvain; Minlebaev, Marat; Ivanov, Anton; Represa, Alfonso; Khazipov, Rustem; Holmes, Gregory L; Ben-Ari, Yehezkel; Zilberter, Yuri

    2008-08-01

    GABA depolarizes immature cortical neurons. However, whether GABA excites immature neocortical neurons and drives network oscillations as in other brain structures remains controversial. Excitatory actions of GABA depend on three fundamental parameters: the resting membrane potential (Em), reversal potential of GABA (E(GABA)), and threshold of action potential generation (Vthr). We have shown recently that conventional invasive recording techniques provide an erroneous estimation of these parameters in immature neurons. In this study, we used noninvasive single N-methyl-d-aspartate and GABA channel recordings in rodent brain slices to measure both Em and E(GABA) in the same neuron. We show that GABA strongly depolarizes pyramidal neurons and interneurons in both deep and superficial layers of the immature neocortex (P2-P10). However, GABA generates action potentials in layer 5/6 (L5/6) but not L2/3 pyramidal cells, since L5/6 pyramidal cells have more depolarized resting potentials and more hyperpolarized Vthr. The excitatory GABA transiently drives oscillations generated by L5/6 pyramidal cells and interneurons during development (P5-P12). The NKCC1 co-transporter antagonist bumetanide strongly reduces [Cl(-)]i, GABA-induced depolarization, and network oscillations, confirming the importance of GABA signaling. Thus a strong GABA excitatory drive coupled with high intrinsic excitability of L5/6 pyramidal neurons and interneurons provide a powerful mechanism of synapse-driven oscillatory activity in the rodent neocortex in vitro. In the companion paper, we show that the excitatory GABA drives layer-specific seizures in the immature neocortex.

  14. Traveling wave front solutions in lateral-excitatory neuronal networks

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    Sittipong Ruktamatakul

    2008-05-01

    Full Text Available In this paper, we discuss the shape of traveling wave front solutions to a neuronal model with the connection function to be of lateral excitation type. This means that close connecting cells have an inhibitory influence, while cells that aremore distant have an excitatory influence. We give results on the shape of the wave fronts solutions, which exhibit different shapes depend ing on the size of a threshold parameter.

  15. Location-dependent excitatory synaptic interactions in pyramidal neuron dendrites.

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    Bardia F Behabadi

    Full Text Available Neocortical pyramidal neurons (PNs receive thousands of excitatory synaptic contacts on their basal dendrites. Some act as classical driver inputs while others are thought to modulate PN responses based on sensory or behavioral context, but the biophysical mechanisms that mediate classical-contextual interactions in these dendrites remain poorly understood. We hypothesized that if two excitatory pathways bias their synaptic projections towards proximal vs. distal ends of the basal branches, the very different local spike thresholds and attenuation factors for inputs near and far from the soma might provide the basis for a classical-contextual functional asymmetry. Supporting this possibility, we found both in compartmental models and electrophysiological recordings in brain slices that the responses of basal dendrites to spatially separated inputs are indeed strongly asymmetric. Distal excitation lowers the local spike threshold for more proximal inputs, while having little effect on peak responses at the soma. In contrast, proximal excitation lowers the threshold, but also substantially increases the gain of distally-driven responses. Our findings support the view that PN basal dendrites possess significant analog computing capabilities, and suggest that the diverse forms of nonlinear response modulation seen in the neocortex, including uni-modal, cross-modal, and attentional effects, could depend in part on pathway-specific biases in the spatial distribution of excitatory synaptic contacts onto PN basal dendritic arbors.

  16. Delayed excitatory and inhibitory feedback shape neural information transmission

    Science.gov (United States)

    Chacron, Maurice J.; Longtin, André; Maler, Leonard

    2017-01-01

    Feedback circuitry with conduction and synaptic delays is ubiquitous in the nervous system. Yet the effects of delayed feedback on sensory processing of natural signals are poorly understood. This study explores the consequences of delayed excitatory and inhibitory feedback inputs on the processing of sensory information. We show, through numerical simulations and theory, that excitatory and inhibitory feedback can alter the firing frequency response of stochastic neurons in opposite ways by creating dynamical resonances, which in turn lead to information resonances (i.e., increased information transfer for specific ranges of input frequencies). The resonances are created at the expense of decreased information transfer in other frequency ranges. Using linear response theory for stochastically firing neurons, we explain how feedback signals shape the neural transfer function for a single neuron as a function of network size. We also find that balanced excitatory and inhibitory feedback can further enhance information tuning while maintaining a constant mean firing rate. Finally, we apply this theory to in vivo experimental data from weakly electric fish in which the feedback loop can be opened. We show that it qualitatively predicts the observed effects of inhibitory feedback. Our study of feedback excitation and inhibition reveals a possible mechanism by which optimal processing may be achieved over selected frequency ranges. PMID:16383655

  17. Shape perception enhances perceived contrast: evidence for excitatory predictive feedback?

    Science.gov (United States)

    Han, Biao; VanRullen, Rufin

    2016-03-14

    Predictive coding theory suggests that predictable responses are "explained away" (i.e., reduced) by feedback. Experimental evidence for feedback inhibition, however, is inconsistent: most neuroimaging studies show reduced activity by predictive feedback, while neurophysiology indicates that most inter-areal cortical feedback is excitatory and targets excitatory neurons. In this study, we asked subjects to judge the luminance of two gray disks containing stimulus outlines: one enabling predictive feedback (a 3D-shape) and one impeding it (random-lines). These outlines were comparable to those used in past neuroimaging studies. All 14 subjects consistently perceived the disk with a 3D-shape stimulus brighter; thus, predictive feedback enhanced perceived contrast. Since early visual cortex activity at the population level has been shown to have a monotonic relationship with subjective contrast perception, we speculate that the perceived contrast enhancement could reflect an increase in neuronal activity. In other words, predictive feedback may have had an excitatory influence on neuronal responses. Control experiments ruled out attention bias, local feature differences and response bias as alternate explanations.

  18. Tourette syndrome and excitatory substances: is there a connection?

    Science.gov (United States)

    Zou, Li-Ping; Wang, Ying; Zhang, Li-Ping; Zhao, Jian-Bo; Lu, Jin-Fang; Liu, Qun; Wang, Hang-Yan

    2011-05-01

    The objective of this study is to investigate the relationship between excitatory substances by testing the urine in children with Tourette syndrome (TS). We performed a control study involving 44 patients with TS and 44 normal children by investigating the children's daily eating habits. We used the gas chromatograph-mass spectrometer and liquid chromatograph-mass spectrometer from Agilent. Substances for detection included 197 excitatory substances prohibited by the International Olympic Committee and other substances with similar chemical structures or biological functions for urine samples. Forty-four patients who did not take any drugs in the past 2 weeks enrolled in the study. The positive rate in the experiment group was three cases, while it was negative in the control group. The level of 1-testosterone increased in one extremely severe TS patient who ate large amounts of puffed food and drank an average of 350 ml of cola per day. Cathine and other substances with similar chemical constitution or similar biological effects increased in one severe TS patient who ate bags of instant noodles daily, according to the high score of the Yale Global Tic Severity Scale. An increase in ephedrine type, testosterone, and stimulants may be related to the pathogenesis of TS. Unhealthy food possibly causes TS. The relationship between excitatory substances and TS needs to be explored with the goal of providing more information on diagnosing and treating TS.

  19. Ligands targeting the excitatory amino acid transporters (EAATs).

    Science.gov (United States)

    Dunlop, John; Butera, John A

    2006-01-01

    This review provides an overview of ligands for the excitatory amino acid transporters (EAATs), a family of high-affinity glutamate transporters localized to the plasma membrane of neurons and astroglial cells. Ligand development from the perspective of identifying novel and more selective tools for elucidating transporter subtype function, and the potential of transporter ligands in a therapeutic setting are discussed. Acute pharmacological modulation of EAAT activity in the form of linear and conformationally restricted glutamate and aspartate analogs is presented, in addition to recent strategies aimed more toward modulating transporter expression levels, the latter of particular significance to the development of transporter based therapeutics.

  20. A Role for Excitatory Amino Acids in Diabetic Eye Disease

    Science.gov (United States)

    Pulido, Jose E.; Pulido, Jose S.; Erie, Jay C.; Arroyo, Jorge; Bertram, Kurt; Lu, Miao-Jen; Shippy, Scott A.

    2007-01-01

    Diabetic retinopathy is a leading cause of vision loss. The primary clinical hallmarks are vascular changes that appear to contribute to the loss of sight. In a number of neurodegenerative disorders there is an appreciation that increased levels of excitatory amino acids are excitotoxic. The primary amino acid responsible appears to be the neurotransmitter glutamate. This review examines the nature of glutamatergic signaling at the retina and the growing evidence from clinical and animal model studies that glutamate may be playing similar excitotoxic roles at the diabetic retina. PMID:17713594

  1. A Role for Excitatory Amino Acids in Diabetic Eye Disease

    Directory of Open Access Journals (Sweden)

    Jose E. Pulido

    2007-01-01

    Full Text Available Diabetic retinopathy is a leading cause of vision loss. The primary clinical hallmarks are vascular changes that appear to contribute to the loss of sight. In a number of neurodegenerative disorders there is an appreciation that increased levels of excitatory amino acids are excitotoxic. The primary amino acid responsible appears to be the neurotransmitter glutamate. This review examines the nature of glutamatergic signaling at the retina and the growing evidence from clinical and animal model studies that glutamate may be playing similar excitotoxic roles at the diabetic retina.

  2. Summation of excitatory postsynaptic potentials in electrically-coupled neurones.

    Science.gov (United States)

    Vazquez, Y; Mendez, B; Trueta, C; De-Miguel, F F

    2009-09-29

    Dendritic electrical coupling increases the number of effective synaptic inputs onto neurones by allowing the direct spread of synaptic potentials from one neurone to another. Here we studied the summation of excitatory postsynaptic potentials (EPSPs) produced locally and arriving from the coupled neurone (transjunctional) in pairs of electrically-coupled Retzius neurones of the leech. We combined paired recordings of EPSPs, the production of artificial excitatory postsynaptic potentials (APSPs) in neurone pairs with different coupling coefficients and simulations of EPSPs produced in the coupled dendrites. Summation of the EPSPs produced in the dendrites was always linear, suggesting that synchronous EPSPs are produced at two or more different pairs of coupled dendrites and not in both sides of any one gap junction. The different spatio-temporal relationships explored between pairs of EPSPs or APSPs produced three main effects. (1) Synchronous pairs of EPSPs or APSPs exhibited an elongation of their decay phase compared to single EPSPs. (2) Asymmetries in the amplitudes between the pair of EPSPs added a "hump" to the smallest EPSP. (3) Modelling the inputs near the electrical synapse or anticipating the production of the transjunctional APSP increased the amplitude of the compound EPSP. The magnitude of all these changes depended on the coupling coefficient of the neurones. We also show that the hump improves the passive conduction of EPSPs by adding low frequency components. The diverse effects of summation of local and alien EPSPs shown here endow electrically-coupled neurones with a wider repertoire of adjustable integrative possibilities.

  3. Axonal dynamics of excitatory and inhibitory neurons in somatosensory cortex.

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    Sally A Marik

    Full Text Available Cortical topography can be remapped as a consequence of sensory deprivation, suggesting that cortical circuits are continually modified by experience. To see the effect of altered sensory experience on specific components of cortical circuits, we imaged neurons, labeled with a genetically modified adeno-associated virus, in the intact mouse somatosensory cortex before and after whisker plucking. Following whisker plucking we observed massive and rapid reorganization of the axons of both excitatory and inhibitory neurons, accompanied by a transient increase in bouton density. For horizontally projecting axons of excitatory neurons there was a net increase in axonal projections from the non-deprived whisker barrel columns into the deprived barrel columns. The axon collaterals of inhibitory neurons located in the deprived whisker barrel columns retracted in the vicinity of their somata and sprouted long-range projections beyond their normal reach towards the non-deprived whisker barrel columns. These results suggest that alterations in the balance of excitation and inhibition in deprived and non-deprived barrel columns underlie the topographic remapping associated with sensory deprivation.

  4. The GABA excitatory/inhibitory developmental sequence: a personal journey.

    Science.gov (United States)

    Ben-Ari, Y

    2014-10-24

    The developing brain is talkative but its language is not that of the adult. Most if not all voltage and transmitter-gated ionic currents follow a developmental sequence and network-driven patterns differ in immature and adult brains. This is best illustrated in studies engaged almost three decades ago in which we observed elevated intracellular chloride (Cl(-))i levels and excitatory GABA early during development and a perinatal excitatory/inhibitory shift. This sequence is observed in a wide range of brain structures and animal species suggesting that it has been conserved throughout evolution. It is mediated primarily by a developmentally regulated expression of the NKCC1 and KCC2 chloride importer and exporter respectively. The GABAergic depolarization acts in synergy with N-methyl-d-aspartate (NMDA) receptor-mediated and voltage-gated calcium currents to enhance intracellular calcium exerting trophic effects on neuritic growth, migration and synapse formation. These sequences can be deviated in utero by genetic or environmental insults leading to a persistence of immature features in the adult brain. This "neuroarcheology" concept paves the way to novel therapeutic perspectives based on the use of drugs that block immature but not adult currents. This is illustrated notably with the return to immature high levels of chloride and excitatory actions of GABA observed in many pathological conditions. This is due to the fact that in the immature brain a down regulation of KCC2 and an up regulation of NKCC1 are seen. Here, I present a personal history of how an unexpected observation led to novel concepts in developmental neurobiology and putative treatments of autism and other developmental disorders. Being a personal account, this review is neither exhaustive nor provides an update of this topic with all the studies that have contributed to this evolution. We all rely on previous inventors to allow science to advance. Here, I present a personal summary of this

  5. Psychopathology of excitatory and compulsive aspects of vandalistic graffiti.

    Science.gov (United States)

    Pani, Roberto; Sagliaschi, Samanta

    2009-12-01

    In this paper were explored psychological themes underlying vandalistic graffiti by 162 Italian adolescents (154 boys, 8 girls; M age = 17.5 yr., SD = 2.3) who "felt hooked" on vandalistic graffiti and agreed to participate in an interview with a graffiti writer. Use of this interview could clarify the motivations which led these youths to write on walls, the meaning they give to that act, the emotions they feel as they write, and their perception of risks and excitement involved. Qualitative analysis of their responses suggested these adolescents present a marked excitatory-compulsive trait, report a sense of emptiness, boredom, loneliness, and a lack of internal points of reference, and adopt behaviors linked to a pressing need for immediate gratification.

  6. Optimal properties of analog perceptrons with excitatory weights.

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    Claudia Clopath

    Full Text Available The cerebellum is a brain structure which has been traditionally devoted to supervised learning. According to this theory, plasticity at the Parallel Fiber (PF to Purkinje Cell (PC synapses is guided by the Climbing fibers (CF, which encode an 'error signal'. Purkinje cells have thus been modeled as perceptrons, learning input/output binary associations. At maximal capacity, a perceptron with excitatory weights expresses a large fraction of zero-weight synapses, in agreement with experimental findings. However, numerous experiments indicate that the firing rate of Purkinje cells varies in an analog, not binary, manner. In this paper, we study the perceptron with analog inputs and outputs. We show that the optimal input has a sparse binary distribution, in good agreement with the burst firing of the Granule cells. In addition, we show that the weight distribution consists of a large fraction of silent synapses, as in previously studied binary perceptron models, and as seen experimentally.

  7. Structural and functional dynamics of Excitatory Amino Acid Transporters (EAAT

    Directory of Open Access Journals (Sweden)

    Thomas Rauen

    2014-09-01

    Full Text Available Glutamate transporters control the glutamate homeostasis in the central nervous system, and, thus, are not only crucial for physiological excitatory synaptic signaling, but also for the prevention of a large number of neurodegenerative diseases that are associated with excessive and prolonged presence of the neurotransmitter glutamate in the extracellular space. Until now, five subtypes of high-affinity glutamate transporters (excitatory amino acid transporters, EAATs 1–5 have been identified. These 5 high-affinity glutamate transporter subtypes belong to the solute carrier 1 (SLC1 family of transmembrane proteins: EAAT1/GLAST (SLC1A3, EAAT2/GLT1 (SLC1A2, EAAT3/EAAC1 (SLC1A1, EAAT4 (SLC1A6 and EAAT5 (SLC1A7. EAATs are secondary-active transporters, taking up glutamate into the cell against a substantial concentration gradient. The driving force for concentrative uptake is provided by the co-transport of Na+ ions and the counter-transport of one K+ in a step independent of the glutamate translocation step. Due to the electrogenicity of transport, the transmembrane potential can also act as driving force. Glutamate transporters are also able to run in reverse, resulting in glutamate release from cells. Due to these important physiological functions, glutamate transporter expression and, therefore, the transport rate, are tightly regulated. The EAAT protein family are structurally expected to be highly similar, however, these transporters show a functional diversity that ranges from high capacity glutamate uptake systems (EAATs 1–3 to receptor-like glutamate activated anion channels (EAATs 4–5. Here, we provide an update on most recent progress made on EAAT’s molecular transport mechanism, structure-function relationships, pharmacology, and will add recent insights into mechanism of rapid membrane trafficking of glutamate transporters.

  8. Input-driven oscillations in networks with excitatory and inhibitory neurons with dynamic synapses.

    NARCIS (Netherlands)

    Marinazzo, D.; Kappen, H.J.; Gielen, S.C.A.M.

    2007-01-01

    Previous work has shown that networks of neurons with two coupled layers of excitatory and inhibitory neurons can reveal oscillatory activity. For example, Borgers and Kopell (2003) have shown that oscillations occur when the excitatory neurons receive a sufficiently large input. A constant drive to

  9. Bisphenol A depresses monosynaptic and polysynaptic reflexes in neonatal rat spinal cord in vitro involving estrogen receptor-dependent NO-mediated mechanisms.

    Science.gov (United States)

    Pandey, A K; Deshpande, S B

    2015-03-19

    Bisphenol A (BPA), a toxic chemical from plastics, is known to produce locomotor abnormalities which may imply the alteration in synaptic activity at Ia-α motoneuron synapse also. However the effect of BPA on this synapse is not known. Therefore, this study was undertaken to examine the effect of BPA on reflexes originating at Ia-α motoneuron synapse in the spinal cord. The experiments were performed on isolated hemisected spinal cords from 4 to 6d rats. Stimulation of a dorsal root evoked segmental monosynaptic (MSR) and polysynaptic (PSR) reflex potentials in the corresponding ventral root. Nitrite content (indicator of NO activity) of cords was estimated in the presence of BPA with/without antagonists. Superfusion of BPA (3-100μM) depressed the reflexes in a concentration- and time-dependent manner. The depression was ∼20, ∼50 and ∼70% at 10, 30 and 100μM of BPA, respectively. The 50% depression occurred around 15min at 30μM of BPA. Pretreatment with estrogen receptor (ERα) antagonist, tamoxifen, blocked the BPA-induced depression of reflexes, whereas, 17β-estradiol, ER agonist, did not depress the reflexes even up to 10μM. Further, pretreatment with Nω-Nitro-l-arginine methyl ester hydrochloride (l-NAME) or hemoglobin (Hb) blocked the BPA-induced depression of spinal reflexes. Nitric oxide (NO) donor sodium-nitroprusside depressed the MSR and PSR in a concentration-dependent manner. The nitrite concentration of the cords exposed to BPA was 733μM/gm of tissue (three times the saline group). Pretreatment with tamoxifen/l-NAME/Hb blocked the BPA-induced increase of nitrite levels. The present observations indicate that BPA depressed spinal synaptic transmission through ERα-dependent NO-mediated mechanisms. The altered synaptic activity may implicate for neurobehavioral locomotor abnormalities after exposure to BPA. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Spatial distribution of excitatory synapses on the dendrites of ganglion cells in the mouse retina.

    Science.gov (United States)

    Chen, Yin-Peng; Chiao, Chuan-Chin

    2014-01-01

    Excitatory glutamatergic inputs from bipolar cells affect the physiological properties of ganglion cells in the mammalian retina. The spatial distribution of these excitatory synapses on the dendrites of retinal ganglion cells thus may shape their distinct functions. To visualize the spatial pattern of excitatory glutamatergic input into the ganglion cells in the mouse retina, particle-mediated gene transfer of plasmids expressing postsynaptic density 95-green fluorescent fusion protein (PSD95-GFP) was used to label the excitatory synapses. Despite wide variation in the size and morphology of the retinal ganglion cells, the expression of PSD95 puncta was found to follow two general rules. Firstly, the PSD95 puncta are regularly spaced, at 1-2 µm intervals, along the dendrites, whereby the presence of an excitatory synapse creates an exclusion zone that rules out the presence of other glutamatergic synaptic inputs. Secondly, the spatial distribution of PSD95 puncta on the dendrites of diverse retinal ganglion cells are similar in that the number of excitatory synapses appears to be less on primary dendrites and to increase to a plateau on higher branch order dendrites. These observations suggest that synaptogenesis is spatially regulated along the dendritic segments and that the number of synaptic contacts is relatively constant beyond the primary dendrites. Interestingly, we also found that the linear puncta density is slightly higher in large cells than in small cells. This may suggest that retinal ganglion cells with a large dendritic field tend to show an increased connectivity of excitatory synapses that makes up for their reduced dendrite density. Mapping the spatial distribution pattern of the excitatory synapses on retinal ganglion cells thus provides explicit structural information that is essential for our understanding of how excitatory glutamatergic inputs shape neuronal responses.

  11. Principal component analysis of minimal excitatory postsynaptic potentials.

    Science.gov (United States)

    Astrelin, A V; Sokolov, M V; Behnisch, T; Reymann, K G; Voronin, L L

    1998-02-20

    'Minimal' excitatory postsynaptic potentials (EPSPs) are often recorded from central neurones, specifically for quantal analysis. However the EPSPs may emerge from activation of several fibres or transmission sites so that formal quantal analysis may give false results. Here we extended application of the principal component analysis (PCA) to minimal EPSPs. We tested a PCA algorithm and a new graphical 'alignment' procedure against both simulated data and hippocampal EPSPs. Minimal EPSPs were recorded before and up to 3.5 h following induction of long-term potentiation (LTP) in CA1 neurones. In 29 out of 45 EPSPs, two (N=22) or three (N=7) components were detected which differed in latencies, rise time (Trise) or both. The detected differences ranged from 0.6 to 7.8 ms for the latency and from 1.6-9 ms for Trise. Different components behaved differently following LTP induction. Cases were found when one component was potentiated immediately after tetanus whereas the other with a delay of 15-60 min. The immediately potentiated component could decline in 1-2 h so that the two components contributed differently into early (reflections of synchronized quantal releases. In general, the results demonstrate PCA applicability to separate EPSPs into different components and its usefulness for precise analysis of synaptic transmission.

  12. Amyloid-β depresses excitatory cholinergic synaptic transmission in Drosophila

    Institute of Scientific and Technical Information of China (English)

    Liqun Fang; Jingjing Duan; Dongzhi Ran; Zihao Fan; Ying Yan; Naya Huang; Huaiyu Gu; Yulan Zhu

    2012-01-01

    Objective Decline,disruption,or alterations of nicotinic cholinergic mechanisms contribute to cognitive dysfunctions like Alzheimer's disease (AD).Although amyloid-β (Aβ) aggregation is a pathological hallmark of AD,the mechanisms by which Aβ peptides modulate cholinergic synaptic transmission and memory loss remain obscure.This study was aimed to investigate the potential synaptic modulation by Aβ of the cholinergic synapses between olfactory receptor neurons and projection neurons (PNs) in the olfactory lobe of the fruit fly.Methods Cholinergic spontaneous and miniature excitatory postsynaptic current (mEPSC) were recorded with whole-cell patch clamp from PNs in Drosophila AD models expressing Aβ40,Aβ42,or Aβ42Arc peptides in neural tissue.Results In fly pupae (2 days before eclosion),overexpression of Aβ42 or Aβ42Arc,but not Aβ40,led to a significant decrease of mEPSC frequency,while overexpression of Aβ40,Aβ42,or Aβ42Arc had no significant effect on mEPSC amplitude.In contrast,Pavlovian olfactory associative learning and lifespan assays showed that both short-term memory and lifespan were decreased in the Drosophila models expressing Aβ40,Aβ42,or Aβ42Arc.Conclusion Both electrophysiological and behavioral results showed an effect of Aβ peptide on cholinergic synaptic transmission and suggest a possible mechanism by which Aβ peptides cause cholinergic neuron degeneration and the consequent memory loss.

  13. EIGENVALUE FUNCTIONS IN EXCITATORY-INHIBITORY NEURONAL NETWORKS

    Institute of Scientific and Technical Information of China (English)

    Zhang Linghai

    2004-01-01

    We study the exponential stability of traveling wave solutions of nonlinear systems of integral differential equations arising from nonlinear, nonlocal, synaptically coupled, excitatory-inhibitory neuronal networks. We have proved that exponential stability of traveling waves is equivalent to linear stability. Moreover, if the real parts of nonzero spectrum of an associated linear differential operator have a uniform negative upper bound, namely, max{Reλ: λ∈σ(L), λ≠ 0} ≤ -D, for some positive constant D, and λ = 0 is an algebraically simple eigenvalue of , then the linear stability follows, where is the linear differential operator obtained by linearizing the nonlinear system about its traveling wave and σ(L) denotes the spectrum of . The main aim of this paper is to construct complex analytic functions (also called eigenvalue or Evans functions) for exploring eigenvalues of linear differential operators to study the exponential stability of traveling waves. The zeros of the eigenvalue functions coincide with the eigenvalues of(L) .When studying multipulse solutions, some components of the traveling waves cross their thresholds for many times. These crossings cause great difficulty in the construction of the eigenvalue functions. In particular, we have to solve an over-determined system to construct the eigenvalue functions. By investigating asymptotic behaviors as z → -co of candidates for eigenfunctions, we find a way to construct the eigenvalue functions.By analyzing the zeros of the eigenvalue functions, we can establish the exponential stability of traveling waves arising from neuronal networks.

  14. Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons.

    Science.gov (United States)

    Ripamonti, Silvia; Ambrozkiewicz, Mateusz C; Guzzi, Francesca; Gravati, Marta; Biella, Gerardo; Bormuth, Ingo; Hammer, Matthieu; Tuffy, Liam P; Sigler, Albrecht; Kawabe, Hiroshi; Nishimori, Katsuhiko; Toselli, Mauro; Brose, Nils; Parenti, Marco; Rhee, JeongSeop

    2017-02-23

    Beyond its role in parturition and lactation, oxytocin influences higher brain processes that control social behavior of mammals, and perturbed oxytocin signaling has been linked to the pathogenesis of several psychiatric disorders. However, it is still largely unknown how oxytocin exactly regulates neuronal function. We show that early, transient oxytocin exposure in vitro inhibits the development of hippocampal glutamatergic neurons, leading to reduced dendrite complexity, synapse density, and excitatory transmission, while sparing GABAergic neurons. Conversely, genetic elimination of oxytocin receptors increases the expression of protein components of excitatory synapses and excitatory synaptic transmission in vitro. In vivo, oxytocin-receptor-deficient hippocampal pyramidal neurons develop more complex dendrites, which leads to increased spine number and reduced γ-oscillations. These results indicate that oxytocin controls the development of hippocampal excitatory neurons and contributes to the maintenance of a physiological excitation/inhibition balance, whose disruption can cause neurobehavioral disturbances.

  15. Finite post synaptic potentials cause a fast neuronal response

    Directory of Open Access Journals (Sweden)

    Moritz eHelias

    2011-02-01

    Full Text Available A generic property of the communication between neurons is the exchange of pulsesat discrete time points, the action potentials. However, the prevalenttheory of spiking neuronal networks of integrate-and-fire model neuronsrelies on two assumptions: the superposition of many afferent synapticimpulses is approximated by Gaussian white noise, equivalent to avanishing magnitude of the synaptic impulses, and the transfer oftime varying signals by neurons is assessable by linearization. Goingbeyond both approximations, we find that in the presence of synapticimpulses the response to transient inputs differs qualitatively fromprevious predictions. It is instantaneous rather than exhibiting low-passcharacteristics, depends non-linearly on the amplitude of the impulse,is asymmetric for excitation and inhibition and is promoted by a characteristiclevel of synaptic background noise. These findings resolve contradictionsbetween the earlier theory and experimental observations. Here wereview the recent theoretical progress that enabled these insights.We explain why the membrane potential near threshold is sensitiveto properties of the afferent noise and show how this shapes the neuralresponse. A further extension of the theory to time evolution in discretesteps quantifies simulation artifacts and yields improved methodsto cross check results.

  16. Cysteine transport through excitatory amino acid transporter 3 (EAAT3).

    Science.gov (United States)

    Watts, Spencer D; Torres-Salazar, Delany; Divito, Christopher B; Amara, Susan G

    2014-01-01

    Excitatory amino acid transporters (EAATs) limit glutamatergic signaling and maintain extracellular glutamate concentrations below neurotoxic levels. Of the five known EAAT isoforms (EAATs 1-5), only the neuronal isoform, EAAT3 (EAAC1), can efficiently transport the uncharged amino acid L-cysteine. EAAT3-mediated cysteine transport has been proposed to be a primary mechanism used by neurons to obtain cysteine for the synthesis of glutathione, a key molecule in preventing oxidative stress and neuronal toxicity. The molecular mechanisms underlying the selective transport of cysteine by EAAT3 have not been elucidated. Here we propose that the transport of cysteine through EAAT3 requires formation of the thiolate form of cysteine in the binding site. Using Xenopus oocytes and HEK293 cells expressing EAAT2 and EAAT3, we assessed the transport kinetics of different substrates and measured transporter-associated currents electrophysiologically. Our results show that L-selenocysteine, a cysteine analog that forms a negatively-charged selenolate ion at physiological pH, is efficiently transported by EAATs 1-3 and has a much higher apparent affinity for transport when compared to cysteine. Using a membrane tethered GFP variant to monitor intracellular pH changes associated with transport activity, we observed that transport of either L-glutamate or L-selenocysteine by EAAT3 decreased intracellular pH, whereas transport of cysteine resulted in cytoplasmic alkalinization. No change in pH was observed when cysteine was applied to cells expressing EAAT2, which displays negligible transport of cysteine. Under conditions that favor release of intracellular substrates through EAAT3 we observed release of labeled intracellular glutamate but did not detect cysteine release. Our results support a model whereby cysteine transport through EAAT3 is facilitated through cysteine de-protonation and that once inside, the thiolate is rapidly re-protonated. Moreover, these findings suggest

  17. Activation of perineuronal net-expressing excitatory neurons during associative memory encoding and retrieval

    Science.gov (United States)

    Morikawa, Shota; Ikegaya, Yuji; Narita, Minoru; Tamura, Hideki

    2017-01-01

    Perineuronal nets (PNNs), proteoglycan-rich extracellular matrix structures, are thought to be expressed around inhibitory neurons and contribute to critical periods of brain function and synaptic plasticity. However, in some specific brain regions such as the amygdala, PNNs were predominantly expressed around excitatory neurons. These neurons were recruited during auditory fear conditioning and memory retrieval. Indeed, the activation of PNN-expressing excitatory neurons predicted cognitive performance. PMID:28378772

  18. Excitatory effects of thyrotropin-releasing hormone (TRH) in hypoglossal motoneurons

    DEFF Research Database (Denmark)

    Rekling, J C

    1990-01-01

    The effect of thyrotropin-releasing hormone (TRH) was studied in 30 hypoglossal motoneurons from brainstem slices of guinea pigs. Bath application of TRH resulted in an increase of the spontaneous excitatory synaptic activity, depolarization of the neurons, increase of the input resistance...... and change of the duration of the falling phase of excitatory postsynaptic potentials. The depolarizing response and membrane conductance change was the result of a direct postsynaptic action of TRH, possibly mediated by a reduction of a potassium conductance....

  19. LRRTM3 Regulates Excitatory Synapse Development through Alternative Splicing and Neurexin Binding

    Directory of Open Access Journals (Sweden)

    Ji Won Um

    2016-02-01

    Full Text Available The four members of the LRRTM family (LRRTM1-4 are postsynaptic adhesion molecules essential for excitatory synapse development. They have also been implicated in neuropsychiatric diseases. Here, we focus on LRRTM3, showing that two distinct LRRTM3 variants generated by alternative splicing regulate LRRTM3 interaction with PSD-95, but not its excitatory synapse-promoting activity. Overexpression of either LRRTM3 variant increased excitatory synapse density in dentate gyrus (DG granule neurons, whereas LRRTM3 knockdown decreased it. LRRTM3 also controlled activity-regulated AMPA receptor surface expression in an alternative splicing-dependent manner. Furthermore, Lrrtm3-knockout mice displayed specific alterations in excitatory synapse density, excitatory synaptic transmission and excitability in DG granule neurons but not in CA1 pyramidal neurons. Lastly, LRRTM3 required only specific splice variants of presynaptic neurexins for their synaptogenic activity. Collectively, our data highlight alternative splicing and differential presynaptic ligand utilization in the regulation of LRRTMs, revealing key regulatory mechanisms for excitatory synapse development.

  20. Multiple mechanisms of fast excitatory synaptic transmission in the enteric nervous system.

    Science.gov (United States)

    Galligan, J J; LePard, K J; Schneider, D A; Zhou, X

    2000-07-01

    The enteric nervous system (ENS) can control gastrointestinal function independent of direct connections with the central nervous system. Enteric nerves perform this important function using multiple mechanisms of excitatory neurotransmission in enteric ganglia. Fast excitatory synaptic transmission in the autonomic nervous system (ANS) is largely mediated by acetylcholine (ACh) acting at nicotinic cholinergic receptors but in the ENS there are noncholinergic fast excitatory neurotransmitters. There are two broad types of neurons in the ENS: S neurons and AH neurons. S neurons are interneurons and motoneurons while AH neurons are sensory neurons. Three subsets of S neurons in the myenteric plexus can be distinguished on the basis of the neurotransmitters producing fast excitatory postsynaptic potentials (fEPSPs) in each subset. In one subset, fEPSPs are mediated solely by ACh acting at nicotinic cholinergic receptors. In a second subset of S neurons, ATP acting at P2X purine receptors and ACh contribute to the fEPSP while in a third subset, fEPSPs are mediated by 5-hydroxytryptamine (5-HT) acting at 5-HT(3) receptors and ACh. Some AH neurons also receive fast excitatory synaptic input. The fEPSPs recorded from AH neurons are mediated ACh and also by glutamate acting at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Multiple mechanisms of fast excitatory synaptic transmission in the ENS are likely to contribute to its capacity to regulate complex gastrointestinal functions.

  1. Computer simulations of neural mechanisms explaining upper and lower limb excitatory neural coupling

    Directory of Open Access Journals (Sweden)

    Ferris Daniel P

    2010-12-01

    Full Text Available Abstract Background When humans perform rhythmic upper and lower limb locomotor-like movements, there is an excitatory effect of upper limb exertion on lower limb muscle recruitment. To investigate potential neural mechanisms for this behavioral observation, we developed computer simulations modeling interlimb neural pathways among central pattern generators. We hypothesized that enhancement of muscle recruitment from interlimb spinal mechanisms was not sufficient to explain muscle enhancement levels observed in experimental data. Methods We used Matsuoka oscillators for the central pattern generators (CPG and determined parameters that enhanced amplitudes of rhythmic steady state bursts. Potential mechanisms for output enhancement were excitatory and inhibitory sensory feedback gains, excitatory and inhibitory interlimb coupling gains, and coupling geometry. We first simulated the simplest case, a single CPG, and then expanded the model to have two CPGs and lastly four CPGs. In the two and four CPG models, the lower limb CPGs did not receive supraspinal input such that the only mechanisms available for enhancing output were interlimb coupling gains and sensory feedback gains. Results In a two-CPG model with inhibitory sensory feedback gains, only excitatory gains of ipsilateral flexor-extensor/extensor-flexor coupling produced reciprocal upper-lower limb bursts and enhanced output up to 26%. In a two-CPG model with excitatory sensory feedback gains, excitatory gains of contralateral flexor-flexor/extensor-extensor coupling produced reciprocal upper-lower limb bursts and enhanced output up to 100%. However, within a given excitatory sensory feedback gain, enhancement due to excitatory interlimb gains could only reach levels up to 20%. Interconnecting four CPGs to have ipsilateral flexor-extensor/extensor-flexor coupling, contralateral flexor-flexor/extensor-extensor coupling, and bilateral flexor-extensor/extensor-flexor coupling could enhance

  2. Cysteine transport through excitatory amino acid transporter 3 (EAAT3.

    Directory of Open Access Journals (Sweden)

    Spencer D Watts

    Full Text Available Excitatory amino acid transporters (EAATs limit glutamatergic signaling and maintain extracellular glutamate concentrations below neurotoxic levels. Of the five known EAAT isoforms (EAATs 1-5, only the neuronal isoform, EAAT3 (EAAC1, can efficiently transport the uncharged amino acid L-cysteine. EAAT3-mediated cysteine transport has been proposed to be a primary mechanism used by neurons to obtain cysteine for the synthesis of glutathione, a key molecule in preventing oxidative stress and neuronal toxicity. The molecular mechanisms underlying the selective transport of cysteine by EAAT3 have not been elucidated. Here we propose that the transport of cysteine through EAAT3 requires formation of the thiolate form of cysteine in the binding site. Using Xenopus oocytes and HEK293 cells expressing EAAT2 and EAAT3, we assessed the transport kinetics of different substrates and measured transporter-associated currents electrophysiologically. Our results show that L-selenocysteine, a cysteine analog that forms a negatively-charged selenolate ion at physiological pH, is efficiently transported by EAATs 1-3 and has a much higher apparent affinity for transport when compared to cysteine. Using a membrane tethered GFP variant to monitor intracellular pH changes associated with transport activity, we observed that transport of either L-glutamate or L-selenocysteine by EAAT3 decreased intracellular pH, whereas transport of cysteine resulted in cytoplasmic alkalinization. No change in pH was observed when cysteine was applied to cells expressing EAAT2, which displays negligible transport of cysteine. Under conditions that favor release of intracellular substrates through EAAT3 we observed release of labeled intracellular glutamate but did not detect cysteine release. Our results support a model whereby cysteine transport through EAAT3 is facilitated through cysteine de-protonation and that once inside, the thiolate is rapidly re-protonated. Moreover, these

  3. Distinct modifications of convergent excitatory and inhibitory inputs in developing olfactory circuits.

    Science.gov (United States)

    Ma, T-F; Chen, P-H; Hu, X-Q; Zhao, X-L; Tian, T; Lu, W

    2014-06-06

    The interaction between excitatory and inhibitory inputs is critical to neuronal signal processing. However, little is known about this fundamental property, largely due to the inability to clearly isolate the respective inputs. Here we took advantage of the characteristic stereotypical architecture of synaptic connections in the main olfactory bulb, which enabled us to entirely separate excitatory and inhibitory inputs. Using paired stimulation of two glomeruli located apart at different intensities, we separately elicited excitatory and inhibitory inputs and mimicked stimulation of competing mitral cells (MCs) with different odorants. We performed dual whole-cell patch recording of evoked excitatory postsynaptic responses (EPSPs) and inhibitory postsynaptic responses (IPSPs) in current-clamp mode from two competitive MCs that are connected to the two stimulated glomeruli in slices of the main olfactory bulb in 2-3-week-old rats. We deliberately held the recorded cells at a relative hyperpolarized potential. This manipulation not only suppressed action potential generation but also excluded the possible contamination of inhibitory components in excitatory inputs. We found that in weakly activated MCs repetitive EPSP-IPSP interactions (5 Hz, 180 times) induced long-term potentiation (LTP) and long-term depression (LTD) in convergent excitatory and inhibitory inputs, respectively. Unexpectedly, these forms of plasticity depend on activity of somatic (mainly non-synaptic) NMDA receptors (NMDARs). In contrast, the same repetitive stimulation induced the LTP of excitatory inputs in strongly activated MCs (MC2) that require activity of synaptic NMDARs. These distinct forms of plasticity in the developing olfactory circuit may represent a novel rule of modification in convergent inputs that leads to decorrelation of inputs and facilitates odor discrimination.

  4. Inhibitory and Excitatory Spike-Timing-Dependent Plasticity in the Auditory Cortex

    Science.gov (United States)

    D'amour, James A.; Froemke, Robert C.

    2015-01-01

    Summary Synapses are plastic and can be modified by changes of spike timing. While most studies of long-term synaptic plasticity focus on excitation, inhibitory plasticity may be critical for controlling information processing, memory storage, and overall excitability in neural circuits. Here we examine spike-timing-dependent plasticity (STDP) of inhibitory synapses onto layer 5 neurons in slices of mouse auditory cortex, together with concomitant STDP of excitatory synapses. Pairing pre- and postsynaptic spikes potentiated inhibitory inputs irrespective of precise temporal order within ~10 msec. This was in contrast to excitatory inputs, which displayed an asymmetrical STDP time window. These combined synaptic modifications both required NMDA receptor activation, and adjusted the excitatory-inhibitory ratio of events paired together with postsynaptic spiking. Finally, subthreshold events became suprathreshold, and the time window between excitation and inhibition became more precise. These findings demonstrate that cortical inhibitory plasticity requires interactions with co-activated excitatory synapses to properly regulate excitatory-inhibitory balance. PMID:25843405

  5. Prefrontal NMDA receptors expressed in excitatory neurons control fear discrimination and fear extinction.

    Science.gov (United States)

    Vieira, Philip A; Corches, Alex; Lovelace, Jonathan W; Westbrook, Kevin B; Mendoza, Michael; Korzus, Edward

    2015-03-01

    N-methyl-D-aspartate receptors (NMDARs) are critically involved in various learning mechanisms including modulation of fear memory, brain development and brain disorders. While NMDARs mediate opposite effects on medial prefrontal cortex (mPFC) interneurons and excitatory neurons, NMDAR antagonists trigger profound cortical activation. The objectives of the present study were to determine the involvement of NMDARs expressed specifically in excitatory neurons in mPFC-dependent adaptive behaviors, specifically fear discrimination and fear extinction. To achieve this, we tested mice with locally deleted Grin1 gene encoding the obligatory NR1 subunit of the NMDAR from prefrontal CamKIIα positive neurons for their ability to distinguish frequency modulated (FM) tones in fear discrimination test. We demonstrated that NMDAR-dependent signaling in the mPFC is critical for effective fear discrimination following initial generalization of conditioned fear. While mice with deficient NMDARs in prefrontal excitatory neurons maintain normal responses to a dangerous fear-conditioned stimulus, they exhibit abnormal generalization decrement. These studies provide evidence that NMDAR-dependent neural signaling in the mPFC is a component of a neural mechanism for disambiguating the meaning of fear signals and supports discriminative fear learning by retaining proper gating information, viz. both dangerous and harmless cues. We also found that selective deletion of NMDARs from excitatory neurons in the mPFC leads to a deficit in fear extinction of auditory conditioned stimuli. These studies suggest that prefrontal NMDARs expressed in excitatory neurons are involved in adaptive behavior.

  6. Excitatory amino acid transporters: recent insights into molecular mechanisms, novel modes of modulation and new therapeutic possibilities

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Fahlke, Christoph; Bjørn-Yoshimoto, Walden Emil;

    2015-01-01

    The five excitatory amino acid transporters (EAAT1–5) mediating the synaptic uptake of the major excitatory neurotransmitter glutamate are differently expressed throughout the CNS and at the synaptic level. Although EAATs are crucial for normal excitatory neurotransmission, explorations into the ...... of EAATs and their intricate transport process, the novel approaches to pharmacological modulation of the transporters that have emerged, and interesting new perspectives in EAAT as drug targets proposed in recent years....

  7. Neural signal transduction aided by noise in multisynaptic excitatory and inhibitory pathways with saturation

    Science.gov (United States)

    Duan, Fabing; Chapeau-Blondeau, François; Abbott, Derek

    2011-08-01

    We study the stochastic resonance phenomenon in saturating dynamical models of neural signal transduction, at the synaptic stage, wherein the noise in multipathways enhances the processing of neuronal information integrated by excitatory and inhibitory synaptic currents. For an excitatory synaptic pathway, the additive intervention of an inhibitory pathway reduces the stochastic resonance effect. However, as the number of synaptic pathways increases, the signal transduction is greatly improved for parallel multipathways that feature both excitation and inhibition. The obtained results lead us to the realization that the collective property of inhibitory synapses assists neural signal transmission, and a parallel array of neurons can enhance their responses to multiple synaptic currents by adjusting the contributions of excitatory and inhibitory currents.

  8. Spatial patterning of excitatory and inhibitory neuropil territories during spinal circuit development.

    Science.gov (United States)

    Yan, Qing; Zhai, Lu; Zhang, Bo; Dallman, Julia E

    2017-05-01

    To generate rhythmic motor behaviors, both single neurons and neural circuits require a balance between excitatory inputs that trigger action potentials and inhibitory inputs that promote a stable resting potential (E/I balance). Previous studies have focused on individual neurons and have shown that, over a short spatial scale, excitatory and inhibitory (E/I) synapses tend to form structured territories with inhibitory inputs enriched on cell bodies and proximal dendrites and excitatory inputs on distal dendrites. However, systems-level E/I patterns, at spatial scales larger than single neurons, are largely uncharted. We used immunostaining for PSD-95 and gephyrin postsynaptic scaffolding proteins as proxies for excitatory and inhibitory synapses, respectively, to quantify the numbers and map the distributions of E/I synapses in zebrafish spinal cord at both an embryonic stage and a larval stage. At the embryonic stage, we found that PSD-95 puncta outnumber gephyrin puncta, with the number of gephyrin puncta increasing to match that of PSD-95 puncta at the larval stage. At both stages, PSD-95 puncta are enriched in the most lateral neuropil corresponding to distal dendrites while gephyrin puncta are enriched on neuronal somata and in the medial neuropil. Significantly, similar to synaptic puncta, neuronal processes also exhibit medial-lateral territories at both developmental stages with enrichment of glutamatergic (excitatory) processes laterally and glycinergic (inhibitory) processes medially. This establishment of neuropil excitatory-inhibitory structure largely precedes dendritic arborization of primary motor neurons, suggesting that the structured neuropil could provide a framework for the development of E/I balance at the cellular level. J. Comp. Neurol. 525:1649-1667, 2017. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  9. Bistability Analysis of Excitatory-Inhibitory Neural Networks in Limited-Sustained-Activity Regime

    Institute of Scientific and Technical Information of China (English)

    倪赟; 吴亮; 吴丹; 朱士群

    2011-01-01

    Bistable behavior of neuronal complex networks is investigated in the limited-sustained-activity regime when the network is composed of excitatory and inhibitory neurons. The standard stability analysis is performed on the two metastable states separately. Both theoretical analysis and numerical simulations show consistently that the difference between time scales of excitatory and inhibitory populations can influence the dynamical behaviors of the neuronal networks dramatically, leading to the transition from bistable behaviors with memory effects to the collapse of bistable behaviors. These results may suggest one possible neuronal information processing by only tuning time scales.

  10. Excitatory effects of Buthus C56 toxin on Drosophila larval neuromuscular junction

    Directory of Open Access Journals (Sweden)

    S. P. Gawade

    2003-01-01

    Full Text Available Buthus C56 toxin from venom of the Indian red scorpion Mesobuthus tamulus was studied for its effects on spontaneous miniature excitatory junctional potentials (MEJP on Drosophila larval neuromuscular junctions. C56 toxin was isolated on CM-Cellulose with linear gradient of ammonium acetate buffer, pH 6.0. Toxin purity was determined on SDS slab gel electrophoresis. Effective concentration of C56 toxin was based on contraction paralysis units (CPU in Drosophila 3rd instar larvae by microinjection (0.1 CPU/ml = 2 x 10-6 g/ml. The toxin-induced excitatory junctional potentials were studied for calcium dependency (0.2 mM to 1.2 mM Ca2+ in Drosophila Ringer. Excitatory junctional potential amplitude was increased with increasing calcium concentration; maximum increase in the frequency at 0.4 mM Ca2+/4 mM Mg2+ Drosophila Ringer. It was suggested that while amplitude of excitatory junctional potentials was increased with concentration, maximum frequency increase at 0.4 mMCa2+/4 mM Mg2+ Drosophila Ringer may be due to augmented Ca2+ influx in 0.4 mM Ca2+, when NMDA receptors were maximally activated in C56 toxin-treated Drosophila larval neuromuscular junction.

  11. Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons

    Science.gov (United States)

    Ripamonti, Silvia; Ambrozkiewicz, Mateusz C; Guzzi, Francesca; Gravati, Marta; Biella, Gerardo; Bormuth, Ingo; Hammer, Matthieu; Tuffy, Liam P; Sigler, Albrecht; Kawabe, Hiroshi; Nishimori, Katsuhiko; Toselli, Mauro; Brose, Nils; Parenti, Marco; Rhee, JeongSeop

    2017-01-01

    Beyond its role in parturition and lactation, oxytocin influences higher brain processes that control social behavior of mammals, and perturbed oxytocin signaling has been linked to the pathogenesis of several psychiatric disorders. However, it is still largely unknown how oxytocin exactly regulates neuronal function. We show that early, transient oxytocin exposure in vitro inhibits the development of hippocampal glutamatergic neurons, leading to reduced dendrite complexity, synapse density, and excitatory transmission, while sparing GABAergic neurons. Conversely, genetic elimination of oxytocin receptors increases the expression of protein components of excitatory synapses and excitatory synaptic transmission in vitro. In vivo, oxytocin-receptor-deficient hippocampal pyramidal neurons develop more complex dendrites, which leads to increased spine number and reduced γ-oscillations. These results indicate that oxytocin controls the development of hippocampal excitatory neurons and contributes to the maintenance of a physiological excitation/inhibition balance, whose disruption can cause neurobehavioral disturbances. DOI: http://dx.doi.org/10.7554/eLife.22466.001 PMID:28231043

  12. Imperfect space clamp permits electrotonic interactions between inhibitory and excitatory synaptic conductances, distorting voltage clamp recordings.

    Directory of Open Access Journals (Sweden)

    Alon Poleg-Polsky

    Full Text Available The voltage clamp technique is frequently used to examine the strength and composition of synaptic input to neurons. Even accounting for imperfect voltage control of the entire cell membrane ("space clamp", it is often assumed that currents measured at the soma are a proportional indicator of the postsynaptic conductance. Here, using NEURON simulation software to model somatic recordings from morphologically realistic neurons, we show that excitatory conductances recorded in voltage clamp mode are distorted significantly by neighboring inhibitory conductances, even when the postsynaptic membrane potential starts at the reversal potential of the inhibitory conductance. Analogous effects are observed when inhibitory postsynaptic currents are recorded at the reversal potential of the excitatory conductance. Escape potentials in poorly clamped dendrites reduce the amplitude of excitatory or inhibitory postsynaptic currents recorded at the reversal potential of the other conductance. In addition, unclamped postsynaptic inhibitory conductances linearize the recorded current-voltage relationship of excitatory inputs comprising AMPAR and NMDAR-mediated components, leading to significant underestimation of the relative contribution by NMDARs, which are particularly sensitive to small perturbations in membrane potential. Voltage clamp accuracy varies substantially between neurons and dendritic arbors of different morphology; as expected, more reliable recordings are obtained from dendrites near the soma, but up to 80% of the synaptic signal on thin, distant dendrites may be lost when postsynaptic interactions are present. These limitations of the voltage clamp technique may explain how postsynaptic effects on synaptic transmission could, in some cases, be attributed incorrectly to presynaptic mechanisms.

  13. Excitatory amino acid receptors in the ventral tegmental area regulate dopamine release in the ventral striatum

    NARCIS (Netherlands)

    Karreman, M; Westerink, BHC; Moghaddam, B

    1996-01-01

    The role of excitatory amino acid (EAA) receptors located in the ventral tegmental area (VTA) in tonic and phasic regulation of dopamine release in the ventral striatum was investigated. Microdialysis in conscious rats was used to assess dopamine release primarily from the nucleus accumbens shell re

  14. Retinal Physiology: Non-Bipolar-Cell Excitatory Drive in the Inner Retina.

    Science.gov (United States)

    Baden, Tom; Euler, Thomas

    2016-08-01

    The long-held view that bipolar cells provide the exclusive excitatory drive to the mammalian inner retina has been challenged: new studies indicate that, instead, at least two cells that lack the dendrites characteristic for bipolar cells, and therefore resemble amacrine cells, excite inner retinal circuits using glutamate.

  15. Neuronal pentraxin 1 negatively regulates excitatory synapse density and synaptic plasticity.

    Science.gov (United States)

    Figueiro-Silva, Joana; Gruart, Agnès; Clayton, Kevin Bernard; Podlesniy, Petar; Abad, Maria Alba; Gasull, Xavier; Delgado-García, José María; Trullas, Ramon

    2015-04-08

    In mature neurons, the number of synapses is determined by a neuronal activity-dependent dynamic equilibrium between positive and negative regulatory factors. We hypothesized that neuronal pentraxin (NP1), a proapoptotic protein induced by low neuronal activity, could be a negative regulator of synapse density because it is found in dystrophic neurites in Alzheimer's disease-affected brains. Here, we report that knockdown of NP1 increases the number of excitatory synapses and neuronal excitability in cultured rat cortical neurons and enhances excitatory drive and long-term potentiation in the hippocampus of behaving mice. Moreover, we found that NP1 regulates the surface expression of the Kv7.2 subunit of the Kv7 family of potassium channels that control neuronal excitability. Furthermore, pharmacological activation of Kv7 channels prevents, whereas inhibition mimics, the increase in synaptic proteins evoked by the knockdown of NP1. These results indicate that NP1 negatively regulates excitatory synapse number by modulating neuronal excitability and show that NP1 restricts excitatory synaptic plasticity. Copyright © 2015 the authors 0270-6474/15/355504-18$15.00/0.

  16. Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons.

    Science.gov (United States)

    Mao, Wenjie; Watanabe, Takuya; Cho, Sukhee; Frost, Jeffrey L; Truong, Tina; Zhao, Xiaohu; Futai, Kensuke

    2015-04-01

    The Shank genes (SHANK1, 2, 3) encode scaffold proteins highly enriched in postsynaptic densities where they regulate synaptic structure in spiny neurons. Mutations in human Shank genes are linked to autism spectrum disorder and schizophrenia. Shank1 mutant mice exhibit intriguing cognitive phenotypes reminiscent of individuals with autism spectrum disorder. However, the molecular mechanisms leading to the human pathophysiological phenotypes and mouse behaviors have not been elucidated. In this study it is shown that Shank1 protein is highly localized in parvalbumin-expressing (PV+) fast-spiking inhibitory interneurons in the hippocampus. Importantly, a lack of Shank1 in hippocampal CA1 PV+ neurons reduced excitatory synaptic inputs and inhibitory synaptic outputs to pyramidal neurons. Furthermore, it is demonstrated that hippocampal CA1 pyramidal neurons in Shank1 mutant mice exhibit a shift in the excitatory and inhibitory balance (E-I balance), a pathophysiological hallmark of autism spectrum disorder. The mutant mice also exhibit lower expression of gephyrin (a scaffold component of inhibitory synapses), supporting the dysregulation of E-I balance in the hippocampus. These results suggest that Shank1 scaffold in PV+ interneurons regulates excitatory synaptic strength and participates in the maintenance of E-I balance in excitatory neurons.

  17. Morphology and physiology of excitatory neurons in layer 6b of the somatosensory rat barrel cortex.

    Science.gov (United States)

    Marx, Manuel; Feldmeyer, Dirk

    2013-12-01

    Neocortical lamina 6B (L6B) is a largely unexplored layer with a very heterogeneous cellular composition. To date, only little is known about L6B neurons on a systematic and quantitative basis. We investigated the morphological and electrophysiological properties of excitatory L6B neurons in the rat somatosensory barrel cortex using whole-cell patch-clamp recordings and simultaneous biocytin fillings. Subsequent histological processing and computer-assisted 3D reconstructions provided the basis for a classification of excitatory L6B neurons according to their structural and functional characteristics. Three distinct clusters of excitatory L6B neurons were identified: (C1) pyramidal neurons with an apical dendrite pointing towards the pial surface, (C2) neurons with a prominent, "apical"-like dendrite not oriented towards the pia, and (C3) multipolar spiny neurons without any preferential dendritic orientation. The second group could be further subdivided into three categories termed inverted, "tangentially" oriented and "horizontally" oriented neurons. Furthermore, based on the axonal domain two subcategories of L6B pyramidal cells were identified that had either a more barrel-column confined or an extended axonal field. The classification of excitatory L6B neurons provided here may serve as a basis for future studies on the structure, function, and synaptic connectivity of L6B neurons.

  18. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures

    Science.gov (United States)

    Zhang, Wen; Peterson, Matthew; Beyer, Barbara; Frankel, Wayne N.

    2014-01-01

    Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability. PMID:24523563

  19. Cholinergic modulation of excitatory synaptic input integration in hippocampal CA1.

    Science.gov (United States)

    McQuiston, A Rory

    2010-10-01

    During theta rhythm, the timing of inputs to hippocampal CA1 from the perforant path (PP) of the entorhinal cortex and the Schaffer collaterals (SCs) from individual CA3 pyramidal neurons can vary within an individual theta period. Importantly, during theta rhythms these interactions occur during elevated acetylcholine concentrations. Thus, I examined the effect that PP inputs have on SC inputs in hippocampal CA1 during cholinergic receptor activation. To do this I measured the impact that a single electrical stimulus of the stratum lacunosum-moleculare (SLM, which contains the PP) had on excitation evoked by stimulation of the stratum radiatum (SR, which contains the SC) using voltage-sensitive dye imaging, field excitatory postsynaptic potentials and whole cell patch clamping in rat hippocampal brain slices. My data showed that SLM stimulation one half a theta cycle or less (25-75 ms) before SR stimulation resulted in the summation of excitatory events in SR and SP of hippocampal CA1. The summation was unaffected by cholinergic receptor activation by carbachol. SLM stimulation one theta cycle (150-225 ms) preceding SR stimulation significantly suppressed excitatory events measured in SR and SP. This SLM stimulus inhibition of SR-driven excitatory events was augmented by carbachol application. The carbachol effect was blocked by atropine and SLM-driven suppression of excitatory events was blocked by the GABA(B) receptor antagonist CGP 54626. SR field EPSP slopes were unaffected by SLM prepulses. Carbachol increased the probability of SR input to drive action potential firing in CA1 pyramidal neurons, which was inhibited by SLM prepulses (150-225 ms). Together these data provide important information regarding the integration of inputs in hippocampal CA1 during theta rhythms. More specifically, SR inputs can be differentially gated by SLM feedforward inhibition at varying temporal intervals within a theta cycle.

  20. Do personality traits predict individual differences in excitatory and inhibitory learning?

    Directory of Open Access Journals (Sweden)

    Zhimin eHe

    2013-05-01

    Full Text Available Conditioned inhibition (CI is demonstrated in classical conditioning when a stimulus is used to signal the omission of an otherwise expected outcome. This basic learning ability is involved in a wide range of normal behaviour - and thus its disruption could produce a correspondingly wide range of behavioural deficits. The present study employed a computer-based task to measure conditioned excitation and inhibition in the same discrimination procedure. Conditioned inhibition by summation test was clearly demonstrated. Additionally summary measures of excitatory and inhibitory learning (difference scores were calculated in order to explore how performance related to individual differences in a large sample of normal participants (n=176 following exclusion of those not meeting the basic learning criterion. The individual difference measures selected derive from two biologically-based personality theories, Gray’s reinforcement sensitivity theory (1982 and Eysenck’s psychoticism, extraversion and neuroticism theory (1991. Following the behavioural tasks, participants completed the behavioural inhibition system/behavioural activation system scales (BIS/BAS and the Eysenck personality questionnaire revised short scale (EPQ-RS. Analyses of the relationship between scores on each of the scales and summary measures of excitatory and inhibitory learning suggested that those with higher BAS (specifically the drive sub-scale and higher EPQ-RS neuroticism showed reduced levels of excitatory conditioning. Inhibitory conditioning was similarly attenuated in those with higher EPQ-RS neuroticism, as well as in those with higher BIS scores. Thus the findings are consistent with higher levels of neuroticism being accompanied by generally impaired associative learning, both inhibitory and excitatory. There was also evidence for some dissociation in the effects of behavioural activation and behavioural inhibition on excitatory and inhibitory learning respectively.

  1. Do personality traits predict individual differences in excitatory and inhibitory learning?

    Science.gov (United States)

    He, Zhimin; Cassaday, Helen J; Bonardi, Charlotte; Bibby, Peter A

    2013-01-01

    Conditioned inhibition (CI) is demonstrated in classical conditioning when a stimulus is used to signal the omission of an otherwise expected outcome. This basic learning ability is involved in a wide range of normal behavior - and thus its disruption could produce a correspondingly wide range of behavioral deficits. The present study employed a computer-based task to measure conditioned excitation and inhibition in the same discrimination procedure. CI by summation test was clearly demonstrated. Additionally summary measures of excitatory and inhibitory learning (difference scores) were calculated in order to explore how performance related to individual differences in a large sample of normal participants (n = 176 following exclusion of those not meeting the basic learning criterion). The individual difference measures selected derive from two biologically based personality theories, Gray's (1982) reinforcement sensitivity theory and Eysenck and Eysenck (1991) psychoticism, extraversion, and neuroticism theory. Following the behavioral tasks, participants completed the behavioral inhibition system/behavioral activation system (BIS/BAS) scales and the Eysenck personality questionnaire revised short scale (EPQ-RS). Analyses of the relationship between scores on each of the scales and summary measures of excitatory and inhibitory learning suggested that those with higher BAS (specifically the drive sub-scale) and higher EPQ-RS neuroticism showed reduced levels of excitatory conditioning. Inhibitory conditioning was similarly attenuated in those with higher EPQ-RS neuroticism, as well as in those with higher BIS scores. Thus the findings are consistent with higher levels of neuroticism being accompanied by generally impaired associative learning, both inhibitory and excitatory. There was also evidence for some dissociation in the effects of behavioral activation and behavioral inhibition on excitatory and inhibitory learning respectively.

  2. Trophic factor-induced excitatory synaptogenesis involves postsynaptic modulation of nicotinic acetylcholine receptors.

    Science.gov (United States)

    Woodin, Melanie A; Munno, David W; Syed, Naweed I

    2002-01-15

    Neurotrophic factors have well established roles in neuronal development, although their precise involvement in synapse formation and plasticity is yet to be fully determined. Using soma-soma synapses between identified Lymnaea neurons, we have shown recently that trophic factors are required for excitatory but not inhibitory synapse formation. However, neither the precise site (presynaptic versus postsynaptic cell) nor the underlying mechanisms have yet been defined. In the present study, synapse formation between the presynaptic cell visceral dorsal 4 (VD4) and its postsynaptic partner right pedal dorsal 1 (RPeD1) was examined to define the cellular mechanisms mediating trophic factor-induced excitatory synaptogenesis in cell culture. When paired in a soma-soma configuration in the presence of defined media (DM, nonproteinacious), mutually inhibitory synapses were appropriately reconstructed between VD4 and RPeD1. However, when cells were paired in the presence of increasing concentrations of Lymnaea brain-conditioned medium (CM), a biphasic synapse (initial excitatory synaptic component followed by inhibition) developed. The CM-induced excitatory synapse formation required trophic factor-mediated activation of receptor tyrosine kinases in the postsynaptic cell, RPeD1, and a concomitant modulation of existing postsynaptic nicotinic acetylcholine receptors (nAChRs). Specifically, when RPeD1 was isolated in DM, exogenously applied ACh induced a hyperpolarizing response that was sensitive to the AChR antagonist methyllycaconitine (MLA). In contrast, a single RPeD1 isolated in CM exhibited a biphasic response to exogenously applied ACh. The initial depolarizing phase of the biphasic response was sensitive to both mecamylamine and hexamethonium chloride, whereas the hyperpolarizing phase was blocked by MLA. In soma-soma-paired neurons, the VD4-induced synaptic responses in RPeD1 were sensitive to the cholinergic antagonists in a concentration range similar to that

  3. Selective Maturation of Temporal Dynamics of Intracortical Excitatory Transmission at the Critical Period Onset.

    Science.gov (United States)

    Miao, Qinglong; Yao, Li; Rasch, Malte J; Ye, Qian; Li, Xiang; Zhang, Xiaohui

    2016-08-01

    Although the developmental maturation of cortical inhibitory synapses is known to be a critical factor in gating the onset of critical period (CP) for experience-dependent cortical plasticity, how synaptic transmission dynamics of other cortical synapses are regulated during the transition to CP remains unknown. Here, by systematically examining various intracortical synapses within layer 4 of the mouse visual cortex, we demonstrate that synaptic temporal dynamics of intracortical excitatory synapses on principal cells (PCs) and inhibitory parvalbumin- or somatostatin-expressing cells are selectively regulated before the CP onset, whereas those of intracortical inhibitory synapses and long-range thalamocortical excitatory synapses remain unchanged. This selective maturation of synaptic dynamics results from a ubiquitous reduction of presynaptic release and is dependent on visual experience. These findings provide an additional essential circuit mechanism for regulating CP timing in the developing visual cortex.

  4. Selective Maturation of Temporal Dynamics of Intracortical Excitatory Transmission at the Critical Period Onset

    Directory of Open Access Journals (Sweden)

    Qinglong Miao

    2016-08-01

    Full Text Available Although the developmental maturation of cortical inhibitory synapses is known to be a critical factor in gating the onset of critical period (CP for experience-dependent cortical plasticity, how synaptic transmission dynamics of other cortical synapses are regulated during the transition to CP remains unknown. Here, by systematically examining various intracortical synapses within layer 4 of the mouse visual cortex, we demonstrate that synaptic temporal dynamics of intracortical excitatory synapses on principal cells (PCs and inhibitory parvalbumin- or somatostatin-expressing cells are selectively regulated before the CP onset, whereas those of intracortical inhibitory synapses and long-range thalamocortical excitatory synapses remain unchanged. This selective maturation of synaptic dynamics results from a ubiquitous reduction of presynaptic release and is dependent on visual experience. These findings provide an additional essential circuit mechanism for regulating CP timing in the developing visual cortex.

  5. Specification of excitatory neurons in the developing cerebral cortex: progenitor diversity and and environmental influences

    Directory of Open Access Journals (Sweden)

    Marcos R Costa

    2015-01-01

    Full Text Available The mature cerebral cortex harbors a heterogeneous population of glutamatergic neurons, organized into a highly intricate histological architecture. Classically, this mixed population of neurons was thought to be generated sequentially from a seemingly homogenous group of progenitors under the influence of external cues. This view, however, has been challenged in the last decade by evidences pointing to the existence of fate-restricted neuronal progenitors in the developing neocortex. Here, we review classical studies using cell transplantation, retroviral labeling and cell culture, as well as new data from genetic fate-mapping analysis, to discuss the lineage relationships between neocortical progenitors and subclasses of excitatory neurons. We also propose a temporal model to conciliate the existence of fate-restricted progenitors alongside multipotent progenitors in the neocortex. Finally, we discuss evidences for a critical period of plasticity among post mitotic excitatory cortical neurons when environmental influences could change neuronal cell fate.

  6. Selective localization of Shanks to VGLUT1-positive excitatory synapses in the mouse hippocampus

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    Christopher eHeise

    2016-04-01

    Full Text Available AbstractMembers of the Shank family of multidomain proteins (Shank1, Shank2, and Shank3 are core components of the postsynaptic density (PSD of excitatory synapses. At synaptic sites Shanks serve as scaffolding molecules that cluster neurotransmitter receptors as well as cell adhesion molecules attaching them to the actin cytoskeleton. In this study we investigated the synapse specific localization of Shank1-3 and focused on well-defined synaptic contacts within the hippocampal formation. We found that all three family members are present only at VGLUT1-positive synapses, which is particularly visible at mossy fiber contacts. No costaining was found at VGLUT2-positive contacts indicating that the molecular organization of VGLUT2-associated PSDs diverges from classical VGLUT1-positive excitatory contacts in the hippocampus. In light of SHANK mutations in neuropsychiatric disorders, this study indicates which glutamatergic networks within the hippocampus will be primarily affected by shankopathies.

  7. Electrical stimulation of dog pudendal nerve regulates the excitatory pudendal-to-bladder reflex

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    Yan-he Ju

    2016-01-01

    Full Text Available Pudendal nerve plays an important role in urine storage and voiding. Our hypothesis is that a neuroprosthetic device placed in the pudendal nerve trunk can modulate bladder function after suprasacral spinal cord injury. We had confirmed the inhibitory pudendal-to-bladder reflex by stimulating either the branch or the trunk of the pudendal nerve. This study explored the excitatory pudendal-to-bladder reflex in beagle dogs, with intact or injured spinal cord, by electrical stimulation of the pudendal nerve trunk. The optimal stimulation frequency was approximately 15-25 Hz. This excitatory effect was dependent to some extent on the bladder volume. We conclude that stimulation of the pudendal nerve trunk is a promising method to modulate bladder function.

  8. Electrical stimulation of dog pudendal nerve regulates the excitatory pudendal-to-bladder reflex.

    Science.gov (United States)

    Ju, Yan-He; Liao, Li-Min

    2016-04-01

    Pudendal nerve plays an important role in urine storage and voiding. Our hypothesis is that a neuroprosthetic device placed in the pudendal nerve trunk can modulate bladder function after suprasacral spinal cord injury. We had confirmed the inhibitory pudendal-to-bladder reflex by stimulating either the branch or the trunk of the pudendal nerve. This study explored the excitatory pudendal-to-bladder reflex in beagle dogs, with intact or injured spinal cord, by electrical stimulation of the pudendal nerve trunk. The optimal stimulation frequency was approximately 15-25 Hz. This excitatory effect was dependent to some extent on the bladder volume. We conclude that stimulation of the pudendal nerve trunk is a promising method to modulate bladder function.

  9. Excitatory effect of histamine on neuronal activity of rat cerebellar fastigial nucleus in vitro

    Institute of Scientific and Technical Information of China (English)

    TANG Biao; ZHANG Jun; LI HongZhao; ZHU JingNing; WANG JianJun

    2007-01-01

    The cerebellar fastigial nucleus (FN) holds an important role in motor control and body balance. Previous studies have revealed that the nucleus is innervated by direct hypothalamocerebellar histaminergic fibers. However, the functional role of histaminergic projection in cerebellar FN has never been established. In this study, we investigated the effect of histamine on neuronal firing of cerebellar FN by using slice preparations. Sixty-five FN cells were recorded from 47 cerebellar slices, and a vast majority of the cells responded to histamine stimulation with an excitatory response (58/65, 89.2%). Perfusing slices with low-Ca2+/high-Mg2+ medium did not block the histamine-induced excitation (n=10), supporting a direct postsynaptic action of histamine on the cells. Furthermore, the excitatory effect of histamine on FN neurons was not blocked by selective histamine H1 receptor antagonist triprolidine (n=15) or chlorpheniramine (n=10), but was effectively suppressed by ranitidine (n=15), a highly selective histamine H2 receptor antagonist. On the other hand, highly selective histamine H2 receptor agonist dimaprit (n=20) instead of histamine H1 receptor agonist 2-pyridylethylamine (n=16) mimicked the excitatory effect of histamine on FN neurons. The dimaprit-induced FN neuronal excitation was effectively antagonized by selective histamine H2 receptor antagonist ranitidine (n=13) but not influenced by selective histamine H1 receptor antagonist triprolidine (n=15). These results demonstrate that histamine excites cerebellar FN cells via the histamine H2 receptor mechanism and suggest that the hypothalamocerebellar histaminergic fibers may modulate cerebellar FN-mediated sensorimotor integration through their excitatory innervations on FN neurons.

  10. Mechanism of the differentiation of neural responses to excitatory input signals

    Science.gov (United States)

    Zakharov, D. G.; Kuznetsov, A. S.

    2012-08-01

    A dynamical mechanism of the generation of qualitatively different neural responses to typical excitatory stimuli such as an applied current or AMPA and NMDA synaptic currents has been presented. The mechanism is based on a nonlinearity simulating the calcium-dependent potassium current. It has been shown with the FitzHugh-Nagumo equation that, in the presence of such a nonlinearity, only the NMDA synaptic current can strongly increase the frequency of self-sustained oscillations, whereas other stimuli suppress neural activity.

  11. The Relative Contribution of NMDARs to Excitatory Postsynaptic Currents is Controlled by Ca2+-Induced Inactivation

    OpenAIRE

    Fliza eValiullina; Yulia eZakharova; Andreas eDraguhn; Marat eMukhtarov; Nail eBurnashev; Andrei eRozov

    2016-01-01

    NMDA receptors (NMDARs) are important mediators of excitatory synaptic transmission and plasticity. A hallmark of these channels is their high permeability to Ca2+. At the same time, they are themselves inhibited by the elevation of intracellular Ca2+ concentration. It is unclear however, whether the Ca2+ entry associated with single NMDAR mediated synaptic events is sufficient to self-inhibit their activation. Such auto-regulation would have important effects on the dynamics of synaptic exci...

  12. Immature Hippocampal Neuronal Networks do not Develop Tolerance to the Excitatory Actions of Ethanol

    OpenAIRE

    Galindo, Rafael; Valenzuela, C. Fernando

    2006-01-01

    EtOH (ethanol) damages the hippocampus, a brain region that is involved in learning and memory processes. The mechanisms responsible for this effect of EtOH are not fully understood. We recently demonstrated that acute EtOH exposure potently stimulates oscillatory activity driven by the excitatory actions of GABA in the CA3 region of the neonatal rat hippocampus. This activity can be recorded during the growth spurt period as giant depolarizing potentials (GDPs). Here, we characterized the ef...

  13. Inositol hexakisphosphate suppresses excitatory neurotransmission via synaptotagmin-1 C2B domain in the hippocampal neuron

    Science.gov (United States)

    Yang, Shao-Nian; Shi, Yue; Yang, Guang; Li, Yuxin; Yu, Lina; Shin, Ok-Ho; Bacaj, Taulant; Südhof, Thomas C.; Yu, Jia; Berggren, Per-Olof

    2012-01-01

    Inositol hexakisphosphate (InsP6) levels rise and fall with neuronal excitation and silence, respectively, in the hippocampus, suggesting potential signaling functions of this inositol polyphosphate in hippocampal neurons. We now demonstrate that intracellular application of InsP6 caused a concentration-dependent inhibition of autaptic excitatory postsynaptic currents (EPSCs) in cultured hippocampal neurons. The treatment did not alter the size and replenishment rate of the readily releasable pool in autaptic neurons. Intracellular exposure to InsP6 did not affect spontaneous EPSCs or excitatory amino acid-activated currents in neurons lacking autapses. The InsP6-induced inhibition of autaptic EPSCs was effectively abolished by coapplication of an antibody to synaptotagmin-1 C2B domain. Importantly, preabsorption of the antibody with a GST-WT synaptotagmin-1 C2B domain fragment but not with a GST-mutant synaptotagmin-1 C2B domain fragment that poorly reacted with the antibody impaired the activity of the antibody on the InsP6-induced inhibition of autaptic EPSCs. Furthermore, K+ depolarization significantly elevated endogenous levels of InsP6 and occluded the inhibition of autaptic EPSCs by exogenous InsP6. These data reveal that InsP6 suppresses excitatory neurotransmission via inhibition of the presynaptic synaptotagmin-1 C2B domain-mediated fusion via an interaction with the synaptotagmin Ca2+-binding sites rather than via interference with presynaptic Ca2+ levels, synaptic vesicle trafficking, or inactivation of postsynaptic ionotropic glutamate receptors. Therefore, elevated InsP6 in activated neurons serves as a unique negative feedback signal to control hippocampal excitatory neurotransmission. PMID:22778403

  14. Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin

    OpenAIRE

    Shabel, Steven J.; Proulx, Christophe D.; Trias, Anthony; Murphy, Ryan T.; Malinow, Roberto

    2012-01-01

    The lateral habenula (LHb) has recently been identified as a key regulator of the reward system by driving inhibition onto dopaminergic neurons. However, the nature and potential modulation of the major input to the LHb originating from the basal ganglia are poorly understood. Although the output of the basal ganglia is thought to be primarily inhibitory, here we show that transmission from the basal ganglia to the LHb is excitatory, glutamatergic and suppressed by serotonin. Behaviorally, ac...

  15. Some relationships between personality, arousal and the strength of the excitatory process

    OpenAIRE

    Gupta, Sunjai

    1981-01-01

    The primary object of the present investigation was to test the inverted 'U' model developed by investigators of 'arousal' in the west and of the 'strength of the excitatory process' in the Soviet Union to explain the relationship between a variety of factors and measures of behavioural, subjective and physiological response. In the present project adult human subjects took part in four experiments. The following factors were investigated in one or more of them: introversion, neuroticism, 'st...

  16. Complexins facilitate neurotransmitter release at excitatory and inhibitory synapses in mammalian central nervous system.

    Science.gov (United States)

    Xue, Mingshan; Stradomska, Alicja; Chen, Hongmei; Brose, Nils; Zhang, Weiqi; Rosenmund, Christian; Reim, Kerstin

    2008-06-03

    Complexins (Cplxs) are key regulators of synaptic exocytosis, but whether they act as facilitators or inhibitors is currently being disputed controversially. We show that genetic deletion of all Cplxs expressed in the mouse brain causes a reduction in Ca(2+)-triggered and spontaneous neurotransmitter release at both excitatory and inhibitory synapses. Our results demonstrate that at mammalian central nervous system synapses, Cplxs facilitate neurotransmitter release and do not simply act as inhibitory clamps of the synaptic vesicle fusion machinery.

  17. Muscarinic excitatory and inhibitory mechanisms involved in afferent fibre-evoked depolarization of motoneurones in the neonatal rat spinal cord.

    Science.gov (United States)

    Kurihara, T.; Suzuki, H.; Yanagisawa, M.; Yoshioka, K.

    1993-01-01

    1. The involvement of acetylcholine and muscarinic receptors in spinal synaptic responses evoked by electrical and noxious sensory stimuli was investigated in the neonatal rat spinal cord in vitro. 2. Potentials were recorded extracellularly from a ventral root (L3-L5) of the isolated spinal cord, spinal cord-cutaneous nerve, and spinal cord-skin preparations of 1- to 4-day-old rats. Spinal reflexes were elicited by electrical stimulation of the ipsilateral dorsal root or the cutaneous saphenous nerve, or by noxious skin stimulation. 3. Single shock stimulation of supramaximum intensity of a dorsal root induced a mono-synaptic reflex in the corresponding ventral root. Bath-application of the muscarinic agonists, muscarine (0.3-30 microM) and (+)-cis-dioxolane (0.1-100 microM), produced an inhibition of the mono-synaptic reflex and a depolarization of motoneurones. Other muscarinic agonists, arecoline (10 nM-10 microM) and oxotremorine (10 nM-1 microM), inhibited the mono-synaptic reflex with little or no depolarization of motoneurones. Repetitive stimulation of the saphenous nerve at C-fibre strength induced a slow depolarizing response lasting about 30 s of the L3 ventral root. This slow ventral root potential (VRP) was also inhibited by arecoline (10 nM-10 microM) and oxotremorine (10 nM-1 microM). 4. In the spinal cord-saphenous nerve-skin preparation, a slow VRP was evoked by application of capsaicin (0.5 microM), bradykinin (3 microM), or noxious heat (47 degrees C) to skin. This slow VRP was depressed by the muscarinic agonists, arecoline (3 microM) and oxotremorine (1 microM). 5. Of the (+)-cis-dioxolane-induced inhibition of mono-synaptic reflex and motoneurone depolarization, the M2 antagonists, AF-DX 116 (0.1-1 microM) and methoctramine (100-300 nM), preferentially blocked the former response, whereas the M3 antagonists, 4-DAMP (3-10 nM) and p-F-HHSiD (0.3-3 microM), preferentially blocked the latter response. AF-DX 116 (0.1-1 microM) and methoctramine

  18. The amygdala excitatory/inhibitory balance in a valproate-induced rat autism model.

    Directory of Open Access Journals (Sweden)

    Hui-Ching Lin

    Full Text Available The amygdala is an important structure contributing to socio-emotional behavior. However, the role of the amygdala in autism remains inconclusive. In this study, we used the 28-35 days valproate (VPA-induced rat model of autism to observe the autistic phenotypes and evaluate their synaptic characteristics in the lateral nucleus (LA of the amygdala. The VPA-treated offspring demonstrated less social interaction, increased anxiety, enhanced fear learning and impaired fear memory extinction. Slice preparation and electrophysiological recordings of the amygdala showed significantly enhanced long-term potentiation (LTP while stimulating the thalamic-amygdala pathway of the LA. In addition, the pair pulse facilitation (PPF at 30- and 60-ms intervals decreased significantly. Whole-cell recordings of the LA pyramidal neurons showed an increased miniature excitatory postsynaptic current (EPSC frequency and amplitude. The relative contributions of the AMPA receptor and NMDA receptor to the EPSCs did not differ significantly between groups. These results suggested that the enhancement of the presynaptic efficiency of excitatory synaptic transmission might be associated with hyperexcitibility and enhanced LTP in LA pyramidal neurons. Disruption of the synaptic excitatory/inhibitory (E/I balance in the LA of VPA-treated rats might play certain roles in the development of behaviors in the rat that may be relevant to autism. Further experiments to demonstrate the direct link are warranted.

  19. Oscillatory Dynamics and Oscillation Death in Complex Networks Consisting of Both Excitatory and Inhibitory Nodes

    Institute of Scientific and Technical Information of China (English)

    张立升; 廖旭红; 弭元元; 谷伟风; 胡岗

    2012-01-01

    Zn neural networks, both excitatory and inhibitory cells play important roles in determining the functions of systems. Various dynamical networks have been proposed as artificial neural networks to study the properties of biological systems where the influences of excitatory nodes have been extensively investigated while those of inhibitory nodes have been studied much less. In this paper, we consider a model of oscillatory networks of excitable Boolean maps consisting of both excitatory and inhibitory nodes, focusing on the roles of inhibitory nodes. We find that inhibitory nodes in sparse networks (smM1 average connection degree) play decisive roles in weakening oscillations, and oscillation death occurs after continual weakening of oscillation for sufficiently high inhibitory node density. In the sharp contrast, increasing inhibitory nodes in dense networks may result in the increase of oscillation amplitude and sudden oscillation death at much lower inhibitory node density and the nearly highest excitation activities. Mechanism under these peculiar behaviors of dense networks is explained by the competition of the duplex effects of inhibitory nodes.

  20. GABA is the principal fast-acting excitatory transmitter in the neonatal brain.

    Science.gov (United States)

    Leinekugel, X; Khalilov, I; McLean, H; Caillard, O; Gaiarsa, J L; Ben-Ari, Y; Khazipov, R

    1999-01-01

    gamma-aminobutyric acid (GABA) is the principal neurotransmitter of inhibition in the adult mammalian brain. However, at early stages of development, including the embryonic period and first week of postnatal life, GABA plays the role of main neurotransmitter of excitation. The paradoxical excitatory effect of GABA is caused by an inverted chloride gradient and, therefore, a depolarizing direction of GABA type A (GABAA) receptor mediated responses. In addition, another type of GABAergic inhibition mediated by postsynaptic GABA type B (GABAB) receptors is not functional at early stage of life. In the neonatal rat hippocampus, GABA, acting via GABAA receptors, activates voltage-gated sodium and calcium channels and potentiates the activity of N-methyl-D-aspartate (NMDA) receptors by reducing their voltage-dependent Mg2+ block. The temporal window when GABA exerts excitatory actions coincides with a particular pattern of activity of hippocampal neuronal network that is characterized by periodical giant depolarizing potentials (GDPs) reminiscent of interictal-like epileptiform discharges. Recent studies have shown that GDPs result from the synchronous discharge of GABAergic interneurons and principal glutamatergic pyramidal cells, and they are mediated by the synergistic excitatory actions of GABAA and glutamate receptors. GDPs provide synchronous intracellular Ca2+ oscillations and may, therefore, be implicated in hebbian modulation of developing synapses and activity-dependent formation of the hippocampal network.

  1. Distinct Spatiotemporal Response Properties of Excitatory Versus Inhibitory Neurons in the Mouse Auditory Cortex

    Science.gov (United States)

    Maor, Ido; Shalev, Amos; Mizrahi, Adi

    2016-01-01

    In the auditory system, early neural stations such as brain stem are characterized by strict tonotopy, which is used to deconstruct sounds to their basic frequencies. But higher along the auditory hierarchy, as early as primary auditory cortex (A1), tonotopy starts breaking down at local circuits. Here, we studied the response properties of both excitatory and inhibitory neurons in the auditory cortex of anesthetized mice. We used in vivo two photon-targeted cell-attached recordings from identified parvalbumin-positive neurons (PVNs) and their excitatory pyramidal neighbors (PyrNs). We show that PyrNs are locally heterogeneous as characterized by diverse best frequencies, pairwise signal correlations, and response timing. In marked contrast, neighboring PVNs exhibited homogenous response properties in pairwise signal correlations and temporal responses. The distinct physiological microarchitecture of different cell types is maintained qualitatively in response to natural sounds. Excitatory heterogeneity and inhibitory homogeneity within the same circuit suggest different roles for each population in coding natural stimuli. PMID:27600839

  2. Inhibitory effects of propofol on excitatory synaptic transmission in supraoptic nucleus neurons in vitro.

    Science.gov (United States)

    Zhang, Huan-Huan; Zheng, Chao; Wang, Bang-An; Wang, Meng-Ya

    2015-12-25

    The present study was designed to investigate the inhibitory effects of intravenous general anesthetic propofol (0.1-3.0 mmol/L) on excitatory synaptic transmission in supraoptic nucleus (SON) neurons of rats, and to explore the underlying mechanisms by using intracellular recording technique and hypothalamic slice preparation. It was observed that stimulation of the dorsolateral region of SON could elicit the postsynaptic potentials (PSPs) in SON neurons. Of the 8 tested SON neurons, the PSPs of 7 (88%, 7/8) neurons were decreased by propofol in a concentration-dependent manner, in terms of the PSPs' amplitude (P EPSPs) of 7 cells increased in the condition of picrotoxin (30 µmol/L, a GABA(A) receptor antagonist) pretreatment. On this basis, the inhibitory effects of propofol on EPSPs were decreased. These data indicate that the presynaptic and postsynaptic mechanisms may be both involved in the inhibitory effects of propofol on excitatory synaptic transmission in SON neurons. The inhibitory effects of propofol on excitatory synaptic transmission of SON neurons may be related to the activation of GABA(A) receptors, but at a high concentration, propofol may also act directly on glutamate receptors.

  3. Enhanced quantal release of excitatory transmitter in anterior cingulate cortex of adult mice with chronic pain

    Directory of Open Access Journals (Sweden)

    Zhao Ming-Gao

    2009-01-01

    Full Text Available Abstract The anterior cingulate cortex (ACC is a forebrain structure that plays important roles in emotion, learning, memory and persistent pain. Our previous studies have demonstrated that the enhancement of excitatory synaptic transmission was induced by peripheral inflammation and nerve injury in ACC synapses. However, little information is available on their presynaptic mechanisms, since the source of the enhanced synaptic transmission could include the enhanced probability of neurotransmitter release at existing release sites and/or increases in the number of available vesicles. The present study aims to perform quantal analysis of excitatory synapses in the ACC with chronic pain to examine the source of these increases. The quantal analysis revealed that both probability of transmitter release and number of available vesicles were increased in a mouse model of peripheral inflammation, whereas only probability of transmitter release but not number of available vesicles was enhanced in a mouse model of neuropathic pain. In addition, we compared the miniature excitatory postsynaptic potentials (mEPSCs in ACC synapses with those in other pain-related brain areas such as the amygdala and spinal cord. Interestingly, the rate and amplitude of mEPSCs in ACC synapses were significantly lower than those in the amygdala and spinal cord. Our studies provide strong evidences that chronic inflammatory pain increases both probability of transmitter release and number of available vesicles, whereas neuropathic pain increases only probability of transmitter release in the ACC synapses.

  4. Cannabinoid CB1 receptor signaling dichotomously modulates inhibitory and excitatory synaptic transmission in rat inner retina.

    Science.gov (United States)

    Wang, Xiao-Han; Wu, Yi; Yang, Xiao-Fang; Miao, Yanying; Zhang, Chuan-Qiang; Dong, Ling-Dan; Yang, Xiong-Li; Wang, Zhongfeng

    2016-01-01

    In the inner retina, ganglion cells (RGCs) integrate and process excitatory signal from bipolar cells (BCs) and inhibitory signal from amacrine cells (ACs). Using multiple labeling immunohistochemistry, we first revealed the expression of the cannabinoid CB1 receptor (CB1R) at the terminals of ACs and BCs in rat retina. By patch-clamp techniques, we then showed how the activation of this receptor dichotomously regulated miniature inhibitory postsynaptic currents (mIPSCs), mediated by GABAA receptors and glycine receptors, and miniature excitatory postsynaptic currents (mEPSCs), mediated by AMPA receptors, of RGCs in rat retinal slices. WIN55212-2 (WIN), a CB1R agonist, reduced the mIPSC frequency due to an inhibition of L-type Ca(2+) channels no matter whether AMPA receptors were blocked. In contrast, WIN reduced the mEPSC frequency by suppressing T-type Ca(2+) channels only when inhibitory inputs to RGCs were present, which could be in part due to less T-type Ca(2+) channels of cone BCs, presynaptic to RGCs, being in an inactivation state under such condition. This unique feature of CB1R-mediated retrograde regulation provides a novel mechanism for modulating excitatory synaptic transmission in the inner retina. Moreover, depolarization of RGCs suppressed mIPSCs of these cells, an effect that was eliminated by the CB1R antagonist SR141716, suggesting that endocannabinoid is indeed released from RGCs.

  5. AIDA-1 Moves out of the Postsynaptic Density Core under Excitatory Conditions.

    Directory of Open Access Journals (Sweden)

    Ayse Dosemeci

    Full Text Available AIDA-1 is highly enriched in postsynaptic density (PSD fractions and is considered a major component of the PSD complex. In the present study, immunogold electron microscopy was applied to determine localization as well as the activity-induced redistribution of AIDA-1 at the PSD using two antibodies that recognize two different epitopes. In cultured rat hippocampal neurons under basal conditions, immunogold label for AIDA-1 is mostly located within the dense core of the PSD, with a median distance of ~30 nm from the postsynaptic membrane. Under excitatory conditions, such as depolarization with high K+ (90 mM, 2 min or application of NMDA (50 μM, 2 min, AIDA-1 label density at the PSD core is reduced to 40% of controls and the median distance of label from the postsynaptic membrane increases to ~55 nm. The effect of excitatory conditions on the postsynaptic distribution of AIDA-1 is reversed within 30 minutes after returning to control conditions. The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95. Activity-induced transient translocation of these abundant proteins from the PSD core could promote structural flexibility, vacate sites on PSD-95 for the insertion of other components and thus may create a window for synaptic modification.

  6. Propofol facilitated excitatory postsynaptic currents frequency on nucleus tractus solitarii (NTS) neurons.

    Science.gov (United States)

    Jin, Zhenhua; Choi, Myung-Jin; Park, Cheung-Seog; Park, Young Seek; Jin, Young-Ho

    2012-01-13

    Propofol, an intravenous anesthetic, is broadly used for general anesthesia and diagnostic sedations due to its fast onset and recovery. Propofol depresses respiratory and cardiovascular reflex responses, however, their underlying mechanisms are not well known. Cardiorespiratory information from visceral afferent vagus nerves is integrated in the nucleus tractus solitarii (NTS). Cardiac and respiratory signals transducing vagal afferent neurons release the excitatory neurotransmitter glutamate onto NTS neurons in an activity dependent manner and trigger negative feedback reflex responses. In this experiment, the effects of propofol on glutamatergic synaptic responses at NTS neurons was tested using patch clamp methods. Glutamatergic excitatory postsynaptic currents (EPSC) were recorded at chloride reversal potential (-49mV) without γ-aminobutyric acid type A (GABA(A)) receptor antagonists. Propofol (≥3μM) facilitated frequency of the spontaneous EPSCs in a concentration dependent manner without altering amplitude and decay time. The GABA(A) receptor selective antagonist, gabazine (6μM), attenuated propofol effects on glutamate release. Propofol (10μM) evoked glutamate release was also blocked in the presence of the voltage dependent Na(+) and Ca(2+) channel blockers TTX (0.3μM) and Cd(2+) (0.2mM), respectively. In addition, the Na(+)-K(+)-Cl(-) cotransporter type 1 antagonist bumetanide (10μM) also inhibited propofol evoked increase in sEPSC frequency. These results suggest that propofol evoked glutamate release onto NTS neurons by GABA(A) receptor-mediated depolarization of the presynaptic excitatory terminals.

  7. Intrinsic conductances actively shape excitatory and inhibitory postsynaptic responses in olfactory bulb external tufted cells.

    Science.gov (United States)

    Liu, Shaolin; Shipley, Michael T

    2008-10-08

    The initial synapse in the olfactory system is from olfactory nerve (ON) terminals to postsynaptic targets in olfactory bulb glomeruli. Recent studies have disclosed multiple presynaptic factors that regulate this important linkage, but less is known about the contribution of postsynaptic intrinsic conductances to integration at these synapses. The present study demonstrates voltage-dependent amplification of EPSPs in external tufted (ET) cells in response to monosynaptic (ON) inputs. This amplification is mainly exerted by persistent Na(+) conductance. Larger EPSPs, which bring the membrane potential to a relatively depolarized level, are further boosted by the low-voltage-activated Ca(2+) conductance. In contrast, the hyperpolarization-activated nonselective cation conductance (I(h)) attenuates EPSPs mainly by reducing EPSP duration; this also reduces temporal summation of multiple EPSPs. Regulation of EPSPs by these subthreshold, voltage-dependent conductances can enhance both the signal-to-noise ratio and the temporal summation of multiple synaptic inputs and thus help ET cells differentiate high- and low-frequency synaptic inputs. I(h) can also transform inhibitory inputs to postsynaptic excitation. When the ET cell membrane potential is relatively depolarized, as during a burst of action potentials, IPSPs produce classic inhibition. However, near resting membrane potentials where I(h) is engaged, IPSPs produce rebound bursts of action potentials. ET cells excite GABAergic PG cells. Thus, the transformation of inhibitory inputs to postsynaptic excitation in ET cells may enhance intraglomerular inhibition of mitral/tufted cells, the main output neurons in the olfactory bulb, and hence shape signaling to olfactory cortex.

  8. Homeostatic regulation of excitatory synapses on striatal medium spiny neurons expressing the D2 dopamine receptor.

    Science.gov (United States)

    Thibault, Dominic; Giguère, Nicolas; Loustalot, Fabien; Bourque, Marie-Josée; Ducrot, Charles; El Mestikawy, Salah; Trudeau, Louis-Éric

    2016-05-01

    Striatal medium spiny neurons (MSNs) are contacted by glutamatergic axon terminals originating from cortex, thalamus and other regions. The striatum is also innervated by dopaminergic (DAergic) terminals, some of which release glutamate as a co-transmitter. Despite evidence for functional DA release at birth in the striatum, the role of DA in the establishment of striatal circuitry is unclear. In light of recent work suggesting activity-dependent homeostatic regulation of glutamatergic terminals on MSNs expressing the D2 DA receptor (D2-MSNs), we used primary co-cultures to test the hypothesis that stimulation of DA and glutamate receptors regulates the homeostasis of glutamatergic synapses on MSNs. Co-culture of D2-MSNs with mesencephalic DA neurons or with cortical neurons produced an increase in spines and functional glutamate synapses expressing VGLUT2 or VGLUT1, respectively. The density of VGLUT2-positive terminals was reduced by the conditional knockout of this gene from DA neurons. In the presence of both mesencephalic and cortical neurons, the density of synapses reached the same total, compatible with the possibility of a homeostatic mechanism capping excitatory synaptic density. Blockade of D2 receptors increased the density of cortical and mesencephalic glutamatergic terminals, without changing MSN spine density or mEPSC frequency. Combined blockade of AMPA and NMDA glutamate receptors increased the density of cortical terminals and decreased that of mesencephalic VGLUT2-positive terminals, with no net change in total excitatory terminal density or in mEPSC frequency. These results suggest that DA and glutamate signaling regulate excitatory inputs to striatal D2-MSNs at both the pre- and postsynaptic level, under the influence of a homeostatic mechanism controlling functional output of the circuit.

  9. Enhancement by citral of glutamatergic spontaneous excitatory transmission in adult rat substantia gelatinosa neurons.

    Science.gov (United States)

    Zhu, Lan; Fujita, Tsugumi; Jiang, Chang-Yu; Kumamoto, Eiichi

    2016-02-10

    Although citral, which is abundantly present in lemongrass, has various actions including antinociception, how citral affects synaptic transmission has not been examined as yet. Citral activates in heterologous cells transient receptor potential vanilloid-1, ankyrin-1, and melastatin-8 (TRPV1, TRPA1, and TRPM8, respectively) channels, the activation of which in the spinal lamina II [substantia gelatinosa (SG)] increases the spontaneous release of L-glutamate from nerve terminals. It remains to be examined what types of transient receptor potential channel in native neurons are activated by citral. With a focus on transient receptor potential activation, we examined the effect of citral on glutamatergic spontaneous excitatory transmission using the whole-cell patch-clamp technique to SG neurons in adult rat spinal cord slices. Bath-applied citral for 3 min increased the frequency of spontaneous excitatory postsynaptic current in a concentration-dependent manner (half-maximal effective concentration=0.58 mM), with a small increase in its amplitude. The spontaneous excitatory postsynaptic current frequency increase produced by citral was repeated at a time interval of 30 min, albeit this action recovered with a slow time course after washout. The presynaptic effect of citral was inhibited by TRPA1 antagonist HC-030031, but not by voltage-gated Na-channel blocker tetrodotoxin, TRPV1 antagonist capsazepine, and TRPM8 antagonist BCTC. It is concluded that citral increases spontaneous L-glutamate release in SG neurons by activating TRPA1 channels. Considering that the SG plays a pivotal role in modulating nociceptive transmission from the periphery, the citral activity could contribute toward at least a part of the modulation.

  10. Excitatory and inhibitory actions of isoflurane on the cholinergic ascending arousal system of the rat.

    Science.gov (United States)

    Dong, Hai-Long; Fukuda, Satoru; Murata, Eri; Higuchi, Takashi

    2006-01-01

    The cholinergic arousal systems are known to critically regulate the state of consciousness. The aim of this study was to determine the effect of isoflurane on the inhibitory or excitatory neurotransmitters efflux in important nuclei within the cholinergic arousal system using in vivo intracerebral microdialysis. The efflux of glutamate, gamma-aminobutyric acid (GABA), or acetylcholine in the posterior hypothalamus (PH), the basal forebrain (BF), and the somatosensory cortex (S1BF) of rats was detected using intracerebral microdialysis under an awake condition and at 0.5-2.0 minimum alveolar concentration (MAC) isoflurane anesthesia. The intrabasalis perfusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate on the cortical acetylcholine effluxes was also examined under both conditions. Isoflurane had no influence on the glutamate and GABA efflux in the PH, whereas in the BF, it dose-dependently increased glutamate efflux and decreased GABA efflux. A transient increase in glutamate efflux at 1.0 MAC and a decrease in GABA at 0.5-1.5 MAC were observed in the S1BF. Isoflurane dose-dependently decreased acetylcholine efflux in the S1BF. Perfusion of the BF with AMPA increased acetylcholine efflux in the S1BF with electroencephalographic activation during 0.75 MAC isoflurane anesthesia, suggesting an inhibitory action of isoflurane on AMPA receptors in the BF. However, N-methyl-D-aspartate had no effect on these parameters. Isoflurane induces both excitatory and inhibitory actions in the cholinergic arousal system. The predominant inhibitory action of isoflurane over its excitatory action at the BF would result in the decrease in the acetylcholine efflux in the S1BF.

  11. Loss of SynDIG1 Reduces Excitatory Synapse Maturation But Not Formation In Vivo

    Science.gov (United States)

    Kaur, Inderpreet; Liu, Xiao-Bo; Kirk, Lyndsey M.; Speca, David J.; McMahon, Samuel A.; Zito, Karen

    2016-01-01

    Abstract Modification of the strength of excitatory synaptic connections is a fundamental mechanism by which neural circuits are refined during development and learning. Synapse Differentiation Induced Gene 1 (SynDIG1) has been shown to play a key role in regulating synaptic strength in vitro. Here, we investigated the role of SynDIG1 in vivo in mice with a disruption of the SynDIG1 gene rather than use an alternate loxP-flanked conditional mutant that we find retains a partial protein product. The gene-trap insertion with a reporter cassette mutant mice shows that the SynDIG1 promoter is active during embryogenesis in the retina with some activity in the brain, and postnatally in the mouse hippocampus, cortex, hindbrain, and spinal cord. Ultrastructural analysis of the hippocampal CA1 region shows a decrease in the average PSD length of synapses and a decrease in the number of synapses with a mature phenotype. Intriguingly, the total synapse number appears to be increased in SynDIG1 mutant mice. Electrophysiological analyses show a decrease in AMPA and NMDA receptor function in SynDIG1-deficient hippocampal neurons. Glutamate stimulation of individual dendritic spines in hippocampal slices from SynDIG1-deficient mice reveals increased short-term structural plasticity. Notably, the overall levels of PSD-95 or glutamate receptors enriched in postsynaptic biochemical fractions remain unaltered; however, activity-dependent synapse development is strongly compromised upon the loss of SynDIG1, supporting its importance for excitatory synapse maturation. Together, these data are consistent with a model in which SynDIG1 regulates the maturation of excitatory synapse structure and function in the mouse hippocampus in vivo.

  12. Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1

    DEFF Research Database (Denmark)

    Jensen, Anders Asbjørn; Erichsen, Mette Navy; Nielsen, Christina Wøhlk

    2009-01-01

    The discovery of the first class of subtype-selective inhibitors of the human excitatory amino acid transporter subtype 1 (EAAT1) and its rat orthologue GLAST is reported. An opening structure-activity relationship of 25 analogues is presented that addresses the influence of substitutions at the ......- and 7-positions of the parental skeleton 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile. The most potent analogue 1o displays high nanomolar inhibitory activity at EAAT1 and a >400-fold selectivity over EAAT2 and EAAT3, making it a highly valuable pharmacological tool....

  13. Excitatory and inhibitory pathways modulate kainate excitotoxicity in hippocampal slice cultures

    DEFF Research Database (Denmark)

    Casaccia-Bonnefil, P; Benedikz, Eirikur; Rai, R;

    1993-01-01

    In organotypic hippocampal slice cultures, kainate (KA) specifically induces cell loss in the CA3 region while N-methyl-D-aspartate induces cell loss in the CA1 region. The sensitivity of slice cultures to KA toxicity appears only after 2 weeks in vitro which parallels the appearance of mossy...... fibers. KA toxicity is potentiated by co-application with the GABA-A antagonist, picrotoxin. These data suggest that the excitotoxicity of KA in slice cultures is modulated by both excitatory and inhibitory synapses....

  14. Neuronal chloride accumulation and excitatory GABA underlie aggravation of neonatal epileptiform activities by phenobarbital.

    Science.gov (United States)

    Nardou, Romain; Yamamoto, Sumii; Chazal, Geneviève; Bhar, Asma; Ferrand, Nadine; Dulac, Olivier; Ben-Ari, Yehezkel; Khalilov, Ilgam

    2011-04-01

    Phenobarbital produces its anti-epileptic actions by increasing the inhibitory drive of γ-aminobutyric acid. However, following recurrent seizures, γ-aminobutyric acid excites neurons because of a persistent increase of chloride raising the important issue of whether phenobarbital could aggravate persistent seizures. Here we compared the actions of phenobarbital on initial and established ictal-like events in an in vitro model of mirror focus. Using the in vitro three-compartment chamber preparation with the two hippocampi and their commissural fibres placed in three different chambers, kainate was applied to one hippocampus and phenobarbital contralaterally, either after one ictal-like event or after many recurrent ictal-like events that produce an epileptogenic mirror focus. Field, perforated patch and single-channel recordings were used to determine the effects of γ-aminobutyric acid and their modulation by phenobarbital, and alterations of the chloride cotransporters were investigated using sodium-potassium-chloride cotransporter 1 and potassium chloride cotransporter 2 antagonists, potassium chloride cotransporter 2 immunocytochemistry and sodium-potassium-chloride cotransporter 1 knockouts. Phenobarbital reduced initial ictal-like events and prevented the formation of a mirror focus when applied from the start. In contrast, phenobarbital aggravated epileptiform activities when applied after many ictal-like events by enhancing the excitatory actions of γ-aminobutyric acid due to increased chloride. The accumulation of chloride and the excitatory actions of γ-aminobutyric acid in mirror foci neurons are mediated by the sodium-potassium-chloride cotransporter 1 chloride importer and by downregulation and internalization of the chloride-exporter potassium-chloride cotransporter 2. Finally, concomitant applications of the sodium-potassium-chloride cotransporter 1 antagonist bumetanide and phenobarbital decreased excitatory actions of γ-aminobutyric acid and

  15. Diurnal rhythms in neurexins transcripts and inhibitory/excitatory synapse scaffold proteins in the biological clock.

    Directory of Open Access Journals (Sweden)

    Mika Shapiro-Reznik

    Full Text Available The neurexin genes (NRXN1/2/3 encode two families (α and β of highly polymorphic presynaptic proteins that are involved in excitatory/inhibitory synaptic balance. Recent studies indicate that neuronal activation and memory formation affect NRXN1/2/3α expression and alternative splicing at splice sites 3 and 4 (SS#3/SS#4. Neurons in the biological clock residing in the suprachiasmatic nuclei of the hypothalamus (SCN act as self-sustained oscillators, generating rhythms in gene expression and electrical activity, to entrain circadian bodily rhythms to the 24 hours day/night cycles. Cell autonomous oscillations in NRXN1/2/3α expression and SS#3/SS#4 exons splicing and their links to rhythms in excitatory/inhibitory synaptic balance in the circadian clock were explored. NRXN1/2/3α expression and SS#3/SS#4 splicing, levels of neurexin-2α and the synaptic scaffolding proteins PSD-95 and gephyrin (representing excitatory and inhibitory synapses, respectively were studied in mRNA and protein extracts obtained from SCN of C3H/J mice at different times of the 24 hours day/night cycle. Further studies explored the circadian oscillations in these components and causality relationships in immortalized rat SCN2.2 cells. Diurnal rhythms in mNRXN1α and mNRXN2α transcription, SS#3/SS#4 exon-inclusion and PSD-95 gephyrin and neurexin-2α levels were found in the SCN in vivo. No such rhythms were found with mNRXN3α. SCN2.2 cells also exhibited autonomous circadian rhythms in rNRXN1/2 expression SS#3/SS#4 exon inclusion and PSD-95, gephyrin and neurexin-2α levels. rNRXN3α and rNRXN1/2β were not expressed. Causal relationships were demonstrated, by use of specific siRNAs, between rNRXN2α SS#3 exon included transcripts and gephyrin levels in the SCN2.2 cells. These results show for the first time dynamic, cell autonomous, diurnal rhythms in expression and splicing of NRXN1/2 and subsequent effects on the expression of neurexin-2α and postsynaptic

  16. Excitatory and inhibitory synaptic mechanisms at the first stage of integration in the electroreception system of the shark.

    Science.gov (United States)

    Rotem, Naama; Sestieri, Emanuel; Hounsgaard, Jorn; Yarom, Yosef

    2014-01-01

    High impulse rate in afferent nerves is a common feature in many sensory systems that serve to accommodate a wide dynamic range. However, the first stage of integration should be endowed with specific properties that enable efficient handling of the incoming information. In elasmobranches, the afferent nerve originating from the ampullae of Lorenzini targets specific neurons located at the Dorsal Octavolateral Nucleus (DON), the first stage of integration in the electroreception system. Using intracellular recordings in an isolated brainstem preparation from the shark we analyze the properties of this afferent pathway. We found that stimulating the afferent nerve activates a mixture of excitatory and inhibitory synapses mediated by AMPA-like and GABAA receptors, respectively. The excitatory synapses that are extremely efficient in activating the postsynaptic neurons display unusual voltage dependence, enabling them to operate as a current source. The inhibitory input is powerful enough to completely eliminate the excitatory action of the afferent nerve but is ineffective regarding other excitatory inputs. These observations can be explained by the location and efficiency of the synapses. We conclude that the afferent nerve provides powerful and reliable excitatory input as well as a feed-forward inhibitory input, which is partially presynaptic in origin. These results question the cellular location within the DON where cancelation of expected incoming signals occurs.

  17. Excitatory and inhibitory synaptic mechanisms at the first stage of integration in the electroreception system of the shark

    Directory of Open Access Journals (Sweden)

    Naama eRotem

    2014-03-01

    Full Text Available High impulse rate in afferent nerves is a common feature in many sensory systems that serve to accommodate a wide dynamic range. However, the first stage of integration should be endowed with specific properties that enable efficient handling of the incoming information. In elasmobranches, the afferent nerve originating from the ampullae of Lorenzini targets specific neurons located at the Dorsal Octavolateral Nucleus (DON, the first stage of integration in the electroreception system. Using intracellular recordings in an isolated brainstem preparation from the shark we analyze the properties of this afferent pathway. We found that stimulating the afferent nerve activates a mixture of excitatory and inhibitory synapses mediated by AMPA-like and GABAA receptors, respectively. The excitatory synapses that are extremely efficient in activating the postsynaptic neurons display unusual voltage dependence, enabling them to operate as a current source. The inhibitory input is powerful enough to completely eliminate the excitatory action of the afferent nerve but is ineffective regarding other excitatory inputs. These observations can be explained by the location and efficiency of the synapses. We conclude that the afferent nerve provides powerful and reliable excitatory input as well as a feed-forward inhibitory input, which is partially presynaptic in origin. These results question the cellular location within the dorsal octavolateral nucleus where cancelation of expected incoming signals occurs.

  18. Dynamical Responses to External Stimuli for Both Cases of Excitatory and Inhibitory Synchronization in A Complex Neuronal Network

    CERN Document Server

    Kim, Sang-Yoon

    2016-01-01

    For studying how dynamical responses to external stimuli depend on the synaptic-coupling type, we consider two types of excitatory and inhibitory synchronization (i.e., synchronization via synaptic excitation and inhibition) in complex small-world networks of excitatory regular spiking (RS) pyramidal neurons and inhibitory fast spiking (FS) interneurons. For both cases of excitatory and inhibitory synchronization, effects of synaptic couplings on dynamical responses to external time-periodic stimuli $S(t)$ (applied to a fraction of neurons) are investigated by varying the driving amplitude $A$ of $S(t)$. Stimulated neurons are phase-locked to external stimuli for both cases of excitatory and inhibitory couplings. On the other hand, the stimulation effect on non-stimulated neurons depends on the type of synaptic coupling. The external stimulus $S(t)$ makes a constructive effect on excitatory non-stimulated RS neurons (i.e., it causes external phase lockings in the non-stimulated sub-population), while $S(t)$ m...

  19. Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit

    Directory of Open Access Journals (Sweden)

    Lisa eMapelli

    2015-05-01

    Full Text Available The way long-term potentiation (LTP and depression (LTD are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network , in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei and correspondingly regulate the function of their three main neurons: granule cells (GrCs, Purkinje cells (PCs and deep cerebellar nuclear (DCN cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

  20. Encoding of naturalistic stimuli by local field potential spectra in networks of excitatory and inhibitory neurons.

    Directory of Open Access Journals (Sweden)

    Alberto Mazzoni

    2008-12-01

    Full Text Available Recordings of local field potentials (LFPs reveal that the sensory cortex displays rhythmic activity and fluctuations over a wide range of frequencies and amplitudes. Yet, the role of this kind of activity in encoding sensory information remains largely unknown. To understand the rules of translation between the structure of sensory stimuli and the fluctuations of cortical responses, we simulated a sparsely connected network of excitatory and inhibitory neurons modeling a local cortical population, and we determined how the LFPs generated by the network encode information about input stimuli. We first considered simple static and periodic stimuli and then naturalistic input stimuli based on electrophysiological recordings from the thalamus of anesthetized monkeys watching natural movie scenes. We found that the simulated network produced stimulus-related LFP changes that were in striking agreement with the LFPs obtained from the primary visual cortex. Moreover, our results demonstrate that the network encoded static input spike rates into gamma-range oscillations generated by inhibitory-excitatory neural interactions and encoded slow dynamic features of the input into slow LFP fluctuations mediated by stimulus-neural interactions. The model cortical network processed dynamic stimuli with naturalistic temporal structure by using low and high response frequencies as independent communication channels, again in agreement with recent reports from visual cortex responses to naturalistic movies. One potential function of this frequency decomposition into independent information channels operated by the cortical network may be that of enhancing the capacity of the cortical column to encode our complex sensory environment.

  1. Remodeling and Tenacity of Inhibitory Synapses: Relationships with Network Activity and Neighboring Excitatory Synapses.

    Science.gov (United States)

    Rubinski, Anna; Ziv, Noam E

    2015-11-01

    Glutamatergic synapse size remodeling is governed not only by specific activity forms but also by apparently stochastic processes with well-defined statistics. These spontaneous remodeling processes can give rise to skewed and stable synaptic size distributions, underlie scaling of these distributions and drive changes in glutamatergic synapse size "configurations". Where inhibitory synapses are concerned, however, little is known on spontaneous remodeling dynamics, their statistics, their activity dependence or their long-term consequences. Here we followed individual inhibitory synapses for days, and analyzed their size remodeling dynamics within the statistical framework previously developed for glutamatergic synapses. Similar to glutamatergic synapses, size distributions of inhibitory synapses were skewed and stable; at the same time, however, sizes of individual synapses changed considerably, leading to gradual changes in synaptic size configurations. The suppression of network activity only transiently affected spontaneous remodeling dynamics, did not affect synaptic size configuration change rates and was not followed by the scaling of inhibitory synapse size distributions. Comparisons with glutamatergic synapses within the same dendrites revealed a degree of coupling between nearby inhibitory and excitatory synapse remodeling, but also revealed that inhibitory synapse size configurations changed at considerably slower rates than those of their glutamatergic neighbors. These findings point to quantitative differences in spontaneous remodeling dynamics of inhibitory and excitatory synapses but also reveal deep qualitative similarities in the processes that control their sizes and govern their remodeling dynamics.

  2. Cancer metastasis-suppressing peptide metastin upregulates excitatory synaptic transmission in hippocampal dentate granule cells.

    Science.gov (United States)

    Arai, Amy C; Xia, Yan-Fang; Suzuki, Erika; Kessler, Markus; Civelli, Olivier; Nothacker, Hans-Peter

    2005-11-01

    Metastin is an antimetastatic peptide encoded by the KiSS-1 gene in cancer cells. Recent studies found that metastin is a ligand for the orphan G-protein-coupled receptor GPR54, which is highly expressed in specific brain regions such as the hypothalamus and parts of the hippocampus. This study shows that activation of GPR54 by submicromolar concentrations of metastin reversibly enhances excitatory synaptic transmission in hippocampal dentate granule cells in a mitogen-activated protein (MAP) kinase-dependent manner. Synaptic enhancement by metastin was suppressed by intracellular application of the G-protein inhibitor GDP-beta-S and the calcium chelator BAPTA. Analysis of miniature excitatory postsynaptic currents (mEPSCs) revealed an increase in the mean amplitude but no change in event frequency. This indicates that GPR54 and the mechanism responsible for the increase in EPSCs are postsynaptic. Metastin-induced synaptic potentiation was abolished by 50 microM PD98059 and 20 microM U0126, two inhibitors of the MAP kinases ERK1 and ERK2. The effect was also blocked by inhibitors of calcium/calmodulin-dependent kinases and tyrosine kinases. RT-PCR experiments showed that both KiSS-1 and GPR54 are expressed in the hippocampal dentate gyrus. Metastin is thus a novel endogenous factor that modulates synaptic excitability in the dentate gyrus through mechanisms involving MAP kinases, which in turn may be controlled upstream by calcium-activated kinases and tyrosine kinases.

  3. Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity.

    Science.gov (United States)

    Xu, Jin-Chong; Fan, Jing; Wang, Xueqing; Eacker, Stephen M; Kam, Tae-In; Chen, Li; Yin, Xiling; Zhu, Juehua; Chi, Zhikai; Jiang, Haisong; Chen, Rong; Dawson, Ted M; Dawson, Valina L

    2016-04-06

    Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1(+) neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuronal cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and poly(ADP-ribose) polymerase (PARP) (a cell death pathway called parthanatos that is distinct from apoptosis, necroptosis, and other forms of cell death). Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons.

  4. New players tip the scales in the balance between excitatory and inhibitory synapses

    Directory of Open Access Journals (Sweden)

    El-Husseini Alaa

    2005-03-01

    Full Text Available Abstract Synaptogenesis is a highly controlled process, involving a vast array of players which include cell adhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteins associated with the synaptic vesicle machinery. These molecules cooperate in an intricate manner on both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts. This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputs but virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight control of a balance between the types of synapses formed regulates the overall neuronal excitability, and is thus critical for normal brain function and plasticity. However, little is known about how this balance is achieved. This review discusses recent findings which provide clues to how neurons may control excitatory and inhibitory synapse formation, with focus on the involvement of the neuroligin family and PSD-95 in this process.

  5. Excitatory and inhibitory neurotransmitters in the generation and degeneration of hippocampal neuroarchitecture.

    Science.gov (United States)

    Mattson, M P; Kater, S B

    1989-01-30

    The possibility that excitatory and inhibitory inputs to neurons can affect the generation and degeneration of neuroarchitecture was examined in hippocampal pyramidal neurons in isolated cell culture. Dendritic outgrowth and cell survival were directly monitored in neurons exposed to: the excitatory neurotransmitter glutamate, the inhibitory transmitter GABA, anticonvulsants or combinations of these agents. Glutamate caused a graded series of changes in pyramidal neuron cytoarchitecture: a selective inhibition in dendritic outgrowth and dendritic pruning was observed with subtoxic levels of glutamate while cell death was induced by higher levels. Low levels of GABA alone or in combination with diazepam, carbamazepine, phenobarbital or phenytoin were without effect on dendrite outgrowth while higher levels caused moderate reductions in outgrowth. Neither GABA nor the anticonvulsants affected cell survival. GABA plus diazepam, phenobarbital, carbamazepine and phenytoin each significantly reduced the dendritic regression and cell death normally caused by glutamate. Elevation of extracellular K+ to 50 mM caused dendritic regression and 100 mM K+ caused cell death; these effects were greatly reduced by GABA and anticonvulsants. The calcium channel blocker Co2+ prevented the dendritic regression and cell death caused by both glutamate and K+ indicating that calcium influx was required for the neuroarchitectural responses. Taken together, these results demonstrate that neurotransmitters and neuromodulatory drugs can have direct and interactive effects on both neurite outgrowth and cell survival. Such neurotransmitter actions may play roles in both the formation and degeneration of the neuronal circuits in which they participate in information coding.

  6. Intrinsic bursters increase the robustness of rhythm generation in an excitatory network.

    Science.gov (United States)

    Purvis, L K; Smith, J C; Koizumi, H; Butera, R J

    2007-02-01

    The pre-Botzinger complex (pBC) is a vital subcircuit of the respiratory central pattern generator. Although the existence of neurons with pacemaker-like bursting properties in this network is not questioned, their role in network rhythmogenesis is unresolved. Modeling is ideally suited to address this debate because of the ease with which biophysical parameters of individual cells and network architecture can be manipulated. We modeled the parameter variability of experimental data from pBC bursting pacemaker and nonpacemaker neurons using a modified version of our previously developed pBC neuron and network models. To investigate the role of pacemakers in networkwide rhythmogenesis, we simulated networks of these neurons and varied the fraction of the population made up of pacemakers. For each number of pacemaker neurons, we varied the amount of tonic drive to the network and measured the frequency of synchronous networkwide bursting produced. Both excitatory networks with all-to-all coupling and sparsely connected networks were explored for several levels of synaptic coupling strength. Networks containing only nonpacemakers were able to produce networkwide bursting, but with a low probability of bursting and low input and output ranges. Our results indicate that inclusion of pacemakers in an excitatory network increases robustness of the network by more than tripling the input and output ranges compared with networks containing no pacemakers. The largest increase in dynamic range occurs when the number of pacemakers in the network is greater than 20% of the population. Experimental tests of our model predictions are proposed.

  7. The Susd2 protein regulates neurite growth and excitatory synaptic density in hippocampal cultures.

    Science.gov (United States)

    Nadjar, Yann; Triller, Antoine; Bessereau, Jean-Louis; Dumoulin, Andrea

    2015-03-01

    Complement control protein (CCP) domains have adhesion properties and are commonly found in proteins that control the complement immune system. However, an increasing number of proteins containing CCP domains have been reported to display neuronal functions. Susd2 is a transmembrane protein containing one CCP domain. It was previously identified as a tumor-reversing protein, but has no characterized function in the CNS. The present study investigates the expression and function of Susd2 in the rat hippocampus. Characterization of Susd2 during development showed a peak in mRNA expression two weeks after birth. In hippocampal neuronal cultures, the same expression profile was observed at 15days in vitro for both mRNA and protein, a time consistent with synaptogenesis in our model. At the subcellular level, Susd2 was located on the soma, axons and dendrites, and appeared to associate preferentially with excitatory synapses. Inhibition of Susd2 by shRNAs led to decreased numbers of excitatory synaptic profiles, exclusively. Also, morphological parameters were studied on young (5DIV) developing neurons. After Susd2 inhibition, an increase in dendritic tree length but a decrease in axon elongation were observed, suggesting changes in adhesion properties. Our results demonstrate a dual role for Susd2 at different developmental stages, and raise the question whether Susd2 and other CCP-containing proteins expressed in the CNS could be function-related.

  8. Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

    Science.gov (United States)

    Mapelli, Lisa; Pagani, Martina; Garrido, Jesus A; D'Angelo, Egidio

    2015-01-01

    The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

  9. The Balance of Excitatory and Inhibitory Synaptic Inputs for Coding Sound Location

    Science.gov (United States)

    Ono, Munenori

    2014-01-01

    The localization of high-frequency sounds in the horizontal plane uses an interaural-level difference (ILD) cue, yet little is known about the synaptic mechanisms that underlie processing this cue in the inferior colliculus (IC) of mouse. Here, we study the synaptic currents that process ILD in vivo and use stimuli in which ILD varies around a constant average binaural level (ABL) to approximate sounds on the horizontal plane. Monaural stimulation in either ear produced EPSCs and IPSCs in most neurons. The temporal properties of monaural responses were well matched, suggesting connected functional zones with matched inputs. The EPSCs had three patterns in response to ABL stimuli, preference for the sound field with the highest level stimulus: (1) contralateral; (2) bilateral highly lateralized; or (3) at the center near 0 ILD. EPSCs and IPSCs were well correlated except in center-preferred neurons. Summation of the monaural EPSCs predicted the binaural excitatory response but less well than the summation of monaural IPSCs. Binaural EPSCs often showed a nonlinearity that strengthened the response to specific ILDs. Extracellular spike and intracellular current recordings from the same neuron showed that the ILD tuning of the spikes was sharper than that of the EPSCs. Thus, in the IC, balanced excitatory and inhibitory inputs may be a general feature of synaptic coding for many types of sound processing. PMID:24599475

  10. Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia

    Directory of Open Access Journals (Sweden)

    Colin Kehrer

    2008-04-01

    Full Text Available Schizophrenia is a common psychiatric disorder of high incidence, affecting approximately 1% of the world population. The essential neurotransmitter pathology of schizophrenia remains poorly defined, despite huge advances over the past half-century in identifying neurochemical and pathological abnormalities in the disease. The dopamine/serotonin hypothesis has originally provided much of the momentum for neurochemical research in schizophrenia. In recent years, the attention has, however, shifted to the glutamate system, the major excitatory neurotransmitter in the CNS and towards a concept of functional imbalance between excitatory and inhibitory transmission at the network level in various brain regions in schizophrenia. The evidence indicating a central role for the NMDAreceptor subtype in the etiology of schizophrenia has led to the NMDA-hypofunction model of this disease and the use of phencyclidines as a means to induce the NMDA-hypofunction state in animal models. The purpose of this review is to discuss recent findings highlighting the importance of the NMDA-hypofunction model of schizophrenia, both from a clinical perspective, as well as in opening a line of research, which enables electrophysiological studies at the cellular and network level in vitro. In particular, changes in excitation-inhibition (E/I balance in the NMDA-hypofunction model of the disease and the resulting changes in network behaviours, particularly in gamma frequency oscillatory activity, will be discussed.

  11. Aberrant development and plasticity of excitatory visual cortical networks in the absence of cpg15.

    Science.gov (United States)

    Picard, Nathalie; Leslie, Jennifer H; Trowbridge, Sara K; Subramanian, Jaichandar; Nedivi, Elly; Fagiolini, Michela

    2014-03-05

    During development, experience plays a crucial role in sculpting neuronal connections. Patterned neural activity guides formation of functional neural circuits through the selective stabilization of some synapses and the pruning of others. Activity-regulated factors are fundamental to this process, but their roles in synapse stabilization and maturation is still poorly understood. CPG15, encoded by the activity-regulated gene candidate plasticity gene 15, is a small, glycosylphosphatidylinositol (GPI)-linked, extracellular protein that promotes synapse stabilization. Here we show that global knock-out of cpg15 results in abnormal postnatal development of the excitatory network in visual cortex and an associated disruption in development of visual receptive field properties. In addition, whereas repeated stimulation induced potentiation and depression in wild-type mice, the depression was slower in cpg15 knock-out mice, suggesting impairment in short-term depression-like mechanisms. These findings establish the requirement for cpg15 in activity-dependent development of the visual system and demonstrate the importance of timely excitatory network development for normal visual function.

  12. NR2 subunits and NMDA receptors on lamina II inhibitory and excitatory interneurons of the mouse dorsal horn

    Directory of Open Access Journals (Sweden)

    MacDermott Amy B

    2010-05-01

    Full Text Available Abstract Background NMDA receptors expressed by spinal cord neurons in the superficial dorsal horn are involved in the development of chronic pain associated with inflammation and nerve injury. The superficial dorsal horn has a complex and still poorly understood circuitry that is mainly populated by inhibitory and excitatory interneurons. Little is known about how NMDA receptor subunit composition, and therefore pharmacology and voltage dependence, varies with neuronal cell type. NMDA receptors are typically composed of two NR1 subunits and two of four NR2 subunits, NR2A-2D. We took advantage of the differences in Mg2+ sensitivity of the NMDA receptor subtypes together with subtype preferring antagonists to identify the NR2 subunit composition of NMDA receptors expressed on lamina II inhibitory and excitatory interneurons. To distinguish between excitatory and inhibitory interneurons, we used transgenic mice expressing enhanced green fluorescent protein driven by the GAD67 promoter. Results Analysis of conductance ratio and selective antagonists showed that lamina II GABAergic interneurons express both the NR2A/B containing Mg2+ sensitive receptors and the NR2C/D containing NMDA receptors with less Mg2+ sensitivity. In contrast, excitatory lamina II interneurons express primarily NR2A/B containing receptors. Despite this clear difference in NMDA receptor subunit expression in the two neuronal populations, focally stimulated synaptic input is mediated exclusively by NR2A and 2B containing receptors in both neuronal populations. Conclusions Stronger expression of NMDA receptors with NR2C/D subunits by inhibitory interneurons compared to excitatory interneurons may provide a mechanism to selectively increase activity of inhibitory neurons during intense excitatory drive that can provide inhibitory feedback.

  13. The effect of STDP temporal kernel structure on the learning dynamics of single excitatory and inhibitory synapses.

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    Yotam Luz

    Full Text Available Spike-Timing Dependent Plasticity (STDP is characterized by a wide range of temporal kernels. However, much of the theoretical work has focused on a specific kernel - the "temporally asymmetric Hebbian" learning rules. Previous studies linked excitatory STDP to positive feedback that can account for the emergence of response selectivity. Inhibitory plasticity was associated with negative feedback that can balance the excitatory and inhibitory inputs. Here we study the possible computational role of the temporal structure of the STDP. We represent the STDP as a superposition of two processes: potentiation and depression. This allows us to model a wide range of experimentally observed STDP kernels, from Hebbian to anti-Hebbian, by varying a single parameter. We investigate STDP dynamics of a single excitatory or inhibitory synapse in purely feed-forward architecture. We derive a mean-field-Fokker-Planck dynamics for the synaptic weight and analyze the effect of STDP structure on the fixed points of the mean field dynamics. We find a phase transition along the Hebbian to anti-Hebbian parameter from a phase that is characterized by a unimodal distribution of the synaptic weight, in which the STDP dynamics is governed by negative feedback, to a phase with positive feedback characterized by a bimodal distribution. The critical point of this transition depends on general properties of the STDP dynamics and not on the fine details. Namely, the dynamics is affected by the pre-post correlations only via a single number that quantifies its overlap with the STDP kernel. We find that by manipulating the STDP temporal kernel, negative feedback can be induced in excitatory synapses and positive feedback in inhibitory. Moreover, there is an exact symmetry between inhibitory and excitatory plasticity, i.e., for every STDP rule of inhibitory synapse there exists an STDP rule for excitatory synapse, such that their dynamics is identical.

  14. Modulation of Long-Term Potentiation and Epileptiform Activity in the Rat Dentate Gyrus by the Group II Metabotropic Glutamate Receptor Subtype mGluR3

    Science.gov (United States)

    2006-05-31

    200 µM) blocked LTP of extracellular excitatory post-synaptic potentials ( EPSPs ) after high-frequency stimulation (100Hz; 2s) of the medial perforant...affect EPSPs recorded in a paired-pulse paradigm which argues against a presynaptic effect. These data are the first to indicate competitive effects...acetylaspartylglutamate (NAAG; 50 and 200 µM) blocked LTP of extracellular excitatory post-synaptic potentials ( EPSPs ) after high-frequency stimulation

  15. Prenatal Ethanol Exposure Persistently Alters Endocannabinoid Signaling and Endocannabinoid-Mediated Excitatory Synaptic Plasticity in Ventral Tegmental Area Dopamine Neurons.

    Science.gov (United States)

    Hausknecht, Kathryn; Shen, Ying-Ling; Wang, Rui-Xiang; Haj-Dahmane, Samir; Shen, Roh-Yu

    2017-06-14

    Prenatal ethanol exposure (PE) leads to increased addiction risk which could be mediated by enhanced excitatory synaptic strength in ventral tegmental area (VTA) dopamine (DA) neurons. Previous studies have shown that PE enhances excitatory synaptic strength by facilitating an anti-Hebbian form of long-term potentiation (LTP). In this study, we investigated the effect of PE on endocannabinoid-mediated long-term depression (eCB-LTD) in VTA DA neurons. Rats were exposed to moderate (3 g/kg/d) or high (6 g/kg/d) levels of ethanol during gestation. Whole-cell recordings were conducted in male offspring between 4 and 10 weeks old.We found that PE led to increased amphetamine self-administration. Both moderate and high levels of PE persistently reduced low-frequency stimulation-induced eCB-LTD. Furthermore, action potential-independent glutamate release was regulated by tonic eCB signaling in PE animals. Mechanistic studies for impaired eCB-LTD revealed that PE downregulated CB1 receptor function. Interestingly, eCB-LTD in PE animals was rescued by metabotropic glutamate receptor I activation, suggesting that PE did not impair the synthesis/release of eCBs. In contrast, eCB-LTD in PE animals was not rescued by increasing presynaptic activity, which actually led to LTP in PE animals, whereas LTD was still observed in controls. This result shows that the regulation of excitatory synaptic plasticity is fundamentally altered in PE animals. Together, PE leads to impaired eCB-LTD at the excitatory synapses of VTA DA neurons primarily due to CB1 receptor downregulation. This effect could contribute to enhanced LTP and the maintenance of augmented excitatory synaptic strength in VTA DA neurons and increased addiction risk after PE.SIGNIFICANCE STATEMENT Prenatal ethanol exposure (PE) is among many adverse developmental factors known to increase drug addiction risk. Increased excitatory synaptic strength in VTA DA neurons is a critical cellular mechanism for addiction risk. Our

  16. Development of Adult-Generated Cell Connectivity with Excitatory and Inhibitory Cell Populations in the Hippocampus.

    Science.gov (United States)

    Restivo, Leonardo; Niibori, Yosuke; Mercaldo, Valentina; Josselyn, Sheena A; Frankland, Paul W

    2015-07-22

    New neurons are generated continuously in the subgranular zone of the hippocampus and integrate into existing hippocampal circuits throughout adulthood. Although the addition of these new neurons may facilitate the formation of new memories, as they integrate, they provide additional excitatory drive to CA3 pyramidal neurons. During development, to maintain homeostasis, new neurons form preferential contacts with local inhibitory circuits. Using retroviral and transgenic approaches to label adult-generated granule cells, we first asked whether a comparable process occurs in the adult hippocampus in mice. Similar to development, we found that, during adulthood, new neurons form connections with inhibitory cells in the dentate gyrus, hilus, and CA3 regions as they integrate into hippocampal circuits. In particular, en passant bouton and filopodia connections with CA3 interneurons peak when adult-generated dentate granule cells (DGCs) are ∼4 weeks of age, a time point when these cells are most excitable. Consistent with this, optical stimulation of 4-week-old (but not 6- or 8-week-old) adult-generated DGCs strongly activated CA3 interneurons. Finally, we found that CA3 interneurons were activated robustly during learning and that their activity was strongly coupled with activity of 4-week-old (but not older) adult-generated DGCs. These data indicate that, as adult-generated neurons integrate into hippocampal circuits, they transiently form strong anatomical, effective, and functional connections with local inhibitory circuits in CA3. Significance statement: New neurons are generated continuously in the subgranular zone of the hippocampus and integrate into existing hippocampal circuits throughout adulthood. Understanding how these cells integrate within well formed circuits will increase our knowledge about the basic principles governing circuit assembly in the adult hippocampus. This study uses a combined connectivity analysis (anatomical, functional, and effective

  17. Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss.

    Science.gov (United States)

    Alhadeff, Amber L; Holland, Ruby A; Zheng, Huiyuan; Rinaman, Linda; Grill, Harvey J; De Jonghe, Bart C

    2017-01-11

    Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN) and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We demonstrated previously that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we used neuroanatomical tracing, immunofluorescence, and confocal imaging to demonstrate that virtually all NTS→lPBN and lPBN→CeA CGRP projections coexpress vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation. To test whether lPBN→CeA projection neurons are required for cisplatin-induced anorexia and weight loss, we inhibited these neurons chemogenetically using a retrograde Cre-recombinase-expressing canine adenovirus-2 in combination with Cre-dependent inhibitory Designer Receptors Exclusive Activated by Designer Drugs (DREADDs) before cisplatin treatment. Inhibition of lPBN→CeA neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Using a similar approach, we additionally demonstrated that inhibition of NTS→lPBN neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Together, our data support the view that excitatory hindbrain-forebrain projections are necessary for cisplatin's untoward effects on energy intake, elucidating a key neuroanatomical circuit driving pathological anorexia and weight loss that accompanies chemotherapy treatment. Chemotherapy treatments are commonly used to treat cancers despite accompanying anorexia and weight loss that may limit treatment adherence and reduce patient quality of life. Strikingly, we lack a neural understanding of, and effective treatments for, chemotherapy-induced anorexia and weight loss. The current data

  18. Excitatory synaptic inputs on myenteric Dogiel type II neurones of the pig ileum.

    Science.gov (United States)

    Cornelissen, W; de Laet, A; Kroese, A B; van Bogaert, P P; Scheuermann, D W; Timmermans, J P

    2001-04-01

    The synaptic input on myenteric Dogiel type II neurones (n = 63) obtained from the ileum of 17 pigs was studied by intracellular recording. In 77% of the neurones, electrical stimulation of a fibre tract evoked fast excitatory postsynaptic potentials (fEPSPs) with an amplitude of 6 +/- 5 mV (mean +/- S.D.) and lasting 49 +/- 29 ms. The nicotinic nature of the fEPSPs was demonstrated by superfusing hexamethonium (20 microM). High-frequency stimulation (up to 20 Hz, 3 seconds) did not result in a rundown of the fEPSPs, and did not evoke slow excitatory or inhibitory postsynaptic potentials. The effects of neurotransmitters, possibly involved in these excitatory responses, were investigated. Pressure microejection of acetylcholine (10 mM in pipette) resulted in a fast nicotinic depolarisation in 67%(18/27) of the neurones (13 +/- 9 mV, duration 7.0 +/- 7.2 seconds) as did 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) application (10 mM; 14 +/- 10 mV, duration 4.1 +/- 2.8 seconds) in 76% of the cells. The fast nicotinic response to acetylcholine was sometimes (6/27) followed by a slow muscarinic depolarisation (8 +/- 4 mV; duration 38.7 +/- 10.8 seconds). Immunostaining revealed 5-hydroxytryptamine hydrochloride (5-HT)- and calcitonin gene-related peptide (CGRP)-positive neuronal baskets distributed around and in close vicinity to Dogiel type II neuronal cell bodies. Microejection of 5-HT (10 mM) resulted in a fast nicotinic-like depolarisation (12 +/- 6 mV, duration 3.0 +/- 1.3 seconds) in 4 of 8 neurones tested, whereas microejection of CGRP (20 mM) gave rise to a slow muscarinic-like depolarisation (6 +/- 2 mV, duration 56.0 +/- 27.5 seconds) in 8 of 12 neurones tested. In conclusion, myenteric Dogiel type II neurones in the porcine ileum receive diverse synaptic input. Mainly with regard to the prominent presence of nicotinic responses, these neurones behave contrary to their guinea pig counterparts.

  19. Domestication of the dog from the wolf was promoted by enhanced excitatory synaptic plasticity: a hypothesis.

    Science.gov (United States)

    Li, Yan; Wang, Guo-Dong; Wang, Ming-Shan; Irwin, David M; Wu, Dong-Dong; Zhang, Ya-Ping

    2014-11-05

    Dogs shared a much closer relationship with humans than any other domesticated animals, probably due to their unique social cognitive capabilities, which were hypothesized to be a by-product of selection for tameness toward humans. Here, we demonstrate that genes involved in glutamate metabolism, which account partially for fear response, indeed show the greatest population differentiation by whole-genome comparison of dogs and wolves. However, the changing direction of their expression supports a role in increasing excitatory synaptic plasticity in dogs rather than reducing fear response. Because synaptic plasticity are widely believed to be cellular correlates of learning and memory, this change may alter the learning and memory abilities of ancient scavenging wolves, weaken the fear reaction toward humans, and prompt the initial interspecific contact.

  20. BDNF has opposite effects on the quantal amplitude of pyramidal neuron and interneuron excitatory synapses.

    Science.gov (United States)

    Rutherford, L C; Nelson, S B; Turrigiano, G G

    1998-09-01

    Recently, we have identified a novel form of synaptic plasticity that acts to stabilize neocortical firing rates by scaling the quantal amplitude of AMPA-mediated synaptic inputs up or down as a function of neuronal activity. Here, we show that the effects of activity blockade on quantal amplitude are mediated through the neurotrophin brain-derived neurotrophic factor (BDNF). Exogenous BDNF prevented, and a TrkB-IgG fusion protein reproduced, the effects of activity blockade on pyramidal quantal amplitude. BDNF had opposite effects on pyramidal neuron and interneuron quantal amplitudes and modified the ratio of pyramidal neuron to interneuron firing rates. These data demonstrate a novel role for BDNF in the homeostatic regulation of excitatory synaptic strengths and in the maintenance of the balance of cortical excitation and inhibition.

  1. Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain

    Directory of Open Access Journals (Sweden)

    Christian Bonansco

    2016-01-01

    Full Text Available Synaptic plasticity is the capacity generated by experience to modify the neural function and, thereby, adapt our behaviour. Long-term plasticity of glutamatergic and GABAergic transmission occurs in a concerted manner, finely adjusting the excitatory-inhibitory (E/I balance. Imbalances of E/I function are related to several neurological diseases including epilepsy. Several evidences have demonstrated that astrocytes are able to control the synaptic plasticity, with astrocytes being active partners in synaptic physiology and E/I balance. Here, we revise molecular evidences showing the epileptic stage as an abnormal form of long-term brain plasticity and propose the possible participation of astrocytes to the abnormal increase of glutamatergic and decrease of GABAergic neurotransmission in epileptic networks.

  2. Excitatory actions of gaba during development: the nature of the nurture.

    Science.gov (United States)

    Ben-Ari, Yehezkel

    2002-09-01

    In the immature brain, GABA (gamma-aminobutyric acid) is excitatory, and GABA-releasing synapses are formed before glutamatergic contacts in a wide range of species and structures. GABA becomes inhibitory by the delayed expression of a chloride exporter, leading to a negative shift in the reversal potential for choride ions. I propose that this mechanism provides a solution to the problem of how to excite developing neurons to promote growth and synapse formation while avoiding the potentially toxic effects of a mismatch between GABA-mediated inhibition and glutamatergic excitation. As key elements of this cascade are activity dependent, the formation of inhibition adds an element of nurture to the construction of cortical networks.

  3. Alteration of Excitatory Amino Acid in Experimental Spinal Cord Injury in Rats

    Institute of Scientific and Technical Information of China (English)

    张宁; 罗永湘

    2002-01-01

    Objective To detect the effect of excitatory amino acid (EAA) in the sec-ondary damage following spinal cord injury (SCI). Methods Glutamate (Glu) and Aspartate(Asp) on the injury site (T8) were studied using a rat SCI model induced by Allen's weight drop method(10g×2.5cm). The result suggested that Asp and Glu were significantly increased in 10 min. Re-sults Glu was significantly decreased from 2 h to 24 h,while Asp was a little reduced in 2 h,andslightly rose in 4 h as compared with Control Group. Though elevated in 8 h, it dropped again in 24 h ascompared with Control Group. Conclusion The result indicates that the rise of EAA following SCIcould be the cause of the secondary spinal cord damage.

  4. Ionotropic excitatory amino acid receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antagonist

    DEFF Research Database (Denmark)

    Madsen, U; Sløk, F A; Stensbøl, T B;

    2000-01-01

    We have previously described the potent and selective (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4......-isoxazolyl]propionic acid (AMOA). Using these AMPA receptor ligands as leads, a series of compounds have been developed as tools for further elucidation of the structural requirements for activation and blockade of AMPA receptors. The synthesized compounds have been tested for activity at ionotropic...... excitatory amino acid (EAA) receptors using receptor binding and electrophysiological techniques, and for activity at metabotropic EAA receptors using second messenger assays. Compounds 1 and 4 were essentially inactive. (RS)-2-Amino-3-[3-(2-carboxyethyl)-5-methyl-4-isoxazolyl]propionic acid (ACMP, 2...

  5. Chaos and Correlated Avalanches in Excitatory Neural Networks with Synaptic Plasticity

    Science.gov (United States)

    Pittorino, Fabrizio; Ibáñez-Berganza, Miguel; di Volo, Matteo; Vezzani, Alessandro; Burioni, Raffaella

    2017-03-01

    A collective chaotic phase with power law scaling of activity events is observed in a disordered mean field network of purely excitatory leaky integrate-and-fire neurons with short-term synaptic plasticity. The dynamical phase diagram exhibits two transitions from quasisynchronous and asynchronous regimes to the nontrivial, collective, bursty regime with avalanches. In the homogeneous case without disorder, the system synchronizes and the bursty behavior is reflected into a period doubling transition to chaos for a two dimensional discrete map. Numerical simulations show that the bursty chaotic phase with avalanches exhibits a spontaneous emergence of persistent time correlations and enhanced Kolmogorov complexity. Our analysis reveals a mechanism for the generation of irregular avalanches that emerges from the combination of disorder and deterministic underlying chaotic dynamics.

  6. Heterogeneous reallocation of presynaptic efficacy in recurrent excitatory circuits adapting to inactivity.

    Science.gov (United States)

    Mitra, Ananya; Mitra, Siddhartha S; Tsien, Richard W

    2011-12-18

    Recurrent excitatory circuits face extreme challenges in balancing efficacy and stability. We recorded from CA3 pyramidal neuron pairs in rat hippocampal slice cultures to characterize synaptic and circuit-level changes in recurrent synapses resulting from long-term inactivity. Chronic tetrodotoxin treatment greatly reduced the percentage of connected CA3-CA3 neurons, but enhanced the strength of the remaining connections; presynaptic release probability sharply increased, whereas quantal size was unaltered. Connectivity was decreased in activity-deprived circuits by functional silencing of synapses, whereas three-dimensional anatomical analysis revealed no change in spine or bouton density or aggregate dendrite length. The silencing arose from enhanced Cdk5 activity and could be reverted by acute Cdk5 inhibition with roscovitine. Our results suggest that recurrent circuits adapt to chronic inactivity by reallocating presynaptic weights heterogeneously, strengthening certain connections while silencing others. This restricts synaptic output and input, preserving signaling efficacy among a subset of neuronal ensembles while protecting network stability.

  7. Glutathione in Cellular Redox Homeostasis: Association with the Excitatory Amino Acid Carrier 1 (EAAC1

    Directory of Open Access Journals (Sweden)

    Koji Aoyama

    2015-05-01

    Full Text Available Reactive oxygen species (ROS are by-products of the cellular metabolism of oxygen consumption, produced mainly in the mitochondria. ROS are known to be highly reactive ions or free radicals containing oxygen that impair redox homeostasis and cellular functions, leading to cell death. Under physiological conditions, a variety of antioxidant systems scavenge ROS to maintain the intracellular redox homeostasis and normal cellular functions. This review focuses on the antioxidant system’s roles in maintaining redox homeostasis. Especially, glutathione (GSH is the most important thiol-containing molecule, as it functions as a redox buffer, antioxidant, and enzyme cofactor against oxidative stress. In the brain, dysfunction of GSH synthesis leading to GSH depletion exacerbates oxidative stress, which is linked to a pathogenesis of aging-related neurodegenerative diseases. Excitatory amino acid carrier 1 (EAAC1 plays a pivotal role in neuronal GSH synthesis. The regulatory mechanism of EAAC1 is also discussed.

  8. Rhythmic Oscillations of Excitatory Bursting Hodkin-Huxley Neuronal Network with Synaptic Learning.

    Science.gov (United States)

    Shi, Qi; Han, Fang; Wang, Zhijie; Li, Caiyun

    2016-01-01

    Rhythmic oscillations of neuronal network are actually kind of synchronous behaviors, which play an important role in neural systems. In this paper, the properties of excitement degree and oscillation frequency of excitatory bursting Hodkin-Huxley neuronal network which incorporates a synaptic learning rule are studied. The effects of coupling strength, synaptic learning rate, and other parameters of chemical synapses, such as synaptic delay and decay time constant, are explored, respectively. It is found that the increase of the coupling strength can weaken the extent of excitement, whereas increasing the synaptic learning rate makes the network more excited in a certain range; along with the increasing of the delay time and the decay time constant, the excitement degree increases at the beginning, then decreases, and keeps stable. It is also found that, along with the increase of the synaptic learning rate, the coupling strength, the delay time, and the decay time constant, the oscillation frequency of the network decreases monotonically.

  9. Opioid Tolerance and Physical Dependence: Role of Spinal Neuropeptides, Excitatory Amino Acids and Their Messengers

    Directory of Open Access Journals (Sweden)

    Khem Jhamandas

    2000-01-01

    Full Text Available Chronic opioid treatment results in the development of tolerance and physical dependence. The mechanisms underlying opioid tolerance and/or physical dependence are unclear. Recent studies suggest that opioid receptor or nociceptive, neural network-based adaptations contribute to this phenomenon. At the spinal level, the genesis of tolerance and physical dependence is associated with increased excitatory amino acid activity expressed through N-methyl-D-aspartate receptors in the dorsal horn. However, recent evidence also implicates spinal neuropeptide transmitters such as calcitonin gene-related peptide (CGRP and  substance P in the development of opioid tolerance. Long term spinal morphine treatment increases CGRP-like immunostaining in the dorsal horn, and coadministration of morphine with CGRP8-37, a competitive CGRP1 receptor antagonist, prevents this response as well as loss of the analgesic potency. CGRP8-37, like N-methyl-D-aspartate receptor antagonists, has the potential to restore morphine potency in experimental animals who are already tolerant to the opioid agonist. Recent evidence suggests that the effects of excitatory amino acid and neuropeptide receptor activity may be expressed through the generation of messengers such as nitric oxide and prostanoids. Agents that inhibit the synthesis of nitric oxide and prostanoids have the potential to inhibit and reverse spinal opioid tolerance, suggesting that this phenomenon may be expressed through the activity of these mediators. Nociceptive transmission in the dorsal horn of the spinal cord also involves activity of a number of other mediators including morphine modulatory neuropeptides, neuropeptide FF  and neuropeptide SF. The role of these mediators and their relationship with other factors implicated in tolerance remain to be determined.

  10. Neuroligin-1 loss is associated with reduced tenacity of excitatory synapses.

    Directory of Open Access Journals (Sweden)

    Adel Zeidan

    Full Text Available Neuroligins (Nlgns are postsynaptic, integral membrane cell adhesion molecules that play important roles in the formation, validation, and maturation of synapses in the mammalian central nervous system. Given their prominent roles in the life cycle of synapses, it might be expected that the loss of neuroligin family members would affect the stability of synaptic organization, and ultimately, affect the tenacity and persistence of individual synaptic junctions. Here we examined whether and to what extent the loss of Nlgn-1 affects the dynamics of several key synaptic molecules and the constancy of their contents at individual synapses over time. Fluorescently tagged versions of the postsynaptic scaffold molecule PSD-95, the AMPA-type glutamate receptor subunit GluA2 and the presynaptic vesicle molecule SV2A were expressed in primary cortical cultures from Nlgn-1 KO mice and wild-type (WT littermates, and live imaging was used to follow the constancy of their contents at individual synapses over periods of 8-12 hours. We found that the loss of Nlgn-1 was associated with larger fluctuations in the synaptic contents of these molecules and a poorer preservation of their contents at individual synapses. Furthermore, rates of synaptic turnover were somewhat greater in neurons from Nlgn-1 knockout mice. Finally, the increased GluA2 redistribution rates observed in neurons from Nlgn-1 knockout mice were negated by suppressing spontaneous network activity. These findings suggest that the loss of Nlgn-1 is associated with some use-dependent destabilization of excitatory synapse organization, and indicate that in the absence of Nlgn-1, the tenacity of excitatory synapses might be somewhat impaired.

  11. Excitatory effects of parvalbumin-expressing interneurons maintain hippocampal epileptiform activity via synchronous afterdischarges.

    Science.gov (United States)

    Ellender, Tommas J; Raimondo, Joseph V; Irkle, Agnese; Lamsa, Karri P; Akerman, Colin J

    2014-11-12

    Epileptic seizures are characterized by periods of hypersynchronous, hyperexcitability within brain networks. Most seizures involve two stages: an initial tonic phase, followed by a longer clonic phase that is characterized by rhythmic bouts of synchronized network activity called afterdischarges (ADs). Here we investigate the cellular and network mechanisms underlying hippocampal ADs in an effort to understand how they maintain seizure activity. Using in vitro hippocampal slice models from rats and mice, we performed electrophysiological recordings from CA3 pyramidal neurons to monitor network activity and changes in GABAergic signaling during epileptiform activity. First, we show that the highest synchrony occurs during clonic ADs, consistent with the idea that specific circuit dynamics underlie this phase of the epileptiform activity. We then show that ADs require intact GABAergic synaptic transmission, which becomes excitatory as a result of a transient collapse in the chloride (Cl(-)) reversal potential. The depolarizing effects of GABA are strongest at the soma of pyramidal neurons, which implicates somatic-targeting interneurons in AD activity. To test this, we used optogenetic techniques to selectively control the activity of somatic-targeting parvalbumin-expressing (PV(+)) interneurons. Channelrhodopsin-2-mediated activation of PV(+) interneurons during the clonic phase generated excitatory GABAergic responses in pyramidal neurons, which were sufficient to elicit and entrain synchronous AD activity across the network. Finally, archaerhodopsin-mediated selective silencing of PV(+) interneurons reduced the occurrence of ADs during the clonic phase. Therefore, we propose that activity-dependent Cl(-) accumulation subverts the actions of PV(+) interneurons to perpetuate rather than terminate pathological network hyperexcitability during the clonic phase of seizures.

  12. Somatodendritic and excitatory postsynaptic distribution of neuron-type dystrophin isoform, Dp40, in hippocampal neurons

    Energy Technology Data Exchange (ETDEWEB)

    Fujimoto, Takahiro; Itoh, Kyoko, E-mail: kxi14@koto.kpu-m.ac.jp; Yaoi, Takeshi; Fushiki, Shinji

    2014-09-12

    Highlights: • Identification of dystrophin (Dp) shortest isoform, Dp40, is a neuron-type Dp. • Dp40 expression is temporally and differentially regulated in comparison to Dp71. • Somatodendritic and nuclear localization of Dp40. • Dp40 is localized to excitatory postsynapses. • Dp40 might play roles in dendritic and synaptic functions. - Abstract: The Duchenne muscular dystrophy (DMD) gene produces multiple dystrophin (Dp) products due to the presence of several promoters. We previously reported the existence of a novel short isoform of Dp, Dp40, in adult mouse brain. However, the exact biochemical expression profile and cytological distribution of the Dp40 protein remain unknown. In this study, we generated a polyclonal antibody against the NH{sub 2}-terminal region of the Dp40 and identified the expression profile of Dp40 in the mouse brain. Through an analysis using embryonic and postnatal mouse cerebrums, we found that Dp40 emerged from the early neonatal stages until adulthood, whereas Dp71, an another Dp short isoform, was highly detected in both prenatal and postnatal cerebrums. Intriguingly, relative expressions of Dp40 and Dp71 were prominent in cultured dissociated neurons and non-neuronal cells derived from mouse hippocampus, respectively. Furthermore, the immunocytological distribution of Dp40 was analyzed in dissociated cultured neurons, revealing that Dp40 is detected in the soma and its dendrites, but not in the axon. It is worthy to note that Dp40 is localized along the subplasmalemmal region of the dendritic shafts, as well as at excitatory postsynaptic sites. Thus, Dp40 was identified as a neuron-type Dp possibly involving dendritic and synaptic functions.

  13. Two classes of excitatory synaptic responses in rat thalamic reticular neurons.

    Science.gov (United States)

    Deleuze, Charlotte; Huguenard, John R

    2016-09-01

    The thalamic reticular nucleus (nRt), composed of GABAergic cells providing inhibition of relay neurons in the dorsal thalamus, receives excitation from the neocortex and thalamus. The two excitatory pathways promoting feedback or feedforward inhibition of thalamocortical neurons contribute to sensory processing and rhythm generation. While synaptic inhibition within the nRt has been carefully characterized, little is known regarding the biophysics of synaptic excitation. To characterize the functional properties of thalamocortical and corticothalamic connections to the nRt, we recorded minimal electrically evoked excitatory postsynaptic currents from nRt cells in vitro. A hierarchical clustering algorithm distinguished two types of events. Type 1 events had larger amplitudes and faster kinetics, largely mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, whereas type 2 responses had more prominent N-methyl-d-aspartate (NMDA) receptor contribution. Type 1 responses showed subnormal axonal propagation and paired pulse depression, consistent with thalamocortical inputs. Furthermore, responses kinetically similar to type 1 events were evoked by glutamate-mediated activation of thalamic neurons. Type 2 responses, in contrast, likely arise from corticothalamic inputs, with larger NMDA conductance and weak Mg(2+)-dependent block, suggesting that NMDA receptors are critical for the cortical excitation of reticular neurons. The long-lasting action of NMDA receptors would promote reticular cell burst firing and produce powerful inhibitory output to relay neurons proposed to be important in triggering epilepsy. This work provides the first complete voltage-clamp analysis of the kinetics and voltage dependence of AMPA and NMDA responses of thalamocortical and corticothalamic synapses in the nRt and will be critical in optimizing biologically realistic neural network models of thalamocortical circuits relevant to sensory processing and

  14. ATP participates in three excitatory postsynaptic potentials in the submucous plexus of the guinea pig ileum.

    Science.gov (United States)

    Monro, R L; Bertrand, P P; Bornstein, J C

    2004-04-15

    Synaptic transmission between neurones intrinsic to the wall of the intestine involves multiple neurotransmitters. This study aimed to identify neurotransmitters responsible for non-cholinergic excitatory synaptic transmission in the submucous plexus of the guinea pig ileum. Intracellular recordings were made from secretomotor and vasodilator neurones. A single electrical stimulus to a fibre tract evoked excitatory postsynaptic potentials (EPSPs) with three different time courses - fast, slow and an EPSP with an intermediate time course (latency 96 ms, duration 1.2 s). In all neurones, blocking nicotinic receptors reduced fast EPSPs, but they were abolished in only 57 of 78 neurones. Fast EPSPs were also reduced by P2 purinoceptor blockade (5 of 27 neurones) or 5-HT(3) receptor blockade (3 of 20 neurones). The intermediate EPSP was abolished by P2 receptor blockade (13 of 13 neurones) or by the specific P2Y(1) receptor antagonist MRS 2179 (5 of 5 neurones) and was always preceded by a nicotinic or mixed nicotinic/purinergic fast EPSP. Intermediate EPSPs were observed in over half of all neurones including most non-cholinergic secretomotor neurones identified by immunoreactivity for vasoactive intestinal peptide. The slow EPSP evoked by a single pulse stimulus was also abolished by P2 receptor blockade (5 of 5 neurones) or by MRS 2179 (3 of 3 neurones). We conclude that fast EPSPs in submucous neurones are mediated by acetylcholine acting at nicotinic receptors, ATP acting at P2X receptors and 5-HT acting at 5-HT(3) receptors. Both the intermediate EPSP and the single stimulus slow EPSP are mediated by ATP acting at P2Y(1) receptors.

  15. Excitatory and inhibitory projections in parallel pathways from the inferior colliculus to the auditory thalamus

    Directory of Open Access Journals (Sweden)

    Jeffrey Garrett Mellott

    2014-11-01

    Full Text Available Individual subdivisions of the medial geniculate body (MG receive a majority of their ascending inputs from 1 or 2 subdivisions of the inferior colliculus (IC. This establishes parallel pathways that provide a model for understanding auditory projections from the IC through the MG and on to auditory cortex. A striking discovery about the tectothalamic circuit was identification of a substantial GABAergic component. Whether GABAergic projections match the parallel pathway organization has not been examined. We asked whether the parallel pathway concept is reflected in guinea pig tectothalamic pathways and to what degree GABAergic cells contribute to each pathway. We deposited retrograde tracers into individual MG subdivisions (ventral, MGv; medial, MGm; dorsal, MGd; suprageniculate, MGsg to label tectothalamic cells and used immunochemistry to identify GABAergic cells. The MGv receives most of its IC input (~75% from the IC central nucleus (ICc; MGd and MGsg receive most of their input (~70% from IC dorsal cortex (ICd; and MGm receives substantial input from both ICc (~40% and IC lateral cortex (~40%. Each MG subdivision receives additional input (up to 32% from non-dominant IC subdivisions, suggesting cross-talk between the pathways. The proportion of GABAergic cells in each pathway depended on the MG subdivision. GABAergic cells formed ~20% of IC inputs to MGv or MGm, ~11% of inputs to MGd, and 4% of inputs to MGsg. Thus, non-GABAergic (i.e., glutamatergic cells are most numerous in each pathway with GABAergic cells contributing to different extents. Despite smaller numbers of GABAergic cells, their distributions across IC subdivisions mimicked the parallel pathways. Projections outside the dominant pathways suggest opportunities for excitatory and inhibitory crosstalk. The results demonstrate parallel tectothalamic pathways in guinea pigs and suggest numerous opportunities for excitatory and inhibitory interactions within and between pathways.

  16. Training Excitatory-Inhibitory Recurrent Neural Networks for Cognitive Tasks: A Simple and Flexible Framework.

    Directory of Open Access Journals (Sweden)

    H Francis Song

    2016-02-01

    Full Text Available The ability to simultaneously record from large numbers of neurons in behaving animals has ushered in a new era for the study of the neural circuit mechanisms underlying cognitive functions. One promising approach to uncovering the dynamical and computational principles governing population responses is to analyze model recurrent neural networks (RNNs that have been optimized to perform the same tasks as behaving animals. Because the optimization of network parameters specifies the desired output but not the manner in which to achieve this output, "trained" networks serve as a source of mechanistic hypotheses and a testing ground for data analyses that link neural computation to behavior. Complete access to the activity and connectivity of the circuit, and the ability to manipulate them arbitrarily, make trained networks a convenient proxy for biological circuits and a valuable platform for theoretical investigation. However, existing RNNs lack basic biological features such as the distinction between excitatory and inhibitory units (Dale's principle, which are essential if RNNs are to provide insights into the operation of biological circuits. Moreover, trained networks can achieve the same behavioral performance but differ substantially in their structure and dynamics, highlighting the need for a simple and flexible framework for the exploratory training of RNNs. Here, we describe a framework for gradient descent-based training of excitatory-inhibitory RNNs that can incorporate a variety of biological knowledge. We provide an implementation based on the machine learning library Theano, whose automatic differentiation capabilities facilitate modifications and extensions. We validate this framework by applying it to well-known experimental paradigms such as perceptual decision-making, context-dependent integration, multisensory integration, parametric working memory, and motor sequence generation. Our results demonstrate the wide range of neural

  17. Adolescent chronic mild stress alters hippocampal CB1 receptor-mediated excitatory neurotransmission and plasticity.

    Science.gov (United States)

    Reich, C G; Mihalik, G R; Iskander, A N; Seckler, J C; Weiss, M S

    2013-12-03

    Endocannabinoids (eCBs) are involved in the stress response and alterations in eCB signaling may contribute to the etiology of mood disorders. Exposure to chronic mild stress (CMS), a model of depression, produces downregulation of the cannabinoid 1 (CB1) receptor in the hippocampus of male rats. However, it is unknown how this stress-induced change in CB1 levels affects eCB-mediated neurotransmission. In vitro, field potential recordings from CMS-exposed (21-days) rats were performed to assess the effects of stress on eCB-regulated glutamatergic neurotransmission in/on hippocampal area CA1. We observed that application of the CB1 agonist, WIN 55,212-5 (1 μM), in stress animals resulted in a ∼135% increase in excitatory neurotransmission, whereas CB1 activation in non-stress animals leads to a ∼30% decrease. However, during blockade of GABA(A) neurotransmission with picrotoxin, CB1 activation yielded a ∼35% decrease in stress animals. These findings indicate that CMS does not directly affect glutamatergic neurotransmission. Rather, CMS sensitizes CB1 function on GABAergic terminals, leading to less inhibition and an increase in excitatory neurotransmission. This finding is reinforced in that induction of weak long-term-potentiation (LTP) is enhanced in CMS-exposed animals compared to controls and this enhancement is CB1-dependent. Lastly, we observed that the LTP-blocking property of WIN 55,212-5 shifts from being glutamate-dependent in non-stress animals to being GABA-dependent in stress animals. These results effectively demonstrate that CMS significantly alters hippocampal eCB-mediated neurotransmission and synaptic plasticity.

  18. Dynamics of networks of excitatory and inhibitory neurons in response to time-dependent inputs.

    Science.gov (United States)

    Ledoux, Erwan; Brunel, Nicolas

    2011-01-01

    We investigate the dynamics of recurrent networks of excitatory (E) and inhibitory (I) neurons in the presence of time-dependent inputs. The dynamics is characterized by the network dynamical transfer function, i.e., how the population firing rate is modulated by sinusoidal inputs at arbitrary frequencies. Two types of networks are studied and compared: (i) a Wilson-Cowan type firing rate model; and (ii) a fully connected network of leaky integrate-and-fire (LIF) neurons, in a strong noise regime. We first characterize the region of stability of the "asynchronous state" (a state in which population activity is constant in time when external inputs are constant) in the space of parameters characterizing the connectivity of the network. We then systematically characterize the qualitative behaviors of the dynamical transfer function, as a function of the connectivity. We find that the transfer function can be either low-pass, or with a single or double resonance, depending on the connection strengths and synaptic time constants. Resonances appear when the system is close to Hopf bifurcations, that can be induced by two separate mechanisms: the I-I connectivity and the E-I connectivity. Double resonances can appear when excitatory delays are larger than inhibitory delays, due to the fact that two distinct instabilities exist with a finite gap between the corresponding frequencies. In networks of LIF neurons, changes in external inputs and external noise are shown to be able to change qualitatively the network transfer function. Firing rate models are shown to exhibit the same diversity of transfer functions as the LIF network, provided delays are present. They can also exhibit input-dependent changes of the transfer function, provided a suitable static non-linearity is incorporated.

  19. Dynamics of networks of excitatory and inhibitory neuronsin response to time-dependent inputs

    Directory of Open Access Journals (Sweden)

    Erwan eLedoux

    2011-05-01

    Full Text Available We investigate the dynamics of recurrent networks of excitatory (E and inhibitory(I neurons in the presence of time-dependent inputs. The dynamics is characterizedby the network dynamical transfer function, i.e. how the population firing rate ismodulated by sinusoidal inputs at arbitrary frequencies. Two types of networks arestudied and compared: (i a Wilson-Cowan type firing rate model; and (ii a fullyconnected network of leaky integrate-and-fire neurons, in a strong noise regime. Wefirst characterize the region of stability of the ‘asynchronous state’ (a state in whichpopulation activity is constant in time when external inputs are constant in the spaceof parameters characterizing the connectivity of the network. We then systematicallycharacterize the qualitative behaviors of the dynamical transfer function, as a functionof the connectivity. We find that the transfer function can be either low-pass, or witha single or double resonance, depending on the connection strengths and synaptic timeconstants. Resonances appear when the system is close to Hopf bifurcations, that canbe induced by two separate mechanisms: the I-I connectivity and the E-I connectivity.Double resonances can appear when excitatory delays are larger than inhibitory delays,due to the fact that two distinct instabilities exist with a finite gap between thecorresponding frequencies. In networks of LIF neurons, changes in external inputs andexternal noise are shown to be able to change qualitatively the network transfer function.Firing rate models are shown to exhibit the same diversity of transfer functions asthe LIF network, provided delays are present. They can also exhibit input-dependentchanges of the transfer function, provided a suitable static nonlinearity is incorporated.

  20. Dynamics of excitatory synaptic components in sustained firing at low rates.

    Science.gov (United States)

    Wyart, Claire; Cocco, Simona; Bourdieu, Laurent; Léger, Jean-Francois; Herr, Catherine; Chatenay, Didier

    2005-06-01

    Sustained firing is necessary for the persistent activity associated with working memory. The relative contributions of the reverberation of excitation and of the temporal dynamics of the excitatory postsynaptic potential (EPSP) to the maintenance of activity are difficult to evaluate in classical preparations. We used simplified models of synchronous excitatory networks, hippocampal autapses and pairs, to study the synaptic mechanisms underlying firing at low rates. Calcium imaging and cell attached recordings showed that these neurons spontaneously fired bursts of action potentials that lasted for seconds over a wide range of frequencies. In 2-wk-old cells, the median firing frequency was low (11 +/- 8.8 Hz), whereas in 3- to 4-wk-old cells, it decreased to a very low value (2 +/- 1.3 Hz). In both cases, we have shown that the slowest synaptic component supported firing. In 2-wk-old autapses, antagonists of N-methyl-d-aspartate receptors (NMDARs) induced rare isolated spikes showing that the NMDA component of the EPSP was essential for bursts at low frequency. In 3- to 4-wk-old neurons, the very low frequency firing was maintained without the NMDAR activation. However EGTA-AM or alpha-methyl-4-carboxyphenylglycine (MCPG) removed the very slow depolarizing component of the EPSP and prevented the sustained firing at very low rate. A metabotropic glutamate receptor (mGluR)-activated calcium sensitive conductance is therefore responsible for a very slow synaptic component associated with firing at very low rate. In addition, our observations suggested that the asynchronous release of glutamate might participate also in the recurring bursting.

  1. GABA B receptor modulation of excitatory and inhibitory synaptic transmission onto rat CA3 hippocampal interneurons.

    Science.gov (United States)

    Lei, Saobo; McBain, Chris J

    2003-01-15

    Hippocampal stratum radiatum inhibitory interneurons receive glutamatergic excitatory innervation via the recurrent collateral fibers of CA3 pyramidal neurons and GABAergic inhibition from other interneurons. We examined both presynaptic- and postsynaptic-GABA(B) receptor-mediated responses at both synapse types. Postsynaptic GABA(B) receptor-mediated responses were absent in recordings from young (P16-18) but present in recordings from older animals (> or =P30) suggesting developmental regulation. In young animals, the GABA(B) receptor agonist, baclofen, inhibited the amplitude of evoked EPSCs and IPSCs, an effect blocked by prior application of the selective antagonist CGP55845. Baclofen enhanced the paired-pulse ratio and coefficient of variation of evoked EPSCs and IPSCs, consistent with a presynaptic mechanism of regulation. In addition, baclofen reduced the frequency of miniature IPSCs but not mEPSCs. However, baclofen reduced the frequency of KCl-induced mEPSCs; an effect blocked by Cd(2+), implicating presynaptic voltage-gated Ca(2+) channels as a target for baclofen modulation. In contrast, although Cd(2+) prevented the KCl-induced increase in mIPSC frequency, it failed to block baclofen's reduction of mIPSC frequency. Whereas N- and P/Q-types of Ca(2+) channels contributed equally to GABA(B) receptor-mediated inhibition of EPSCs, more P/Q-type Ca(2+) channels were involved in GABA(B) receptor-mediated inhibition of IPSCs. Finally, baclofen blocked the frequency-dependent depression of EPSCs and IPSCs, but was less effective at blocking frequency-dependent facilitation of EPSCs. Our results demonstrate that presynaptic GABA(B) receptors are expressed on the terminals of both excitatory and inhibitory synapses onto CA3 interneurons and that their activation modulates essential components of the release process underlying transmission at these two synapse types.

  2. mGluRs modulate strength and timing of excitatory transmission in hippocampal area CA3.

    Science.gov (United States)

    Cosgrove, Kathleen E; Galván, Emilio J; Barrionuevo, Germán; Meriney, Stephen D

    2011-08-01

    Excitatory transmission within hippocampal area CA3 stems from three major glutamatergic pathways: the perforant path formed by axons of layer II stellate cells in the entorhinal cortex, the mossy fiber axons originating from the dentate gyrus granule cells, and the recurrent axon collaterals of CA3 pyramidal cells. The synaptic communication of each of these pathways is modulated by metabotropic glutamate receptors that fine-tune the signal by affecting both the timing and strength of the connection. Within area CA3 of the hippocampus, group I mGluRs (mGluR1 and mGluR5) are expressed postsynaptically, whereas group II (mGluR2 and mGluR3) and III mGluRs (mGluR4, mGluR7, and mGluR8) are expressed presynaptically. Receptors from each group have been demonstrated to be required for different forms of pre- and postsynaptic long-term plasticity and also have been implicated in regulating short-term plasticity. A recent observation has demonstrated that a presynaptically expressed mGluR can affect the timing of action potentials elicited in the postsynaptic target. Interestingly, mGluRs can be distributed in a target-specific manner, such that synaptic input from one presynaptic neuron can be modulated by different receptors at each of its postsynaptic targets. Consequently, mGluRs provide a mechanism for synaptic specialization of glutamatergic transmission in the hippocampus. This review will highlight the variability in mGluR modulation of excitatory transmission within area CA3 with an emphasis on how these receptors contribute to the strength and timing of network activity within pyramidal cells and interneurons.

  3. Training Excitatory-Inhibitory Recurrent Neural Networks for Cognitive Tasks: A Simple and Flexible Framework.

    Science.gov (United States)

    Song, H Francis; Yang, Guangyu R; Wang, Xiao-Jing

    2016-02-01

    The ability to simultaneously record from large numbers of neurons in behaving animals has ushered in a new era for the study of the neural circuit mechanisms underlying cognitive functions. One promising approach to uncovering the dynamical and computational principles governing population responses is to analyze model recurrent neural networks (RNNs) that have been optimized to perform the same tasks as behaving animals. Because the optimization of network parameters specifies the desired output but not the manner in which to achieve this output, "trained" networks serve as a source of mechanistic hypotheses and a testing ground for data analyses that link neural computation to behavior. Complete access to the activity and connectivity of the circuit, and the ability to manipulate them arbitrarily, make trained networks a convenient proxy for biological circuits and a valuable platform for theoretical investigation. However, existing RNNs lack basic biological features such as the distinction between excitatory and inhibitory units (Dale's principle), which are essential if RNNs are to provide insights into the operation of biological circuits. Moreover, trained networks can achieve the same behavioral performance but differ substantially in their structure and dynamics, highlighting the need for a simple and flexible framework for the exploratory training of RNNs. Here, we describe a framework for gradient descent-based training of excitatory-inhibitory RNNs that can incorporate a variety of biological knowledge. We provide an implementation based on the machine learning library Theano, whose automatic differentiation capabilities facilitate modifications and extensions. We validate this framework by applying it to well-known experimental paradigms such as perceptual decision-making, context-dependent integration, multisensory integration, parametric working memory, and motor sequence generation. Our results demonstrate the wide range of neural activity patterns

  4. Hyperactivity of Newborn Pten Knock-out Neurons Results from Increased Excitatory Synaptic Drive

    Science.gov (United States)

    Williams, Michael R.; DeSpenza, Tyrone; Li, Meijie; Gulledge, Allan T.

    2015-01-01

    Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either “birthdate” or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons. PMID:25609613

  5. Bioavailability Studies and in vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH‐102

    DEFF Research Database (Denmark)

    Haym, Isabell; Huynh, Tri H. V.; Hansen, Stinne W.

    2016-01-01

    Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH‐101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood–brain barrier makes it unsuitable for in vivo studies...

  6. Superficially projecting principal neurons in layer V of medial entorhinal cortex in the rat receive excitatory retrosplenial input.

    Science.gov (United States)

    Czajkowski, Rafał; Sugar, Jørgen; Zhang, Sheng-Jia; Couey, Jonathan J; Ye, Jing; Witter, Menno P

    2013-10-01

    Principal cells in layer V of the medial entorhinal cortex (MEC) have a nodal position in the cortical-hippocampal network. They are the main recipients of hippocampal output and receive inputs from several cortical areas, including a prominent one from the retrosplenial cortex (RSC), likely targeting basal dendrites of layer V neurons. The latter project to extrahippocampal structures but also relay information to the superficial layers of MEC, closing the hippocampal-entorhinal loop. In the rat, we electrophysiologically and morphologically characterized RSC input into MEC and conclude that RSC provides an excitatory input to layer V pyramidal cells. Ultrastructural analyses of anterogradely labeled RSC projections showed that RSC axons in layer V of MEC form predominantly asymmetrical, likely excitatory, synapses on dendritic spines (90%) or shafts (8%), with 2% symmetrical, likely inhibitory, synapses on shafts and spines. The overall excitatory nature of the RSC input was confirmed by an optogenetic approach. Patterned laser stimulation of channelrhodopsin-expressing presynaptic RSC axons evoked exclusively EPSPs in recorded postsynaptic layer V cells. All responding layer V pyramidal cells had an axon extending toward the white matter. Half of these neurons also sent an axon to superficial layers. Confocal imaging of RSC synapses onto MEC layer V neurons shown to project superficially by way of retrogradely labeling from superficial layers confirmed that proximal dendrites of superficially projecting cells are among the targets of inputs from RSC. The excitatory RSC input thus interacts with both entorhinal-cortical and entorhinal-hippocampal circuits.

  7. Excitatory amino acid transporters EAAT-1 and EAAT-2 in temporal lobe and hippocampus in intractable temporal lobe epilepsy

    DEFF Research Database (Denmark)

    Sarac, Sinan; Afzal, Shoaib; Broholm, Helle;

    2009-01-01

    extra-cellular clearance of glutamate by excitatory amino acid transporters (EAAT-1 to EAAT-5). EAAT-1 and EAAT-2 are mainly expressed on astroglial cells for the reuptake of glutamate from the extra-cellular space. We have studied the expression of EAAT-1 and EAAT-2 in the hippocampus and temporal lobe...

  8. Effects of excitatory and inhibitory neurotransmission on motor patterns of human sigmoid colon in vitro

    Science.gov (United States)

    Aulí, M; Martínez, E; Gallego, D; Opazo, A; Espín, F; Martí-Gallostra, M; Jiménez, M; Clavé, P

    2008-01-01

    Background and purpose: To characterize the in vitro motor patterns and the neurotransmitters released by enteric motor neurons (EMNs) in the human sigmoid colon. Experimental approach: Sigmoid circular strips were studied in organ baths. EMNs were stimulated by electrical field stimulation (EFS) and through nicotinic ACh receptors. Key results: Strips developed weak spontaneous rhythmic contractions (3.67±0.49 g, 2.54±0.15 min) unaffected by the neurotoxin tetrodotoxin (TTX; 1 μM). EFS induced strong contractions during (on, 56%) or after electrical stimulus (off, 44%), both abolished by TTX. Nicotine (1–100 μM) inhibited spontaneous contractions. Latency of off-contractions and nicotine responses were reduced by NG-nitro-L-arginine (1 mM) and blocked after further addition of apamin (1 μM) or the P2Y1 receptor antagonist MRS 2179 (10 μM) and were unaffected by the P2X antagonist NF279 (10 μM) or α-chymotrypsin (10 U mL−1). Amplitude of on- and off-contractions was reduced by atropine (1 μM) and the selective NK2 receptor antagonist Bz-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (1 μM). MRS 2179 reduced the amplitude of EFS on- and off-contractions without altering direct muscular contractions induced by ACh (1 nM–1 mM) or substance P (1 nM–10 μM). Conclusions and implications: Latency of EFS-induced off-contractions and inhibition of spontaneous motility by nicotine are caused by stimulation of inhibitory EMNs coreleasing NO and a purine acting at muscular P2Y1 receptors through apamin-sensitive K+ channels. EFS-induced on- and off-contractions are caused by stimulation of excitatory EMNs coreleasing ACh and tachykinins acting on muscular muscarinic and NK2 receptors. Prejunctional P2Y1 receptors might modulate the activity of excitatory EMNs. P2Y1 and NK2 receptors might be therapeutic targets for colonic motor disorders. PMID:18846038

  9. Local connections of excitatory neurons in motor-associated cortical areas of the rat

    Science.gov (United States)

    Kaneko, Takeshi

    2013-01-01

    In spite of recent progress in brain sciences, the local circuit of the cerebral neocortex, including motor areas, still remains elusive. Morphological works on excitatory cortical circuitry from thalamocortical (TC) afferents to corticospinal neurons (CSNs) in motor-associated areas are reviewed here. First, TC axons of motor thalamic nuclei have been re-examined by the single-neuron labeling method. There are middle layer (ML)-targeting and layer (L) 1-preferring TC axon types in motor-associated areas, being analogous to core and matrix types, respectively, of Jones (1998) in sensory areas. However, the arborization of core-like motor TC axons spreads widely and disregards the columnar structure that is the basis of information processing in sensory areas, suggesting that motor areas adopt a different information-processing framework such as area-wide laminar organization. Second, L5 CSNs receive local excitatory inputs not only from L2/3 pyramidal neurons but also from ML spiny neurons, the latter directly processing cerebellar information of core-like TC neurons (TCNs). In contrast, basal ganglia information is targeted to apical dendrites of L2/3 and L5 pyramidal neurons through matrix TCNs. Third, L6 corticothalamic neurons (CTNs) are most densely innervated by ML spiny neurons located just above CTNs. Since CTNs receive only weak connections from L2/3 and L5 pyramidal neurons, the TC recurrent circuit composed of TCNs, ML spiny neurons and CTNs appears relatively independent of the results of processing in L2/3 and L5. It is proposed that two circuits sharing the same TC projection and ML neurons are embedded in the neocortex: one includes L2/3 and L5 neurons, processes afferent information in a feedforward way and sends the processed information to other cortical areas and subcortical regions; and the other circuit participates in a dynamical system of the TC recurrent circuit and may serve as the basis of autonomous activity of the neocortex. PMID

  10. The relative contribution of NMDARs to excitatory postsynaptic currents is controlled by Ca2+-induced inactivation.

    Directory of Open Access Journals (Sweden)

    Fliza eValiullina

    2016-01-01

    Full Text Available NMDA receptors (NMDARs are important mediators of excitatory synaptic transmission and plasticity. A hallmark of these channels is their high permeability to Ca2+. At the same time, they are themselves inhibited by the elevation of intracellular Ca2+ concentration. It is unclear however, whether the Ca2+ entry associated with single NMDAR mediated synaptic events is sufficient to self-inhibit their activation. Such auto-regulation would have important effects on the dynamics of synaptic excitation in several central networks. Therefore, we studied NMDAR-mediated synaptic currents in mouse hippocampal CA1 pyramidal neurons. Postsynaptic responses to subthreshold Schaffer collateral stimulation depended strongly on the absence or presence of intracellular Ca2+ buffers. Loading of pyramidal cells with exogenous Ca2+ buffers increased the amplitude and decay time of NMDAR mediated EPSCs (EPSP and prolonged the time window for action potential generation.Our data indicate that the Ca2+ influx mediated by unitary synaptic events is sufficient to produce detectable self-inhibition of NMDARs even at a physiological Mg2+ concentration. Therefore, the contribution of NMDARs to synaptic excitation is strongly controlled by both previous synaptic activity as well as by the Ca2+ buffer capacity of postsynaptic neurons.

  11. Glutamate-containing dipeptides do not modulate ligand binding at excitatory amino acid receptors.

    Science.gov (United States)

    Baud, J; Fagg, G E

    1986-10-08

    Dipeptides of the structure X-Glu (e.g. X = Phe, Leu) have been proposed as allosteric modulators of excitatory amino acid receptors in rat brain membranes. Here we report that these dipeptides reduce the binding of L-[3H]Glu (predominantly N-methyl-D-aspartate-sensitive sites) and of [3H]kainate to postsynaptic density preparations isolated from rat brain. However, several observations indicate that the effects of these dipeptides are mediated not by allosteric modulation, but by free L-Glu liberated by the actions of a membrane-associated aminopeptidase. The absolute and relative potencies of the dipeptides are similar at all acidic amino acid binding sites examined to date, suggesting the involvement of a factor with similar activity at each site (e.g. L-Glu). N-Acetyl-Met-Glu is a weak inhibitor of L-Glu and kainate binding, and N-blocked peptides are known to be poor substrates of aminopeptidases. Bestatin, an inhibitor of aminopeptidases, decreases or abolishes the effects of substrate dipeptides on L-Glu and kainate receptor binding, while having no effect itself.

  12. A family of excitatory peptide toxins from venomous crassispirine snails: using Constellation Pharmacology to assess bioactivity.

    Science.gov (United States)

    Imperial, Julita S; Cabang, April B; Song, Jie; Raghuraman, Shrinivasan; Gajewiak, Joanna; Watkins, Maren; Showers-Corneli, Patrice; Fedosov, Alexander; Concepcion, Gisela P; Terlau, Heinrich; Teichert, Russell W; Olivera, Baldomero M

    2014-10-01

    The toxinology of the crassispirine snails, a major group of venomous marine gastropods within the superfamily Conoidea, is largely unknown. Here we define the first venom peptide superfamily, the P-like crassipeptides, and show that the organization of their gene sequences is similar to conotoxin precursors. We provide evidence that one peptide family within the P-like crassipeptide superfamily includes potassium-channel (K-channel) blockers, the κP-crassipeptides. Three of these peptides were chemically synthesized (cce9a, cce9b and iqi9a). Using conventional electrophysiology, cce9b was shown to be an antagonist of both a human Kv1.1 channel isoform (Shaker subfamily of voltage-gated K channels) and a Drosophila K-channel isoform. We assessed the bioactivity of these peptides in native mammalian dorsal root ganglion neurons in culture. We demonstrate that two of these crassipeptides, cce9a and cce9b, elicited an excitatory phenotype in a subset of small-diameter capsaicin-sensitive mouse DRG neurons that were also affected by κJ-conotoxin PlXIVA (pl14a), a blocker of Kv1.6 channels. Given the vast complexity of heteromeric K-channel isoforms, this study demonstrates that the crassispirine venoms are a potentially rich source for discovering novel peptides that can help to identify and characterize the diversity of K-channel subtypes expressed in native neurons and other cell types.

  13. Anatomy and function of an excitatory network in the visual cortex.

    Science.gov (United States)

    Lee, Wei-Chung Allen; Bonin, Vincent; Reed, Michael; Graham, Brett J; Hood, Greg; Glattfelder, Katie; Reid, R Clay

    2016-04-21

    Circuits in the cerebral cortex consist of thousands of neurons connected by millions of synapses. A precise understanding of these local networks requires relating circuit activity with the underlying network structure. For pyramidal cells in superficial mouse visual cortex (V1), a consensus is emerging that neurons with similar visual response properties excite each other, but the anatomical basis of this recurrent synaptic network is unknown. Here we combined physiological imaging and large-scale electron microscopy to study an excitatory network in V1. We found that layer 2/3 neurons organized into subnetworks defined by anatomical connectivity, with more connections within than between groups. More specifically, we found that pyramidal neurons with similar orientation selectivity preferentially formed synapses with each other, despite the fact that axons and dendrites of all orientation selectivities pass near (<5 μm) each other with roughly equal probability. Therefore, we predict that mechanisms of functionally specific connectivity take place at the length scale of spines. Neurons with similar orientation tuning formed larger synapses, potentially enhancing the net effect of synaptic specificity. With the ability to study thousands of connections in a single circuit, functional connectomics is proving a powerful method to uncover the organizational logic of cortical networks.

  14. Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress.

    Science.gov (United States)

    Perova, Zinaida; Delevich, Kristen; Li, Bo

    2015-02-18

    In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events.

  15. The mechanism of noradrenergic alpha 1 excitatory modulation of pontine reticular formation neurons.

    Science.gov (United States)

    Stevens, D R; McCarley, R W; Greene, R W

    1994-11-01

    The alpha 1 adrenergic receptor occurs in all major divisions of the CNS and is thought to play a role in all behaviors influenced by norepinephrine (NE). In the medial pontine reticular formation (mPRF), the proposed site of adrenergic enhancement of startle responses (Davis, 1984), alpha 1 agonists excite most neurons (Gerber et al., 1990). We here report that alpha 1 excitation results from a reduction of a voltage- and calcium-dependent potassium current, not previously recognized as ligand-modulated. The calcium sensitivity is suggested by its antagonism with Mg2+, Cd2+, Ba2+, low concentrations of tetraethylammonium, and charybdotoxin. The voltage sensitivity of this conductance falls within the membrane potential range critical to action potential generation. Based on this voltage sensitivity, the change in repetitive firing characteristics may be predicted according to a mathematical model of the mPRF neuronal electrophysiology. The predicted response to a 50% decrease in the phenylephrine (PE)-sensitive conductance is similar to the observed responses, with respect to both the current response under voltage-clamp conditions and alterations of the AHP and frequency/current curve. In contrast, modeling a reduction of a voltage-insensitive leak current predicts none of these changes. Thus, the noradrenergic reduction of this current depolarizes the membrane, increases the likelihood of an initial response to depolarizing input, and increases firing rate during sustained depolarization in a manner consistent with an NE role as an excitatory neuromodulator of the mPRF.

  16. Comparing the efficacy of excitatory transcranial stimulation methods measuring motor evoked potentials.

    Science.gov (United States)

    Moliadze, Vera; Fritzsche, Georg; Antal, Andrea

    2014-01-01

    The common aim of transcranial stimulation methods is the induction or alterations of cortical excitability in a controlled way. Significant effects of each individual stimulation method have been published; however, conclusive direct comparisons of many of these methods are rare. The aim of the present study was to compare the efficacy of three widely applied stimulation methods inducing excitability enhancement in the motor cortex: 1 mA anodal transcranial direct current stimulation (atDCS), intermittent theta burst stimulation (iTBS), and 1 mA transcranial random noise stimulation (tRNS) within one subject group. The effect of each stimulation condition was quantified by evaluating motor-evoked-potential amplitudes (MEPs) in a fixed time sequence after stimulation. The analyses confirmed a significant enhancement of the M1 excitability caused by all three types of active stimulations compared to sham stimulation. There was no significant difference between the types of active stimulations, although the time course of the excitatory effects slightly differed. Among the stimulation methods, tRNS resulted in the strongest and atDCS significantly longest MEP increase compared to sham. Different time courses of the applied stimulation methods suggest different underlying mechanisms of action. Better understanding may be useful for better targeting of different transcranial stimulation techniques.

  17. Modulation of excitatory neurotransmission by neuronal/glial signalling molecules: interplay between purinergic and glutamatergic systems.

    Science.gov (United States)

    Köles, László; Kató, Erzsébet; Hanuska, Adrienn; Zádori, Zoltán S; Al-Khrasani, Mahmoud; Zelles, Tibor; Rubini, Patrizia; Illes, Peter

    2016-03-01

    Glutamate is the main excitatory neurotransmitter of the central nervous system (CNS), released both from neurons and glial cells. Acting via ionotropic (NMDA, AMPA, kainate) and metabotropic glutamate receptors, it is critically involved in essential regulatory functions. Disturbances of glutamatergic neurotransmission can be detected in cognitive and neurodegenerative disorders. This paper summarizes the present knowledge on the modulation of glutamate-mediated responses in the CNS. Emphasis will be put on NMDA receptor channels, which are essential executive and integrative elements of the glutamatergic system. This receptor is crucial for proper functioning of neuronal circuits; its hypofunction or overactivation can result in neuronal disturbances and neurotoxicity. Somewhat surprisingly, NMDA receptors are not widely targeted by pharmacotherapy in clinics; their robust activation or inhibition seems to be desirable only in exceptional cases. However, their fine-tuning might provide a promising manipulation to optimize the activity of the glutamatergic system and to restore proper CNS function. This orchestration utilizes several neuromodulators. Besides the classical ones such as dopamine, novel candidates emerged in the last two decades. The purinergic system is a promising possibility to optimize the activity of the glutamatergic system. It exerts not only direct and indirect influences on NMDA receptors but, by modulating glutamatergic transmission, also plays an important role in glia-neuron communication. These purinergic functions will be illustrated mostly by depicting the modulatory role of the purinergic system on glutamatergic transmission in the prefrontal cortex, a CNS area important for attention, memory and learning.

  18. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders.

    Science.gov (United States)

    Ben-Ari, Yehezkel; Khalilov, Ilgam; Kahle, Kristopher T; Cherubini, Enrico

    2012-10-01

    Ionic currents and the network-driven patterns they generate differ in immature and adult neurons: The developing brain is not a "small adult brain." One of the most investigated examples is the developmentally regulated shift of actions of the transmitter GABA that inhibit adult neurons but excite immature ones because of an initially higher intracellular chloride concentration [Cl(-)](i), leading to depolarizing and often excitatory actions of GABA instead of hyperpolarizing and inhibitory actions. The levels of [Cl(-)](i) are also highly labile, being readily altered transiently or persistently by enhanced episodes of activity in relation to synaptic plasticity or a variety of pathological conditions, including seizures and brain insults. Among the plethora of channels, transporters, and other devices involved in controlling [Cl(-)](i), two have emerged as playing a particularly important role: the chloride importer NKCC1 and the chloride exporter KCC2. Here, the authors stress the importance of determining how [Cl(-)](i) is dynamically regulated and how this affects brain operation in health and disease. In a clinical perspective, agents that control [Cl(-)](i) and reinstate inhibitory actions of GABA open novel therapeutic perspectives in many neurological disorders, including infantile epilepsies, autism spectrum disorders, and other developmental disorders.

  19. Spatially structured oscillations in a two-dimensional excitatory neuronal network with synaptic depression

    KAUST Repository

    Kilpatrick, Zachary P.

    2009-10-29

    We study the spatiotemporal dynamics of a two-dimensional excitatory neuronal network with synaptic depression. Coupling between populations of neurons is taken to be nonlocal, while depression is taken to be local and presynaptic. We show that the network supports a wide range of spatially structured oscillations, which are suggestive of phenomena seen in cortical slice experiments and in vivo. The particular form of the oscillations depends on initial conditions and the level of background noise. Given an initial, spatially localized stimulus, activity evolves to a spatially localized oscillating core that periodically emits target waves. Low levels of noise can spontaneously generate several pockets of oscillatory activity that interact via their target patterns. Periodic activity in space can also organize into spiral waves, provided that there is some source of rotational symmetry breaking due to external stimuli or noise. In the high gain limit, no oscillatory behavior exists, but a transient stimulus can lead to a single, outward propagating target wave. © Springer Science + Business Media, LLC 2009.

  20. Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction.

    Science.gov (United States)

    Rao, Pss; Yallapu, Murali M; Sari, Youssef; Fisher, Paul B; Kumar, Santosh

    Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

  1. Anti-epileptic effects of focal micro-injection of excitatory amino acid antagonists.

    Science.gov (United States)

    Meldrum, B; Millan, M; Patel, S; de Sarro, G

    1988-01-01

    The role of excitatory synaptic activity at various brain regions in the development and spread of seizure activity has been investigated by the focal microinjection of 2-amino-7-phosphono-heptanoate (2-APH), a selective antagonist at the N-methyl-D-aspartate preferring receptor, or gamma-D-glutamyl-aminomethyl sulphonate (GAMS), a partially selective antagonist at the kainate receptor. In genetically epilepsy prone rats the seizure response to a loud sound in most effectively suppressed by focal injections of 2-APH, 0.1-1.0 nmol, in the inferior colliculus. Protection is also seen after injections of 2-APH, 25 nmoles, in the substantia nigra (pars reticulata) or the midbrain reticular formation. Motor limbic seizures induced by pilocarpine, 380 mg/kg intraperitoneally, are prevented by prior injection into the substantia nigra, pars reticulata, or the entopeduncular nucleus, of 2-APH, 10 nmol or 10 pmol, respectively. Similar protection follows the injection of 2-APH, 1-5 pmol in the piriform cortex. The convulsant effects of pilocarpine are also blocked by the focal injection of GAMS, 10 nmol in the entopeduncular nucleus. This experimental approach can indicate critical sites at which seizure activity is initiated in particular models (e.g., inferior colliculus in sound-induced seizures, and piriform cortex in limbic seizures) and the pathways controlling seizure expression, such as the basal ganglia outputs. It also identifies specific receptors at which anticonvulsant drugs may operate.

  2. Effect of excitatory amino acids on serum TSH and thyroid hormone levels in freely moving rats.

    Science.gov (United States)

    Alfonso, M; Durán, R; Arufe, M C

    2000-01-01

    The actions of glutamate (L-Glu), and glutamate receptor agonists on serum thyroid hormones (T4 and T3) and TSH levels have been studied in conscious and freely moving adult male rats. The excitatory amino acids (EAA), L-Glu, N-methyl-D-aspartate (NMDA), kainic acid (KA) and domoic acid (Dom) were administered intraperitoneally. Blood samples were collected through a cannula implanted in the rats jugular 0--60 min after injection. Thyroid hormone concentrations were measured by enzyme immunoassay, and thyrotrophin (TSH) concentrations were determined by radioimmunoassay. The results showed that L-Glu (20 and 25 mg/kg) and NMDA (25 mg/kg) increased serum thyroxine (T4), triiodothyronine (T3) and TSH concentrations. Serum thyroid hormone levels increased 30 min after treatment, while serum TSH levels increased 5 min after i.p. administration, in both cases serum levels remained elevated during one hour. Injection of the non-NMDA glutamatergic agonists KA (30 mg/kg) and Dom (1 mg/kg) produced an increase in serum thyroid hormones and TSH levels. These results suggest the importance of EAAs in the regulation of hormone secretion from the pituitary-thyroid axis, as well as the importance of the NMDA and non-NMDA receptors in this stimulatory effect.

  3. Synaptic Variability Introduces State-Dependent Modulation of Excitatory Spinal Cord Synapses

    Directory of Open Access Journals (Sweden)

    David Parker

    2015-01-01

    Full Text Available The relevance of neuronal and synaptic variability remains unclear. Cellular and synaptic plasticity and neuromodulation are also variable. This could reflect state-dependent effects caused by the variable initial cellular or synaptic properties or direct variability in plasticity-inducing mechanisms. This study has examined state-dependent influences on synaptic plasticity at connections between excitatory interneurons (EIN and motor neurons in the lamprey spinal cord. State-dependent effects were examined by correlating initial synaptic properties with the substance P-mediated plasticity of low frequency-evoked EPSPs and the reduction of the EPSP depression over spike trains (metaplasticity. The low frequency EPSP potentiation reflected an interaction between the potentiation of NMDA responses and the release probability. The release probability introduced a variable state-dependent subtractive influence on the postsynaptic NMDA-dependent potentiation. The metaplasticity was also state-dependent: it was greater at connections with smaller available vesicle pools and high initial release probabilities. This was supported by the significant reduction in the number of connections showing metaplasticity when the release probability was reduced by high Mg2+ Ringer. Initial synaptic properties thus introduce state-dependent influences that affect the potential for plasticity. Understanding these conditions will be as important as understanding the subsequent changes.

  4. Synaptic Variability Introduces State-Dependent Modulation of Excitatory Spinal Cord Synapses.

    Science.gov (United States)

    Parker, David

    2015-01-01

    The relevance of neuronal and synaptic variability remains unclear. Cellular and synaptic plasticity and neuromodulation are also variable. This could reflect state-dependent effects caused by the variable initial cellular or synaptic properties or direct variability in plasticity-inducing mechanisms. This study has examined state-dependent influences on synaptic plasticity at connections between excitatory interneurons (EIN) and motor neurons in the lamprey spinal cord. State-dependent effects were examined by correlating initial synaptic properties with the substance P-mediated plasticity of low frequency-evoked EPSPs and the reduction of the EPSP depression over spike trains (metaplasticity). The low frequency EPSP potentiation reflected an interaction between the potentiation of NMDA responses and the release probability. The release probability introduced a variable state-dependent subtractive influence on the postsynaptic NMDA-dependent potentiation. The metaplasticity was also state-dependent: it was greater at connections with smaller available vesicle pools and high initial release probabilities. This was supported by the significant reduction in the number of connections showing metaplasticity when the release probability was reduced by high Mg(2+) Ringer. Initial synaptic properties thus introduce state-dependent influences that affect the potential for plasticity. Understanding these conditions will be as important as understanding the subsequent changes.

  5. Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells

    Science.gov (United States)

    Ho, Seok-Man; Hartley, Brigham J.; Julia, TCW; Beaumont, Michael; Stafford, Khalifa; Slesinger, Paul A.; Brennand, Kristen J.

    2015-01-01

    Since the discovery of somatic reprogramming, human induced pluripotent stem cells (hiPSCs) have been exploited to model a variety of neurological and psychiatric disorders. Because hiPSCs represent an almost limitless source of patient-derived neurons that retain the genetic variations thought to contribute to disease etiology, they have been heralded as a patient-specific platform for high throughput drug screening. However, the utility of current protocols for generating neurons from hiPSCs remains limited by protracted differentiation timelines and heterogeneity of the neuronal phenotypes produced. Neuronal induction via the forced expression of exogenous transcription factors rapidly induces defined populations of functional neurons from fibroblasts and hiPSCs. Here, we describe an adapted protocol that accelerates maturation of functional excitatory neurons from hiPSC-derived neural progenitor cells (NPCs) via lentiviral transduction of Neurogenin 2 (using both mNgn2 and hNGN2). This methodology, relying upon a robust and scalable starting population of hiPSC NPCs, should be readily amenable to scaling for hiPSC-based high-throughput drug screening. PMID:26626326

  6. Somatodendritic and excitatory postsynaptic distribution of neuron-type dystrophin isoform, Dp40, in hippocampal neurons.

    Science.gov (United States)

    Fujimoto, Takahiro; Itoh, Kyoko; Yaoi, Takeshi; Fushiki, Shinji

    2014-09-12

    The Duchenne muscular dystrophy (DMD) gene produces multiple dystrophin (Dp) products due to the presence of several promoters. We previously reported the existence of a novel short isoform of Dp, Dp40, in adult mouse brain. However, the exact biochemical expression profile and cytological distribution of the Dp40 protein remain unknown. In this study, we generated a polyclonal antibody against the NH2-terminal region of the Dp40 and identified the expression profile of Dp40 in the mouse brain. Through an analysis using embryonic and postnatal mouse cerebrums, we found that Dp40 emerged from the early neonatal stages until adulthood, whereas Dp71, an another Dp short isoform, was highly detected in both prenatal and postnatal cerebrums. Intriguingly, relative expressions of Dp40 and Dp71 were prominent in cultured dissociated neurons and non-neuronal cells derived from mouse hippocampus, respectively. Furthermore, the immunocytological distribution of Dp40 was analyzed in dissociated cultured neurons, revealing that Dp40 is detected in the soma and its dendrites, but not in the axon. It is worthy to note that Dp40 is localized along the subplasmalemmal region of the dendritic shafts, as well as at excitatory postsynaptic sites. Thus, Dp40 was identified as a neuron-type Dp possibly involving dendritic and synaptic functions.

  7. Excitatory and Inhibitory Neurons in the Hippocampus Exhibit Molecularly Distinct Large Dense Core Vesicles

    Directory of Open Access Journals (Sweden)

    Jose Jorge Ramirez-Franco

    2016-08-01

    Full Text Available Hippocampal interneurons comprise a diverse family of inhibitory neurons which function is critical for fine information processing. Along with gamma-aminobutyric acid (GABA, interneurons secrete a myriad of neuroactive substances via secretory vesicles which molecular composition and regulatory mechanisms remain unknown. In this study, we have carried out an immunohistofluorescence analysis to describe the molecular content of vesicles in distinct populations of hippocampal neurons. Our results indicate that phogrin, an integral protein of secretory vesicles in neuroendocrine cells, is highly enriched in parvalbumin-positive interneurons. Consistently, immunoelectron microscopy revealed phogrin staining in axon terminals of symmetrical synapses establishing inhibitory contacts with cell bodies of CA1 pyramidal neurons. Furthermore, phogrin is highly expressed in CA3 and dentate gyrus interneurons which are both positive for PV and neuropeptide Y. Surprisingly, chromogranin B a canonical large dense core vesicle marker, is excluded from inhibitory cells in the hippocampus but highly expressed in excitatory CA3 pyramidal neurons and dentate gyrus granule cells. Our results provide the first evidence of phogrin expression in hippocampal interneurons and suggest the existence of molecularly distinct populations of secretory vesicles in different types of inhibitory neurons.

  8. APP Homodimers Transduce an Amyloid-β-Mediated Increase in Release Probability at Excitatory Synapses

    Directory of Open Access Journals (Sweden)

    Hilla Fogel

    2014-06-01

    Full Text Available Accumulation of amyloid-β peptides (Aβ, the proteolytic products of the amyloid precursor protein (APP, induces a variety of synaptic dysfunctions ranging from hyperactivity to depression that are thought to cause cognitive decline in Alzheimer’s disease. While depression of synaptic transmission has been extensively studied, the mechanisms underlying synaptic hyperactivity remain unknown. Here, we show that Aβ40 monomers and dimers augment release probability through local fine-tuning of APP-APP interactions at excitatory hippocampal boutons. Aβ40 binds to the APP, increases the APP homodimer fraction at the plasma membrane, and promotes APP-APP interactions. The APP activation induces structural rearrangements in the APP/Gi/o-protein complex, boosting presynaptic calcium flux and vesicle release. The APP growth-factor-like domain (GFLD mediates APP-APP conformational changes and presynaptic enhancement. Thus, the APP homodimer constitutes a presynaptic receptor that transduces signal from Aβ40 to glutamate release. Excessive APP activation may initiate a positive feedback loop, contributing to hippocampal hyperactivity in Alzheimer’s disease.

  9. Theta-burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex.

    Science.gov (United States)

    Di Lazzaro, V; Pilato, F; Saturno, E; Oliviero, A; Dileone, M; Mazzone, P; Insola, A; Tonali, P A; Ranieri, F; Huang, Y Z; Rothwell, J C

    2005-06-15

    In four conscious patients who had electrodes implanted in the cervical epidural space for the control of pain, we recorded corticospinal volleys evoked by single-pulse transcranial magnetic stimulation (TMS) over the motor cortex before and after a 20 s period of continuous theta-burst stimulation (cTBS). It has previously been reported that this form of repetitive TMS reduces the amplitude of motor-evoked potentials (MEPs), with the maximum effect occurring at 5-10 min after the end of stimulation. The present results show that cTBS preferentially decreases the amplitude of the corticospinal I1 wave, with approximately the same time course. This is consistent with a cortical origin of the effect on the MEP. However, other protocols that lead to MEP suppression, such as short-interval intracortical inhibition, are characterized by reduced excitability of late I waves (particularly I3), suggesting that cTBS suppresses MEPs through different mechanisms, such as long-term depression in excitatory synaptic connections.

  10. Traveling waves and breathers in an excitatory-inhibitory neural field

    Science.gov (United States)

    Folias, Stefanos E.

    2017-03-01

    We study existence and stability of traveling activity bump solutions in an excitatory-inhibitory (E-I) neural field with Heaviside firing rate functions by deriving existence conditions for traveling bumps and an Evans function to analyze their spectral stability. Subsequently, we show that these existence and stability results reduce, in the limit of wave speed c →0 , to the equivalent conditions developed for the stationary bump case. Using the results for the stationary bump case, we show that drift bifurcations of stationary bumps serve as a mechanism for generating traveling bump solutions in the E-I neural field as parameters are varied. Furthermore, we explore the interrelations between stationary and traveling types of bumps and breathers (time-periodic oscillatory bumps) by bridging together analytical and simulation results for stationary and traveling bumps and their bifurcations in a region of parameter space. Interestingly, we find evidence for a codimension-2 drift-Hopf bifurcation occurring as two parameters, inhibitory time constant τ and I-to-I synaptic connection strength w¯i i, are varied and show that the codimension-2 point serves as an organizing center for the dynamics of these four types of spatially localized solutions. Additionally, we describe a case involving subcritical bifurcations that lead to traveling waves and breathers as τ is varied.

  11. Different neuropeptides are expressed in different functional subsets of cholinergic excitatory motorneurons in the nematode Ascaris suum.

    Science.gov (United States)

    Konop, Christopher J; Knickelbine, Jennifer J; Sygulla, Molly S; Vestling, Martha M; Stretton, Antony O W

    2015-06-17

    Neuropeptides are known to have dramatic effects on neurons and synapses; however, despite extensive studies of the motorneurons in the parasitic nematode Ascaris suum, their peptide content had not yet been described. We determined the peptide content of single excitatory motorneurons by mass spectrometry and tandem mass spectrometry. There are two subsets of ventral cord excitatory motorneurons, each with neuromuscular output either anterior or posterior to their cell body, mediating forward or backward locomotion, respectively. Strikingly, the two sets of neurons contain different neuropeptides, with AF9 and six novel peptides (As-NLP-21.1-6) in anterior projectors, and the six afp-1 peptides in addition to AF2 in posterior projectors. In situ hybridization confirmed the expression of these peptides, validating the integrity of the dissection technique. This work identifies new components of the functional behavioral circuit, as well as potential targets for antiparasitic drug development.

  12. ELKS controls the pool of readily releasable vesicles at excitatory synapses through its N-terminal coiled-coil domains.

    Science.gov (United States)

    Held, Richard G; Liu, Changliang; Kaeser, Pascal S

    2016-06-02

    In a presynaptic nerve terminal, synaptic strength is determined by the pool of readily releasable vesicles (RRP) and the probability of release (P) of each RRP vesicle. These parameters are controlled at the active zone and vary across synapses, but how such synapse specific control is achieved is not understood. ELKS proteins are enriched at vertebrate active zones and enhance P at inhibitory hippocampal synapses, but ELKS functions at excitatory synapses are not known. Studying conditional knockout mice for ELKS, we find that ELKS enhances the RRP at excitatory synapses without affecting P. Surprisingly, ELKS C-terminal sequences, which interact with RIM, are dispensable for RRP enhancement. Instead, the N-terminal ELKS coiled-coil domains that bind to Liprin-α and Bassoon are necessary to control RRP. Thus, ELKS removal has differential, synapse-specific effects on RRP and P, and our findings establish important roles for ELKS N-terminal domains in synaptic vesicle priming.

  13. Firing clamp: A novel method for single-trial estimation of excitatory and inhibitory synaptic neuronal conductances

    Directory of Open Access Journals (Sweden)

    Anton eChizhov

    2014-03-01

    Full Text Available Understanding non-stationary neuronal activity as seen in vivo requires estimation of both excitatory and inhibitory synaptic conductances from a single trial of recording. We propose a new intracellular recording method for this purpose called firing clamp. Synaptic conductances are estimated from the characteristics of artificially evoked probe spikes, namely the spike amplitude and the mean subthreshold potential, which are sensitive to both excitatory and inhibitory synaptic input signals. The probe spikes, timed at a fixed rate, are evoked in the dynamic-clamp mode by injected meander-like current steps, with the step duration depending on neuronal membrane voltage. We test the method with perforated-patch recordings from isolated cells stimulated by external application or synaptic release of transmitter, and validate the method with simulations of a biophysically-detailed neuron model. The results are compared with the conductance estimates based on conventional current-clamp recordings.

  14. Inhibitory effect of morphine on excitatory synaptic transmission via presynaptic mechanism in rat SON neurons in brain slices

    Institute of Scientific and Technical Information of China (English)

    WANG Xiao-bin; HU San-jue; JU Gong

    2001-01-01

    To observe the effects of morphine on the excitatory postsynaptic currents (EPSCs) and miniature EPSCs (mEPSCs) in rat supraoptic nucleus (SON) neurons and to explore its synaptic mechanism. Methods: Using whole-cell voltage-clamp recording technique in the brain slices, the EPSCS and mEPSCs of rat SON neurons were recorded, respectively. Results: Morphine (20 μmol/L) decreased the frequency of EPSCs and mEPSCs (by 65% for EPSCS and by 45% for mEPSCs), and reduced the amplitude of EPSCs by 44% in all SON neurons, but the amplitude distribution ofmEPSCs was not affected. Conclusion: Morphine inhibits the excitatory transmissions via presynaptic mechanisms in SON neurons from rat brain slices.

  15. Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC

    OpenAIRE

    Kang, SukJae Joshua; Kwak, Chuljung; Lee, Jaejyun; Sim, Su-Eon; Shim, Jaehoon; Choi, Taehyuk; Graham L. Collingridge; Zhou, Min; Kaang, B-K

    2015-01-01

    Neurons in the anterior cingulate cortex (ACC) are assumed to play important roles in the perception of nociceptive signals and the associated emotional responses. However, the neuronal types within the ACC that mediate these functions are poorly understood. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC and to assess their ability to modulate peripheral mechanical hypersensitivity in freely movi...

  16. Excitatory synaptic activity is associated with a rapid structural plasticity of inhibitory synapses on hippocampal CA1 pyramidal cells

    OpenAIRE

    Lushnikova, Irina; Skibo, Galina; Muller, Dominique; Nikonenko, Iryna

    2011-01-01

    Synaptic activity, such as long-term potentiation (LTP), has been shown to induce morphological plasticity of excitatory synapses on dendritic spines through the spine head and postsynaptic density (PSD) enlargement and reorganization. Much less, however, is known about activity-induced morphological modifications of inhibitory synapses. Using an in vitro model of rat organotypic hippocampal slice cultures and electron microscopy, we studied activity-related morphological changes of somatic i...

  17. Evidence for restricted central convergence of cutaneous afferents on an excitatory reflex pathway to medial gastrocnemius motoneurons.

    Science.gov (United States)

    LaBella, L A; McCrea, D A

    1990-08-01

    1. We previously reported that excitatory postsynaptic potentials (EPSPs) produced by low-threshold electrical stimulation of the caudal cutaneous sural nerve (CCS) occur preferentially and with the shortest central latencies in the medial gastrocnemius (MG) portion of the triceps surae motor nuclei. The present study employs the spatial facilitation technique to assess interneuronal convergence on the short-latency excitatory pathway from CCS to MG by several other ipsilateral hindlimb afferents [the lateral cutaneous sural (LCS), caudal cutaneous femoral (CCF), saphenous (SAPH), superficial peroneal (SP), posterior tibial (TIB), and posterior articular (Joint) nerves]. 2. Spatial facilitation of CCF EPSPs in MG motoneurons was demonstrated with conditioning stimulation of the LCS, CCF, SAPH, SP, and TIB nerves, but was most readily and consistently observed with CCF conditioning. Facilitation of CCS and CCF EPSPs was obtained in individual MG motoneurons with a wide range of condition-test intervals. 3. CCF EPSPs in MG motoneurons produced by twice threshold (2T) afferent stimulation had a mean latency of 4.8 ms and often appeared as slowly rising, asynchronous potentials. On the other hand, 2T CCS EPSPs had a mean latency of 2.8 ms and appeared as sharper rising, less variable depolarizations. The optimum condition-test interval for facilitation of CCS and CCF EPSPs was found to be 5.2 ms on average, with CCS stimulation delayed from that of CCF. The longer latency of CCF EPSPs and the finding that the minimum condition-test interval was on the order of 3.9 ms suggests that convergence occurs late in the excitatory CCF pathway to MG motoneurons. 4. Convergence between excitatory pathways to MG from CCF and CCS afferents is discussed with regard to the original observations of Hagbarth on the location of cutaneous receptive fields and excitation of ankle extensors. In addition, evidence for the segregation of these specialized reflex pathways from those involved

  18. Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of FMRP in neurotransmission

    OpenAIRE

    2014-01-01

    Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes Fragile X Syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and the mechanisms of these FMRP actions remain incompletely understood, and the rol...

  19. Vagal nerve stimulation modifies neuronal activity and the proteome of excitatory synapses of amygdala/piriform cortex.

    Science.gov (United States)

    Alexander, Georgia M; Huang, Yang Zhong; Soderblom, Erik J; He, Xiao-Ping; Moseley, M Arthur; McNamara, James O

    2017-02-01

    Vagal Nerve Stimulation (VNS) Therapy(®) is a United States Food and Drug Administration approved neurotherapeutic for medically refractory partial epilepsy and treatment-resistant depression. The molecular mechanisms underlying its beneficial effects are unclear. We hypothesized that one mechanism involves neuronal activity-dependent modifications of central nervous system excitatory synapses. To begin to test this hypothesis, we asked whether VNS modifies the activity of neurons in amygdala and hippocampus. Neuronal recordings from adult, freely moving rats revealed that activity in both amygdala and hippocampus was modified by VNS immediately after its application, and changes were detected following 1 week of stimulation. To investigate whether VNS modifies the proteome of excitatory synapses, we established a label-free, quantitative liquid chromatography-tandem mass spectrometry workflow that enables global analysis of the constituents of the postsynaptic density (PSD) proteome. PSD proteins were biochemically purified from amygdala/piriform cortex of VNS- or dummy-treated rats following 1-week stimulation, and individual PSD protein levels were quantified by liquid chromatography-tandem mass spectrometry analysis. We identified 1899 unique peptides corresponding to 425 proteins in PSD fractions, of which expression levels of 22 proteins were differentially regulated by VNS with changes greater than 150%. Changes in a subset of these proteins, including significantly increased expression of neurexin-1α, cadherin 13 and voltage-dependent calcium channel α2δ1, the primary target of the antiepileptic drug gabapentin, and decreased expression of voltage-dependent calcium channel γ3, were confirmed by western blot analysis of PSD samples. These results demonstrate that VNS modulates excitatory synapses through regulating a subset of the PSD proteome. Our study reveals molecular targets of VNS and point to possible mechanisms underlying its beneficial effects

  20. Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors

    Directory of Open Access Journals (Sweden)

    Gesche eBorn

    2015-02-01

    Full Text Available Human genetics has identified rare copy number variations and deleterious mutations for all neurexin genes (NRXN1-3 in patients with neurodevelopmental diseases, and electrophysiological recordings in animal brains have shown that Nrxns are important for synaptic transmission. While several mouse models for Nrxn1α inactivation have previously been studied for behavioral changes, very little information is available for other variants. Here, we validate that mice lacking Nrxn2α exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior, which partially overlap, partially differ from Nrxn1α mutant behaviors. Using patch-clamp recordings in Nrxn2α knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. We also analyse at this cellular level a novel NRXN2 mouse model that carries a combined deletion of Nrxn2α and Nrxn2β. Electrophysiological analysis of this Nrxn2-mutant mouse shows surprisingly similar defects of excitatory release to Nrxn2α, indicating that the β-variant of Nrxn2 has no strong function in basic transmission at these synapses. Inhibitory transmission as well as synapse densities and ultrastructure remain unchanged in the neocortex of both models. Furthermore, at Nrxn2α and Nrxn2-mutant excitatory synapses we find an altered facilitation and N-methyl-D-aspartate receptor (NMDAR function because NMDAR-dependent decay time and NMDAR-mediated responses are reduced. As Nrxn can indirectly be linked to NMDAR via neuroligin and PSD-95, the trans-synaptic nature of this complex may help to explain occurrence of presynaptic and postsynaptic effects. Since excitatory/inhibitory imbalances and impairment of NMDAR function are alledged to have a role in autism and schizophrenia, our results support the idea of a related pathomechanism in these disorders.

  1. Expression, renaturation and functional analysis of an excitatory insect-specific toxin from scorpion Buthus martensii Karsch.

    Science.gov (United States)

    Li, Chong; Liu, Wei; Bossmans, Frank; Zhu, Rong-Huan; Tytgat, Jan; Wang, Da-Cheng

    2005-10-01

    The cDNA of BmK IT-AP, an excitatory insect toxin from the scorpion Buthus martensi Karsch that has an analgesic effect on mammalian cells, was expressed in E. coli in the form of an inclusion body. Following denaturation and reduction, the recombinant protein was renatured and purified by liquid chromatography. The authenticity of the recombinant product was confirmed by bioassay and its electrophysiological effect on insect sodium channel.

  2. Layer selective presynaptic modulation of excitatory inputs to hippocampal CA1 by μ-opioid receptor activation

    OpenAIRE

    McQuiston, A. Rory

    2007-01-01

    Chronic and acute activation of μ-opioid receptors (MOR) in hippocampal CA1 disrupts rhythmic activity, alters activity-dependent synaptic plasticity and impairs spatial memory formation. In CA1, MORs act by hyperpolarizing inhibitory interneurons and suppressing inhibitory synaptic transmission. MOR modulation of inhibitory synaptic function translates into an increase in excitatory activity in all layers of CA1. However, the exact anatomical sites for MOR actions are not completely known. T...

  3. Differential changes in thalamic and cortical excitatory synapses onto striatal spiny projection neurons in a Huntington disease mouse model.

    Science.gov (United States)

    Kolodziejczyk, Karolina; Raymond, Lynn A

    2016-02-01

    Huntington disease (HD), a neurodegenerative disorder caused by CAG repeat expansion in the gene encoding huntingtin, predominantly affects the striatum, especially the spiny projection neurons (SPN). The striatum receives excitatory input from cortex and thalamus, and the role of the former has been well-studied in HD. Here, we report that mutated huntingtin alters function of thalamostriatal connections. We used a novel thalamostriatal (T-S) coculture and an established corticostriatal (C-S) coculture, generated from YAC128 HD and WT (FVB/NJ background strain) mice, to investigate excitatory neurotransmission onto striatal SPN. SPN in T-S coculture from WT mice showed similar mini-excitatory postsynaptic current (mEPSC) frequency and amplitude as in C-S coculture; however, both the frequency and amplitude were significantly reduced in YAC128 T-S coculture. Further investigation in T-S coculture showed similar excitatory synapse density in WT and YAC128 SPN dendrites by immunostaining, suggesting changes in total dendritic length or probability of release as possible explanations for mEPSC frequency changes. Synaptic N-methyl-D-aspartate receptor (NMDAR) current was similar, but extrasynaptic current, associated with cell death signaling, was enhanced in YAC128 SPN in T-S coculture. Employing optical stimulation of cortical versus thalamic afferents and recording from striatal SPN in brain slice, we found increased glutamate release probability and reduced AMPAR/NMDAR current ratios in thalamostriatal synapses, most prominently in YAC128. Enhanced extrasynaptic NMDAR current in YAC128 SPN was apparent with both cortical and thalamic stimulation. We conclude that thalamic afferents to the striatum are affected early, prior to an overt HD phenotype; however, changes in NMDAR localization in SPN are independent of the source of glutamatergic input.

  4. The cell-autonomous role of excitatory synaptic transmission in the regulation of neuronal structure and function.

    Science.gov (United States)

    Lu, Wei; Bushong, Eric A; Shih, Tiffany P; Ellisman, Mark H; Nicoll, Roger A

    2013-05-08

    The cell-autonomous role of synaptic transmission in the regulation of neuronal structural and electrical properties is unclear. We have now employed a genetic approach to eliminate glutamatergic synaptic transmission onto individual CA1 pyramidal neurons in a mosaic fashion in vivo. Surprisingly, while electrical properties are profoundly affected in these neurons, as well as inhibitory synaptic transmission, we found little perturbation of neuronal morphology, demonstrating a functional segregation of excitatory synaptic transmission from neuronal morphological development.

  5. Medial Superior Olivary Neurons Receive Surprisingly Few Excitatory and Inhibitory Inputs with Balanced Strength and Short-Term Dynamics

    OpenAIRE

    Couchman, Kiri; Grothe, Benedikt; Felmy, Felix

    2010-01-01

    Neurons in the medial superior olive (MSO) process microsecond interaural time differences, the major cue for localizing low-frequency sounds, by comparing the relative arrival time of binaural, glutamatergic excitatory inputs. This coincidence detection mechanism is additionally shaped by highly specialized glycinergic inhibition. Traditionally, it is assumed that the binaural inputs are conveyed by many independent fibers, but such an anatomical arrangement may decrease temporal precision. ...

  6. Associative learning changes the organization of functional excitatory circuits targeting the supragranular layers of mouse barrel cortex

    Directory of Open Access Journals (Sweden)

    Céline eRosselet

    2011-01-01

    Full Text Available In primary sensory cortices, neuronal circuits change throughout life as a function of learning. During associative learning a neutral sensory stimulus acquires the emotional valence of an aversive event or a reward after repetitive contingent pairing. One important consequence is the enlargement of the representational area of the conditioned stimulus in the cortical map of its sensory modality. The details of this phenomenon at the circuit level are still largely unknown.Here, mice were trained in a differential conditioning paradigm where the deflections of one whisker row were paired with tail shocks and the deflections of two others were not. Changes occurring in excitatory circuits of barrel cortex were then examined in brain slices with laser scanning photostimulation mapping. We found that learning affected the projections targeting the supragranular layers in the columns of unpaired whiskers: Pyramidal cells located in layer (L 3 received enhanced inputs from L5A cells located in their home column and new inputs from L2/3 and L4 cells located in the neighboring column of the paired whisker. In contrast, the excitatory projections impinging onto L2/3 cells in the column of the paired whisker were not altered. Together, these data reveal that associative learning alters the canonical columnar organization of functional ascending L4 projections and strengthens transcolumnar excitatory projections in barrel cortex. These phenomena could participate to the transformation of the whisker somatotopic map induced by associative learning.

  7. Repetitive magnetic stimulation induces plasticity of excitatory postsynapses on proximal dendrites of cultured mouse CA1 pyramidal neurons.

    Science.gov (United States)

    Lenz, Maximilian; Platschek, Steffen; Priesemann, Viola; Becker, Denise; Willems, Laurent M; Ziemann, Ulf; Deller, Thomas; Müller-Dahlhaus, Florian; Jedlicka, Peter; Vlachos, Andreas

    2015-11-01

    Repetitive transcranial magnetic stimulation (rTMS) of the human brain can lead to long-lasting changes in cortical excitability. However, the cellular and molecular mechanisms which underlie rTMS-induced plasticity remain incompletely understood. Here, we used repetitive magnetic stimulation (rMS) of mouse entorhino-hippocampal slice cultures to study rMS-induced plasticity of excitatory postsynapses. By employing whole-cell patch-clamp recordings of CA1 pyramidal neurons, local electrical stimulations, immunostainings for the glutamate receptor subunit GluA1 and compartmental modeling, we found evidence for a preferential potentiation of excitatory synapses on proximal dendrites of CA1 neurons (2-4 h after stimulation). This rMS-induced synaptic potentiation required the activation of voltage-gated sodium channels, L-type voltage-gated calcium channels and N-methyl-D-aspartate-receptors. In view of these findings we propose a cellular model for the preferential strengthening of excitatory synapses on proximal dendrites following rMS in vitro, which is based on a cooperative effect of synaptic glutamatergic transmission and postsynaptic depolarization.

  8. TGF-β Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning

    Directory of Open Access Journals (Sweden)

    Sarah X. Luo

    2016-12-01

    Full Text Available Neural circuits involving midbrain dopaminergic (DA neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor β (TGF-β signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-β type II receptor in DA neurons also disrupts the balance in TGF-β1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-β signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus-reward associations. These results support a role for TGF-β in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders.

  9. Excitatory amino acid transporters tonically restrain nTS synaptic and neuronal activity to modulate cardiorespiratory function.

    Science.gov (United States)

    Matott, Michael P; Ruyle, Brian C; Hasser, Eileen M; Kline, David D

    2016-03-01

    The nucleus tractus solitarii (nTS) is the initial central termination site for visceral afferents and is important for modulation and integration of multiple reflexes including cardiorespiratory reflexes. Glutamate is the primary excitatory neurotransmitter in the nTS and is removed from the extracellular milieu by excitatory amino acid transporters (EAATs). The goal of this study was to elucidate the role of EAATs in the nTS on basal synaptic and neuronal function and cardiorespiratory regulation. The majority of glutamate clearance in the central nervous system is believed to be mediated by astrocytic EAAT 1 and 2. We confirmed the presence of EAAT 1 and 2 within the nTS and their colocalization with astrocytic markers. EAAT blockade withdl-threo-β-benzyloxyaspartic acid (TBOA) produced a concentration-related depolarization, increased spontaneous excitatory postsynaptic current (EPSC) frequency, and enhanced action potential discharge in nTS neurons. Solitary tract-evoked EPSCs were significantly reduced by EAAT blockade. Microinjection of TBOA into the nTS of anesthetized rats induced apneic, sympathoinhibitory, depressor, and bradycardic responses. These effects mimicked the response to microinjection of exogenous glutamate, and glutamate responses were enhanced by EAAT blockade. Together these data indicate that EAATs tonically restrain nTS excitability to modulate cardiorespiratory function.

  10. Interstitial cells of Cajal mediate excitatory sympathetic neurotransmission in guinea pig prostate.

    Science.gov (United States)

    Wang, Jiang-ping; Ding, Guo-fu; Wang, Qin-zhang

    2013-06-01

    Morphological and functional studies have confirmed that interstitial cells of Cajal (ICCs) are involved in many enteric motor neurotransmission pathways. Recent investigations have demonstrated that human and guinea pig prostate glands possess a distinct cell type with morphological and immunological similarities to ICCs. These prostate ICCs have a close relationship with nerve bundles and smooth muscle cells. Prostate smooth muscle tone is largely induced by stimulation from the sympathetic nervous system, which releases excitatory norepinephrine (NE) to act on the α1-adrenoceptor. We have performed morphological and functional experiments to determine the role of ICCs in sympathetic neurotransmission in the guinea pig prostate based on the hypothesis that prostate ICCs act as mediators of sympathetic neurotransmission. Immunohistochemistry revealed many close points of contact between ICCs and sympathetic nerve bundles and smooth muscle cells. Double-labeled sections revealed that α1-adrenoceptor and the gap junction protein connexin 43 were expressed in prostate ICCs. Surprisingly, prostate ICCs co-expressed tyrosine hydroxylase and dopamine β-hydroxylase, two markers of sympathetic neurons. Functionally, the application of NE evoked a large single inward current in isolated prostate ICCs in a dose-dependent manner. The inward current evoked by NE was mediated via the activation of α1-adrenoceptors, because it was abolished by the non-specific α-adrenoceptor antagonist, phentolamine and the specific α1-adrenoceptor antagonist, prazosin. Thus, ICCs in the guinea pig prostate are target cells for prostate sympathetic nerves and possess the morphological and functional characteristics required to mediate sympathetic signals.

  11. Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH deficiency suggest a heightened excitatory state during development

    Directory of Open Access Journals (Sweden)

    Snead O Carter

    2008-11-01

    Full Text Available Abstract Background SSADH (aldehyde dehydrogenase 5a1 (Aldh5a1; γ-hydroxybutyric (GHB aciduria deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1-/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives succinate semialdehyde (SSA, homocarnosine (HC, 4,5-dihydroxyhexanoic acid (DHHA and guanidinobutyrate (GB] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1-/- embryo development. Methods Embryos were obtained from pregnant dams sacrificed at E (embryo day of life 10–13, 14–15, 16–17, 18–19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5–15 subjects, Aldh5a1+/+ and Aldh5a1-/- for each gestational age group. Data was evaluated using the t test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95th centile. Results GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1-/- mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5 also revealed significantly increased GABA. Conclusion Our findings indicate early GABAergic alterations in Aldh5a1-/- mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.

  12. The Effects of Excitatory and Inhibitory Social Cues on Cocaine-Seeking Behavior

    Directory of Open Access Journals (Sweden)

    Mark Andrew Smith

    2016-11-01

    Full Text Available Social partners influence the likelihood of using drugs, developing a substance use disorder, and relapse to drug use after a period of abstinence. Preclinical studies report that social cues influence the acquisition of cocaine use, the escalation of cocaine use over time, and the compulsive patterns of cocaine use that emerge during an extended binge. The purpose of this study was to examine the effects of social cues on the reinstatement of cocaine-seeking behavior after a period of abstinence. Male rats were obtained at weaning, assigned to triads (3 rats/cage, reared to adulthood, and implanted with intravenous catheters. Rats from each triad were then assigned to one of three conditions: (1 test rats were trained to self-administer cocaine and were tested for reinstatement, (2 cocaine partners were trained to self-administer cocaine and were predictive of response-contingent cocaine delivery, and (3 abstinent partners were not given access to cocaine and were predictive of extinction. Test rats alternated social partners every 5 days for 20 days such that responding was reinforced with cocaine in the presence of the cocaine partner (S+ for 10 days and not reinforced with cocaine in the presence of the abstinent partner (S- for 10 days. Responding of the test rats was then extinguished over 7 days under isolated conditions. Tests of reinstatement were then conducted in the presence of the cocaine partner and abstinent partner under extinction conditions. Neither social partner reinstated responding relative to that observed on the final day of extinction; however, responding was greater in the presence of the cocaine partner (S+ than the abstinent partner (S- during the reinstatement test. These data fail to demonstrate that a social partner reinstates cocaine-seeking behavior after a period of abstinence, but they do indicate that social partners can serve as either excitatory or inhibitory discriminative stimuli to influence drug

  13. Excitatory action of gamma-aminobutyric acid (GABA) on crustacean neurosecretory cells.

    Science.gov (United States)

    García, U; Onetti, C; Valdiosera, R; Aréchiga, H

    1994-02-01

    1. Intracellular and voltage-clamp recordings were obtained from a selected population of neurosecretory (ns) cells in the X organ of the crayfish isolated eyestalk. Pulses of gamma-aminobutyric acid (GABA) elicited depolarizing responses and bursts of action potentials in a dose-dependent manner. These effects were blocked by picrotoxin (50 microM) but not by bicuculline. Picrotoxin also suppressed spontaneous synaptic activity. 2. The responses to GABA were abolished by severing the neurite of X organ cells, at about 150 microns from the cell body. Responses were larger when the application was made at the neuropil level. 3. Topical application of Cd2+ (2 mM), while suppressing synaptic activity, was incapable of affecting the responses to GABA. 4. Under whole-cell voltage-clamp, GABA elicited an inward current with a reversal potential dependent on the chloride equilibrium potential. The GABA effect was accompanied by an input resistance reduction up to 33% at a -50 mV holding potential. No effect of GABA was detected on potassium, calcium, and sodium currents present in X organ cells. 5. The effect of GABA on steady-state currents was dependent on the intracellular calcium concentration. At 10(-6) M [Ca2+]i, GABA (50 microM) increased the membrane conductance more than threefold and shifted the zero-current potential from -25 to -10 mV. At 10(-9) M [Ca2+]i, GABA induced only a 1.3-fold increase in membrane conductance, without shifting the zero-current potential. 6. These results support the notion that in the population of X organ cells sampled in this study, GABA acts as an excitatory neurotransmitter, opening chloride channels.

  14. The Effects of Excitatory and Inhibitory Social Cues on Cocaine-Seeking Behavior

    Science.gov (United States)

    Smith, Mark A.; Zhang, Huailin; Robinson, Andrea M.

    2016-01-01

    Social partners influence the likelihood of using drugs, developing a substance use disorder and relapse to drug use after a period of abstinence. Preclinical studies report that social cues influence the acquisition of cocaine use, the escalation of cocaine use over time, and the compulsive patterns of cocaine use that emerge during an extended binge. The purpose of this study was to examine the effects of social cues on the reinstatement of cocaine-seeking behavior after a period of abstinence. Male rats were obtained at weaning, assigned to triads (three rats/cage), reared to adulthood and implanted with intravenous catheters. Rats from each triad were then assigned to one of three conditions: (1) test rats were trained to self-administer cocaine and were tested for reinstatement; (2) cocaine partners were trained to self-administer cocaine and were predictive of response-contingent cocaine delivery; and (3) abstinent partners were not given access to cocaine and were predictive of extinction. The test rats alternated social partners every 5 days for 20 days such that responding was reinforced with cocaine in the presence of the cocaine partner (S+) for 10 days and not reinforced with cocaine in the presence of the abstinent partner (S−) for 10 days. Responding of the test rats was then extinguished over 7 days under isolated conditions. Tests of reinstatement were then conducted in the presence of the cocaine partner and abstinent partner under extinction conditions. Neither social partner reinstated responding relative to that observed on the final day of extinction; however, responding was greater in the presence of the cocaine partner (S+) than the abstinent partner (S−) during the reinstatement test. These data fail to demonstrate that a social partner reinstates cocaine-seeking behavior after a period of abstinence, but they do indicate that social partners can serve as either excitatory or inhibitory discriminative stimuli to influence drug

  15. Input-specific learning rules at excitatory synapses onto hippocampal parvalbumin-expressing interneurons

    Science.gov (United States)

    Le Roux, Nicolas; Cabezas, Carolina; Böhm, Urs Lucas; Poncer, Jean Christophe

    2013-01-01

    Hippocampal parvalbumin-expressing interneurons (PV INs) provide fast and reliable GABAergic signalling to principal cells and orchestrate hippocampal ensemble activities. Precise coordination of principal cell activity by PV INs relies in part on the efficacy of excitatory afferents that recruit them in the hippocampal network. Feed-forward (FF) inputs in particular from Schaffer collaterals influence spike timing precision in CA1 principal cells whereas local feedback (FB) inputs may contribute to pacemaker activities. Although PV INs have been shown to undergo activity-dependent long term plasticity, how both inputs are modulated during principal cell firing is unknown. Here we show that FF and FB synapses onto PV INs are endowed with distinct postsynaptic glutamate receptors which set opposing long-term plasticity rules. Inward-rectifying AMPA receptors (AMPARs) expressed at both FF and FB inputs mediate a form of anti-Hebbian long term potentiation (LTP), relying on coincident membrane hyperpolarization and synaptic activation. In contrast, FF inputs are largely devoid of NMDA receptors (NMDARs) which are more abundant at FB afferents and confer on them an additional form of LTP with Hebbian properties. Both forms of LTP are expressed with no apparent change in presynaptic function. The specific endowment of FF and FB inputs with distinct coincidence detectors allow them to be differentially tuned upon high frequency afferent activity. Thus, high frequency (>20 Hz) stimulation specifically potentiates FB, but not FF afferents. We propose that these differential, input-specific learning rules may allow PV INs to adapt to changes in hippocampal activity while preserving their precisely timed, clockwork operation. PMID:23339172

  16. Impaired Excitatory Neurotransmission in the Urinary Bladder from the Obese Zucker Rat: Role of Cannabinoid Receptors

    Science.gov (United States)

    Blaha, Igor; Recio, Paz; Martínez, María Pilar; López-Oliva, María Elvira; Ribeiro, Ana S. F.; Agis-Torres, Ángel; Martínez, Ana Cristina; Benedito, Sara; García-Sacristán, Albino; Fernandes, Vítor S.; Hernández, Medardo

    2016-01-01

    Metabolic syndrome (MS) is a known risk factor for lower urinary tract symptoms. This study investigates whether functional and expression changes of cannabinoid CB1 and CB2 receptors are involved in the bladder dysfunction in an obese rat model with insulin resistance. Bladder samples from obese Zucker rat (OZR) and their respective controls lean Zucker rat (LZR) were processed for immunohistochemistry and western blot for studying the cannabinoid receptors expression. Detrusor smooth muscle (DSM) strips from LZR and OZR were also mounted in myographs for isometric force recordings. Neuronal and smooth muscle CB1 and CB2 receptor expression and the nerve fiber density was diminished in the OZR bladder. Electrical field stimulation (EFS) and acetylcholine (ACh) induced frequency- and concentration-dependent contractions of LZR and OZR DSM. ACh contractile responses were similar in LZR and OZR. EFS-elicited contractions, however, were reduced in OZR bladder. Cannabinoid receptor agonists and antagonists failed to modify the DSM basal tension in LZR and OZR In LZR bladder, EFS responses were inhibited by ACEA and SER-601, CB1 and CB2 receptor agonists, respectively, these effects being reversed by ACEA plus the CB1 antagonist, AM-251 or SER-601 plus the CB2 antagonist, AM-630. In OZR bladder, the inhibitory action of ACEA on nerve-evoked contractions was diminished, whereas that SER-601 did not change EFS responses. These results suggest that a diminished function and expression of neuronal cannabinoid CB1 and CB2 receptors, as well as a lower nerve fiber density is involved in the impaired excitatory neurotransmission of the urinary bladder from the OZR. PMID:27285468

  17. Estimating the time course of population excitatory postsynaptic potentials in motoneurons of spastic stroke survivors.

    Science.gov (United States)

    Hu, Xiaogang; Suresh, Nina L; Rymer, William Z

    2015-03-15

    Hyperexcitable motoneurons are likely to contribute to muscle hypertonia after a stroke injury; however, the origins of this hyperexcitability are not clear. One possibility is that the effective duration of the Ia excitatory postsynaptic potential (EPSP) is prolonged, increasing the potential for temporal summation of EPSPs, making action potential initiation easier. Accordingly, the purpose of this study was to quantify the time course of EPSPs in motoneurons of stroke survivors. The experimental protocol, which was based on parameters derived from simulation, involved sequential subthreshold electrical stimuli delivered to the median nerve of hemispheric stroke survivors. The resulting H-reflex responses were recorded in the flexor carpi radialis muscle. H-reflex response probability was then used to quantify the time course of the underlying EPSPs in the motoneuron pool. A population EPSP was estimated based on the probability of evoking an H reflex from the second electrical stimulus in the absence of a reflex response to the first stimulus. The accuracy of this time-course estimate was quantified using a computer simulation that explored a range of feasible EPSP parameters. Our experimental results showed that in all five hemispheric stroke survivors the rate of decay of the population EPSP was consistently slower in spastic compared with the contralateral motoneuron pools. We propose that one potential mechanism for hyperexcitability of motoneurons in spastic stroke survivors may be linked to this prolongation of the Ia EPSP time course. Our subthreshold double-stimulation approach also provides a noninvasive tool for quantifying the time course of EPSPs in both healthy and pathological conditions.

  18. Adenosine Inhibits the Excitatory Synaptic Inputs to Basal Forebrain Cholinergic, GABAergic and Parvalbumin Neurons in mice

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    Chun eYang

    2013-06-01

    Full Text Available Coffee and tea contain the stimulants caffeine and theophylline. These compounds act as antagonists of adenosine receptors. Adenosine promotes sleep and its extracellular concentration rises in association with prolonged wakefulness, particularly in the basal forebrain (BF region involved in activating the cerebral cortex. However, the effect of adenosine on identified BF neurons, especially non-cholinergic neurons, is incompletely understood. Here we used whole-cell patch-clamp recordings in mouse brain slices prepared from two validated transgenic mouse lines with fluorescent proteins expressed in GABAergic or parvalbumin (PV neurons to determine the effect of adenosine. Whole-cell recordings were made BF cholinergic neurons and from BF GABAergic & PV neurons with the size (>20 µm and intrinsic membrane properties (prominent H-currents corresponding to cortically projecting neurons. A brief (2 min bath application of adenosine (100 μM decreased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents in all groups of BF cholinergic, GABAergic and PV neurons we recorded. In addition, adenosine decreased the frequency of miniature EPSCs in BF cholinergic neurons. Adenosine had no effect on the frequency of spontaneous inhibitory postsynaptic currents in cholinergic neurons or GABAergic neurons with large H-currents but reduced them in a group of GABAergic neurons with smaller H-currents. All effects of adenosine were blocked by a selective, adenosine A1 receptor antagonist, cyclopentyltheophylline (CPT, 1 μM. Adenosine had no postsynaptic effects. Taken together, our work suggests that adenosine promotes sleep by an A1-receptor mediated inhibition of glutamatergic inputs to cortically-projecting cholinergic and GABA/PV neurons. Conversely, caffeine and theophylline promote attentive wakefulness by inhibiting these A1 receptors in BF thereby promoting the high-frequency oscillations in the cortex required for

  19. Cannabinoid CB1 receptor calibrates excitatory synaptic balance in the mouse hippocampus.

    Science.gov (United States)

    Monory, Krisztina; Polack, Martin; Remus, Anita; Lutz, Beat; Korte, Martin

    2015-03-04

    The endocannabinoid system negatively regulates the release of various neurotransmitters in an activity-dependent manner, thereby influencing the excitability of neuronal circuits. In the hippocampus, cannabinoid type 1 (CB1) receptor is present on both GABAergic and glutamatergic axon terminals. CB1 receptor-deficient mice were previously shown to have increased hippocampal long-term potentiation (LTP). In this study, we have investigated the consequences of cell-type-specific deletion of the CB1 receptor on the induction of hippocampal LTP and on CA1 pyramidal cell morphology. Deletion of CB1 receptor in GABAergic neurons in GABA-CB1-KO mice leads to a significantly decreased hippocampal LTP compared with WT controls. Concomitantly, CA1 pyramidal neurons have a significantly reduced dendritic branching both on the apical and on the basal dendrites. Moreover, the average spine density on the apical dendrites of CA1 pyramidal neurons is significantly diminished. In contrast, in mice lacking CB1 receptor in glutamatergic cells (Glu-CB1-KO), hippocampal LTP is significantly enhanced and CA1 pyramidal neurons show an increased branching and an increased spine density in the apical dendritic region. Together, these results indicate that the CB1 receptor signaling system both on inhibitory and excitatory neurons controls functional and structural synaptic plasticity of pyramidal neurons in the hippocampal CA1 region to maintain an appropriate homeostatic state upon neuronal activation. Consequently, if the CB1 receptor is lost in either neuronal population, an allostatic shift will occur leading to a long-term dysregulation of neuronal functions.

  20. Inhibition of release of taurine and excitatory amino acids in ischemia and neuroprotection.

    Science.gov (United States)

    Kimelberg, Harold K; Nestor, Nestor B; Feustel, Paul J

    2004-01-01

    Volume regulated anion channels (VRAC) have been extensively studied in purified single cell systems like cell cultures where they can be activated by cell swelling. This provides a convenient way of analyzing mechanisms and will likely lead to the holy grails of the field, namely the nature or natures of the volume sensor and the nature or natures of VRACs. Important reasons for such an understanding are that these channels are ubiquitous and have important physiological functions which under pathological conditions convert to deleterious effects. Here we summarize data showing the involvement of VRACs in ischemia-induced release of excitatory amino acids (EAAs) in a rat model of global ischemia. Using microdialysis studies we found that reversal of the astrocytic glutamate transporter and VRACs contribute about equally to the large initial release of EAAs and together account for around 80% of the total release. We used the very potent VRAC blocker, tamoxifen, to see if such inhibition of EAA release via VRACs led to significant neuroprotection. Treatment in the focal rat MCA occlusion model led to around 80% reduction in infarct size with an effective post initiation of ischemia therapeutic window of three hours. However, the common problem of other effects for even the most potent inhibitors pertains here, as tamoxifen has other, potentially neuroprotective, effects. Thus it inhibits nitrotyrosine formation, likely due to its inhibition of nNOS and reduction of peroxynitrite formation. Although tamoxifen cannot therefore be used as a test of the "VRAC-excitotxicity" hypothesis it may prove successful for translation of basic stroke research to the clinic because of its multiple targets.

  1. Resting-state hemodynamics are spatiotemporally coupled to synchronized and symmetric neural activity in excitatory neurons.

    Science.gov (United States)

    Ma, Ying; Shaik, Mohammed A; Kozberg, Mariel G; Kim, Sharon H; Portes, Jacob P; Timerman, Dmitriy; Hillman, Elizabeth M C

    2016-12-27

    Brain hemodynamics serve as a proxy for neural activity in a range of noninvasive neuroimaging techniques including functional magnetic resonance imaging (fMRI). In resting-state fMRI, hemodynamic fluctuations have been found to exhibit patterns of bilateral synchrony, with correlated regions inferred to have functional connectivity. However, the relationship between resting-state hemodynamics and underlying neural activity has not been well established, making the neural underpinnings of functional connectivity networks unclear. In this study, neural activity and hemodynamics were recorded simultaneously over the bilateral cortex of awake and anesthetized Thy1-GCaMP mice using wide-field optical mapping. Neural activity was visualized via selective expression of the calcium-sensitive fluorophore GCaMP in layer 2/3 and 5 excitatory neurons. Characteristic patterns of resting-state hemodynamics were accompanied by more rapidly changing bilateral patterns of resting-state neural activity. Spatiotemporal hemodynamics could be modeled by convolving this neural activity with hemodynamic response functions derived through both deconvolution and gamma-variate fitting. Simultaneous imaging and electrophysiology confirmed that Thy1-GCaMP signals are well-predicted by multiunit activity. Neurovascular coupling between resting-state neural activity and hemodynamics was robust and fast in awake animals, whereas coupling in urethane-anesthetized animals was slower, and in some cases included lower-frequency (neural activity. The patterns of bilaterally-symmetric spontaneous neural activity revealed by wide-field Thy1-GCaMP imaging may depict the neural foundation of functional connectivity networks detected in resting-state fMRI.

  2. An excitatory loop with astrocytes contributes to drive neurons to seizure threshold.

    Directory of Open Access Journals (Sweden)

    Marta Gómez-Gonzalo

    Full Text Available Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission that promotes seizure ignition and sustains the ictal discharge. This neuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures.

  3. Action potential broadening induced by lithium may cause a presynaptic enhancement of excitatory synaptic transmission in neonatal rat hippocampus.

    Science.gov (United States)

    Colino, A; García-Seoane, J J; Valentín, A

    1998-07-01

    Lithium enhances excitatory synaptic transmission in CA1 pyramidal cells, but the mechanisms remain unclear. The present study demonstrates that lithium enhances the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) receptor-mediated components of the excitatory postsynaptic current (EPSC). Lithium decreased the magnitude of paired-pulse facilitation and presented an inverse correlation between the lithium-induced enhancement of synaptic transmission and initial paired-pulse facilitation, which is consistent with a presynaptic mode of action. The enhancement of synaptic strength is likely to act, at least in part, by increasing the amplitude of the presynaptic Ca2+ transient. One mechanism which could account for this change of the presynaptic Ca2+ transient is an increase in the duration of the action potential. We investigated action potential in hippocampal pyramidal neurons and found that lithium (0.5-6 mM) increased the half-amplitude duration and reduced the rate of repolarization, whereas the rate of depolarization remained similar. To find out whether the lithium synaptic effects might be explained by spike broadening, we investigated the field recording of the excitatory postsynaptic potential (EPSP) in hippocampal slices and found three lines of evidence. First, the prolongation of the presynaptic action potential with 4-aminopyridine and tetraethylammonium blocked or reduced the synaptic effects of lithium. Second, the lithium-induced synaptic enhancement was modulated when presynaptic Ca2+ influx was varied by changing the external Ca2+ concentration. Finally, both effects, the synaptic transmission increment and the action potential broadening, were independent of inositol depletion. These results suggest that lithium enhances synaptic transmission in the hippocampus via a presynaptic site of action: the mechanism underlying the potentiating effect may be attributable to an increased Ca2+ influx consequent

  4. Parvalbumin-producing cortical interneurons receive inhibitory inputs on proximal portions and cortical excitatory inputs on distal dendrites.

    Science.gov (United States)

    Kameda, Hiroshi; Hioki, Hiroyuki; Tanaka, Yasuyo H; Tanaka, Takuma; Sohn, Jaerin; Sonomura, Takahiro; Furuta, Takahiro; Fujiyama, Fumino; Kaneko, Takeshi

    2012-03-01

    To examine inputs to parvalbumin (PV)-producing interneurons, we generated transgenic mice expressing somatodendritic membrane-targeted green fluorescent protein specifically in the interneurons, and completely visualized their dendrites and somata. Using immunolabeling for vesicular glutamate transporter (VGluT)1, VGluT2, and vesicular GABA transporter, we found that VGluT1-positive terminals made contacts 4- and 3.1-fold more frequently with PV-producing interneurons than VGluT2-positive and GABAergic terminals, respectively, in the primary somatosensory cortex. Even in layer 4, where VGluT2-positive terminals were most densely distributed, VGluT1-positive inputs to PV-producing interneurons were 2.4-fold more frequent than VGluT2-positive inputs. Furthermore, although GABAergic inputs to PV-producing interneurons were as numerous as VGluT2-positive inputs in most cortical layers, GABAergic inputs clearly preferred the proximal dendrites and somata of the interneurons, indicating that the sites of GABAergic inputs were more optimized than those of VGluT2-positive inputs. Simulation analysis with a PV-producing interneuron model compatible with the present morphological data revealed a plausible reason for this observation, by showing that GABAergic and glutamatergic postsynaptic potentials evoked by inputs to distal dendrites were attenuated to 60 and 87%, respectively, of those evoked by somatic inputs. As VGluT1-positive and VGluT2-positive axon terminals were presumed to be cortical and thalamic glutamatergic inputs, respectively, cortical excitatory inputs to PV-producing interneurons outnumbered the thalamic excitatory and intrinsic inhibitory inputs more than two-fold in any cortical layer. Although thalamic inputs are known to evoke about two-fold larger unitary excitatory postsynaptic potentials than cortical ones, the present results suggest that cortical inputs control PV-producing interneurons at least as strongly as thalamic inputs.

  5. Excitatory synaptic activity is associated with a rapid structural plasticity of inhibitory synapses on hippocampal CA1 pyramidal cells.

    Science.gov (United States)

    Lushnikova, Irina; Skibo, Galina; Muller, Dominique; Nikonenko, Irina

    2011-04-01

    Synaptic activity, such as long-term potentiation (LTP), has been shown to induce morphological plasticity of excitatory synapses on dendritic spines through the spine head and postsynaptic density (PSD) enlargement and reorganization. Much less, however, is known about activity-induced morphological modifications of inhibitory synapses. Using an in vitro model of rat organotypic hippocampal slice cultures and electron microscopy, we studied activity-related morphological changes of somatic inhibitory inputs triggered by a brief oxygen-glucose deprivation (OGD) episode, a condition associated with a synaptic enhancement referred to as anoxic LTP and a structural remodeling of excitatory synapses. Three-dimensional reconstruction of inhibitory axo-somatic synapses at different times before and after brief OGD revealed important morphological changes. The PSD area significantly and markedly increased at synapses with large and complex PSDs, but not at synapses with simple, macular PSDs. Activity-related changes of PSD size and presynaptic bouton volume developed in a strongly correlated manner. Analyses of single and serial sections further showed that the density of inhibitory synaptic contacts on the cell soma did not change within 1 h after OGD. In contrast, the proportion of the cell surface covered with inhibitory PSDs, as well as the complexity of these PSDs significantly increased, with less macular PSDs and more complex, segmented shapes. Together, these data reveal a rapid activity-related restructuring of somatic inhibitory synapses characterized by an enlargement and increased complexity of inhibitory PSDs, providing a new mechanism for a quick adjustment of the excitatory-inhibitory balance. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'.

  6. Excitatory action of GABA on immature neurons is not due to absence of ketone bodies metabolites or other energy substrates.

    Science.gov (United States)

    Ben-Ari, Yehezkel; Tyzio, Roman; Nehlig, Astrid

    2011-09-01

    Brain slices incubated with glucose have provided most of our knowledge on cellular, synaptic, and network driven mechanisms. It has been recently suggested that γ-aminobutyric acid (GABA) excites neonatal neurons in conventional glucose-perfused slices but not when ketone bodies metabolites, pyruvate, and/or lactate are added, suggesting that the excitatory actions of GABA are due to energy deprivation when glucose is the sole energy source. In this article, we review the vast number of studies that show that slices are not energy deprived in glucose-containing medium, and that addition of other energy substrates at physiologic concentrations does not alter the excitatory actions of GABA on neonatal neurons. In contrast, lactate, like other weak acids, can produce an intracellular acidification that will cause a reduction of intracellular chloride and a shift of GABA actions. The effects of high concentrations of lactate, and particularly of pyruvate (4-5 mm), as used are relevant primarily to pathologic conditions; these concentrations not being found in the brain in normal "control" conditions. Slices in glucose-containing medium may not be ideal, but additional energy substrates neither correspond to physiologic conditions nor alter GABA actions. In keeping with extensive observations in a wide range of animal species and brain structures, GABA depolarizes immature neurons and the reduction of the intracellular concentration of chloride ([Cl(-)](i)) is a basic property of brain maturation that has been preserved throughout evolution. In addition, this developmental sequence has important clinical implications, notably concerning the higher incidence of seizures early in life and their long-lasting deleterious sequels. Immature neurons have difficulties exporting chloride that accumulates during seizures, leading to permanent increase of [Cl(-)](i) that converts the inhibitory actions of GABA to excitatory and hampers the efficacy of GABA-acting antiepileptic

  7. Inferring Trial-to-Trial Excitatory and Inhibitory Synaptic Inputs from Membrane Potential using Gaussian Mixture Kalman Filtering

    Directory of Open Access Journals (Sweden)

    Milad eLankarany

    2013-09-01

    Full Text Available Time-varying excitatory and inhibitory synaptic inputs govern activity of neurons and process information in the brain. The importance of trial-to-trial fluctuations of synaptic inputs has recently been investigated in neuroscience. Such fluctuations are ignored in the most conventional techniques because they are removed when trials are averaged during linear regression techniques. Here, we propose a novel recursive algorithm based on Gaussian mixture Kalman filtering for estimating time-varying excitatory and inhibitory synaptic inputs from single trials of noisy membrane potential in current clamp recordings. The Kalman filtering is followed by an expectation maximization algorithm to infer the statistical parameters (time-varying mean and variance of the synaptic inputs in a non-parametric manner. As our proposed algorithm is repeated recursively, the inferred parameters of the mixtures are used to initiate the next iteration. Unlike other recent algorithms, our algorithm does not assume an a priori distribution from which the synaptic inputs are generated. Instead, the algorithm recursively estimates such a distribution by fitting a Gaussian mixture model. The performance of the proposed algorithms is compared to a previously proposed PF-based algorithm (Paninski et al., 2012 with several illustrative examples, assuming that the distribution of synaptic input is unknown. If noise is small, the performance of our algorithms is similar to that of the previous one. However, if noise is large, they can significantly outperform the previous proposal. These promising results suggest that our algorithm is a robust and efficient technique for estimating time varying excitatory and inhibitory synaptic conductances from single trials of membrane potential recordings.

  8. Neuroligin-1 regulates excitatory synaptic transmission, LTP and EPSP-spike coupling in the dentate gyrus in vivo.

    Science.gov (United States)

    Jedlicka, Peter; Vnencak, Matej; Krueger, Dilja D; Jungenitz, Tassilo; Brose, Nils; Schwarzacher, Stephan W

    2015-01-01

    Neuroligins are transmembrane cell adhesion proteins with a key role in the regulation of excitatory and inhibitory synapses. Based on previous in vitro and ex vivo studies, neuroligin-1 (NL1) has been suggested to play a selective role in the function of glutamatergic synapses. However, the role of NL1 has not yet been investigated in the brain of live animals. We studied the effects of NL1-deficiency on synaptic transmission in the hippocampal dentate gyrus using field potential recordings evoked by perforant path stimulation in urethane-anesthetized NL1 knockout (KO) mice. We report that in NL1 KOs the activation of glutamatergic perforant path granule cell inputs resulted in reduced synaptic responses. In addition, NL1 KOs displayed impairment in long-term potentiation. Furthermore, field EPSP-population spike (E-S) coupling was greater in NL1 KO than WT mice and paired-pulse inhibition was reduced, indicating a compensatory rise of excitability in NL1 KO granule cells. Consistent with changes in excitatory transmission, NL1 KOs showed a significant reduction in hippocampal synaptosomal expression levels of the AMPA receptor subunit GluA2 and NMDA receptor subunits GluN1, GluN2A and GluN2B. Taken together, we provide first evidence that NL1 is essential for normal excitatory transmission and long-term synaptic plasticity in the hippocampus of intact animals. Our data provide insights into synaptic and circuit mechanisms of neuropsychiatric abnormalities such as learning deficits and autism.

  9. Inferring trial-to-trial excitatory and inhibitory synaptic inputs from membrane potential using Gaussian mixture Kalman filtering.

    Science.gov (United States)

    Lankarany, M; Zhu, W-P; Swamy, M N S; Toyoizumi, Taro

    2013-01-01

    Time-varying excitatory and inhibitory synaptic inputs govern activity of neurons and process information in the brain. The importance of trial-to-trial fluctuations of synaptic inputs has recently been investigated in neuroscience. Such fluctuations are ignored in the most conventional techniques because they are removed when trials are averaged during linear regression techniques. Here, we propose a novel recursive algorithm based on Gaussian mixture Kalman filtering (GMKF) for estimating time-varying excitatory and inhibitory synaptic inputs from single trials of noisy membrane potential in current clamp recordings. The KF is followed by an expectation maximization (EM) algorithm to infer the statistical parameters (time-varying mean and variance) of the synaptic inputs in a non-parametric manner. As our proposed algorithm is repeated recursively, the inferred parameters of the mixtures are used to initiate the next iteration. Unlike other recent algorithms, our algorithm does not assume an a priori distribution from which the synaptic inputs are generated. Instead, the algorithm recursively estimates such a distribution by fitting a Gaussian mixture model (GMM). The performance of the proposed algorithms is compared to a previously proposed PF-based algorithm (Paninski et al., 2012) with several illustrative examples, assuming that the distribution of synaptic input is unknown. If noise is small, the performance of our algorithms is similar to that of the previous one. However, if noise is large, they can significantly outperform the previous proposal. These promising results suggest that our algorithm is a robust and efficient technique for estimating time varying excitatory and inhibitory synaptic conductances from single trials of membrane potential recordings.

  10. Excitatory and inhibitory behavioral responses to the pharmacological stimulation of serotonergic function in dorsalis raphe lesioned rats.

    Science.gov (United States)

    Rodríguez Echandía, E L; González, A S; Fóscolo, M R; Broitman, S T

    1988-01-01

    Neurotoxin-induced lesions of 5-HT neurons produce supersensitivity of 5-HT1 receptors without affecting 5-HT2 receptor binding in the brain. This model was used in the present work to analyze the role of 5-HT receptor subtypes in the mechanism controlling the excitatory and inhibitory behavioral responses to the pharmacological stimulation of 5-HT systems. Dorsalis raphe (DR) lesions were made by stereotaxic injection of kainic acid. At day 30 after injection DR-and control rats displayed similar baseline behavior in hole board tests. Three days later DR-and control rats received an ip injection of fluoxetine (5 or 10 mg/kg) 30 min before injecting ip 5-HTP(15 or 30 mg/kg). Immediately before and after each ip injection the excitatory response (myoclonic syndrome) was evaluated. DR-and control-group showed similar scores of myoclonus in response to fluoxetine-5-HTP. The inhibitory response was investigated in hole board trials performed 30 min after the second ip injection. The DR lesion potentiated the behavioral depressive effect of fluoxetine-5-HTP. In agreement with data in the literature the DR lesion caused 74.9% loss of forebrain 5-HT and 75% increases of 3H-5HT binding in cortex membranes. Most components of the excitatory response, which remained unchanged in the DR-lesioned rats, might be related to 5-HT2 receptors. The increased inhibitory response to 5-HT stimulation in DR-lesioned rats would be due to the supersensitivity of 5-HT1 receptors.

  11. Different responsiveness of excitatory and inhibitory enteric motor neurons in the human esophagus to electrical field stimulation and to nicotine.

    Science.gov (United States)

    González, Asensio A; Farré, Ricard; Clavé, Pere

    2004-07-01

    To compare electrical field stimulation (EFS) with nicotine in the stimulation of excitatory and inhibitory enteric motoneurons (EMN) in the human esophagus, circular lower esophageal sphincter (LES), and circular and longitudinal esophageal body (EB) strips from 20 humans were studied in organ baths. Responses to EFS or nicotine (100 microM) were compared in basal conditions, after N(G)-nitro-l-arginine (l-NNA; 100 microM), and after l-NNA and apamin (1 microM). LES strips developed myogenic tone enhanced by TTX (5 microM) or l-NNA. EFS-LES relaxation was abolished by TTX, unaffected by hexamethonium (100 microM), and enhanced by atropine (3 microM). Nicotine-LES relaxation was higher than EFS relaxation, reduced by TTX or atropine, and blocked by hexamethonium. After l-NNA, EFS elicited a strong cholinergic contraction in circular LES and EB, and nicotine elicited a small relaxation in LES and no contractile effect in EB. After l-NNA and apamin, EFS elicited a strong cholinergic contraction in LES and EB, and nicotine elicited a weak contraction amounting to 6.64 +/- 3.19 and 9.20 +/- 5.51% of that induced by EFS. EFS elicited a contraction in longitudinal strips; after l-NNA and apamin, nicotine did not induce any response. Inhibitory EMN tonically inhibit myogenic LES tone and are efficiently stimulated both by EFS and nicotinic acetylcholine receptors (nAChRs) located in somatodendritic regions and nerve terminals, releasing nitric oxide and an apamin-sensitive neurotransmitter. In contrast, although esophageal excitatory EMN are efficiently stimulated by EFS, their stimulation through nAChRs is difficult and causes weak responses, suggesting the participation of nonnicotinic mechanisms in neurotransmission to excitatory EMN in human esophagus.

  12. The epitranscriptome in modulating spatiotemporal RNA translation in neuronal post-synaptic function

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    Shobbir eHussain

    2015-10-01

    Full Text Available The application of next-generation-sequencing based methods has recently allowed the sequence-specific occurrence of RNA modifications to be investigated in transcriptome-wide settings. This has led to the emergence of a new field of molecular genetics research termed ‘epitranscriptomics’. Investigations have shown that these modifications can exert control over protein synthesis via various mechanisms, and particularly when occurring on messenger RNAs, can be dynamically regulated. Here, we propose that RNA modifications may be a critical regulator over the spatiotemporal control of protein-synthesis in neurons, which is supported by our finding that the RNA methylase NSun2 colocalises with the translational-repressor FMRP at neuronal dendrites. We also observe that NSun2 commonly methylates mRNAs which encode components of the postsynaptic proteome, and further find that NSun2 and FMRP likely share a common subset of mRNA targets which include those that are known to be translated at dendrites in an activity-dependent manner. We consider potential roles for RNA modifications in space- time- and activity-dependent regulation of protein synthesis in neuronal physiology, with a particular focus on synaptic plasticity modulation.

  13. A Post-Synaptic Scaffold at the Origin of the Animal Kingdom

    OpenAIRE

    Onur Sakarya; Armstrong, Kathryn A.; Maja Adamska; Marcin Adamski; I-Fan Wang; Bruce Tidor; Degnan, Bernard M; Todd H Oakley; Kenneth S Kosik

    2007-01-01

    BACKGROUND: The evolution of complex sub-cellular structures such as the synapse requires the assembly of multiple proteins, each conferring added functionality to the integrated structure. Tracking the early evolution of synapses has not been possible without genomic information from the earliest branching animals. As the closest extant relatives to the Eumetazoa, Porifera (sponges) represent a pivotal group for understanding the evolution of nervous systems, because sponges lack neurons wit...

  14. A Gata3-Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing.

    Science.gov (United States)

    Yu, Wei-Ming; Appler, Jessica M; Kim, Ye-Hyun; Nishitani, Allison M; Holt, Jeffrey R; Goodrich, Lisa V

    2013-12-10

    Information flow through neural circuits is determined by the nature of the synapses linking the subtypes of neurons. How neurons acquire features distinct to each synapse remains unknown. We show that the transcription factor Mafb drives the formation of auditory ribbon synapses, which are specialized for rapid transmission from hair cells to spiral ganglion neurons (SGNs). Mafb acts in SGNs to drive differentiation of the large postsynaptic density (PSD) characteristic of the ribbon synapse. In Mafb mutant mice, SGNs fail to develop normal PSDs, leading to reduced synapse number and impaired auditory responses. Conversely, increased Mafb accelerates synaptogenesis. Moreover, Mafb is responsible for executing one branch of the SGN differentiation program orchestrated by the Gata3 transcriptional network. Remarkably, restoration of Mafb rescues the synapse defect in Gata3 mutants. Hence, Mafb is a powerful regulator of cell-type specific features of auditory synaptogenesis that offers a new entry point for treating hearing loss. DOI: http://dx.doi.org/10.7554/eLife.01341.001.

  15. Serotonergic modulation of post-synaptic inhibition and locomotor alternating pattern in the spinal cord

    Directory of Open Access Journals (Sweden)

    Laurent eVinay

    2014-08-01

    Full Text Available The central pattern generators (CPGs for locomotion, located in the lumbar spinal cord, are functional at birth in the rat. Their maturation occurs during the last few days preceding birth, a period during which the first projections from the brainstem start to reach the lumbar enlargement of the spinal cord. Locomotor burst activity in the mature intact spinal cord alternates between flexor and extensor motoneurons through reciprocal inhibition and between left and right sides through commisural inhibitory interneurons. By contrast, all motor bursts are in phase in the fetus. The alternating pattern disappears after neonatal spinal cord transection which suppresses supraspinal influences upon the locomotor networks. This article will review the role of serotonin (5-HT, in particular 5-HT2 receptors, in shaping the alternating pattern. For instance, pharmacological activation of these receptors restores the left-right alternation after injury. Experiments aimed at either reducing the endogenous level of serotonin in the spinal cord or blocking the activation of 5-HT2 receptors.We then describe recent evidence that the action of 5-HT2 receptors is mediated, at least in part, through a modulation of chloride homeostasis. The postsynaptic action of GABA and glycine depends on the intracellular concentration of chloride ions which is regulated by a protein in the plasma membrane, the K+-Cl− cotransporter (KCC2 extruding both K+ and Cl− ions. Absence or reduction of KCC2 expression leads to a depolarizing action of GABA and glycine and a marked reduction in the strength of postsynaptic inhibition. This latter situation is observed early during development and in several pathological conditions, such as after spinal cord injury, thereby causing spasticity and chronic pain. It was recently shown that specific activation of 5-HT2A receptors is able to up-regulate KCC2, restore endogenous inhibition and reduce spasticity.

  16. Serotonergic modulation of post-synaptic inhibition and locomotor alternating pattern in the spinal cord

    OpenAIRE

    Laurent eVinay; Florian eGackière

    2014-01-01

    The central pattern generators (CPGs) for locomotion, located in the lumbar spinal cord, are functional at birth in the rat. Their maturation occurs during the last few days preceding birth, a period during which the first projections from the brainstem start to reach the lumbar enlargement of the spinal cord. Locomotor burst activity in the mature intact spinal cord alternates between flexor and extensor motoneurons through reciprocal inhibition and between left and right sides through commi...

  17. Inhibitory and excitatory amino acids in the cerebrospinal fluid of children with two types of cerebral palsy

    Institute of Scientific and Technical Information of China (English)

    Haibin Yuan; Li Wang; Fei Yin; Li Li; Jing Peng

    2008-01-01

    BACKGROUND: Under normal conditions, excitatory amino acids are dynamically balanced with inhibitory amino acids. Excitatory amino acids have been implicated in perinatal brain injury. OBJECTIVE: To investigate differences in the levels of the excitatory amino acids glutamic acid and aspartic acid, and the inhibitory amino acid gamma-aminobutyric acid (GABA) in the cerebrospinal fluid (CSF) of children with spastic cerebral palsy or athetotic cerebral palsy. DESIGN, TIME AND SETTING: Case-control exploratory observation of neurotransmitter in patients. The experiment was performed in the Pediatrics Department of the Second Affiliated Hospital of Changsba Medical College, the Cerebral Palsy Center of Xiangtan Affiliated Hospital of South China University and the Pediatrics Department of Xiangya Hospital, between February 2006 and May 2007. PARTICIPANTS: We selected 27 children with cerebral palsy, including 13 with spastic cerebral palsy and 14 with athetotic cerebral palsy. We selected 10 patients who were not affected by any neurological disease as controls. METHODS: Two mL blood-free CSF was harvested between the third and fourth lumbar vertebrae of each patient after anesthesia, and stored at 70℃. One mL CSF was mixed with 10 mg sulfosalicylic acid and placed in ice-bath for 10 minutes, then centrifuged 2 000 g for 10 minutes. The supernatant was collected for amino acid quantitation. MAIN OUTCOME MEASURES: The concentrations of glutamic acid, aspartic acid and GABA in the CSF were determined by high-performance liquid chromatography and fluorometric method. The correlation of glutamie acid, aspartic acid and GABA levels with muscular tension in children with cerebral palsy was analyzed using linear dependence. RESULTS: The concentration of GABA was significantly lower in both spastic cerebral palsy and athetotic cerebral palsy patients than in the control group (P 0.05). CONCLUSION: Spastic cerebral palsy and athetotic cerebral palsy patients exhibit an

  18. Impact of weak excitatory synapses on chaotic transients in a diffusively coupled Morris-Lecar neuronal network

    Energy Technology Data Exchange (ETDEWEB)

    Lafranceschina, Jacopo, E-mail: jlafranceschina@alaska.edu; Wackerbauer, Renate, E-mail: rawackerbauer@alaska.edu [Department of Physics, University of Alaska, Fairbanks, Alaska 99775-5920 (United States)

    2015-01-15

    Spatiotemporal chaos collapses to either a rest state or a propagating pulse solution in a ring network of diffusively coupled, excitable Morris-Lecar neurons. Weak excitatory synapses can increase the Lyapunov exponent, expedite the collapse, and promote the collapse to the rest state rather than the pulse state. A single traveling pulse solution may no longer be asymptotic for certain combinations of network topology and (weak) coupling strengths, and initiate spatiotemporal chaos. Multiple pulses can cause chaos initiation due to diffusive and synaptic pulse-pulse interaction. In the presence of chaos initiation, intermittent spatiotemporal chaos exists until typically a collapse to the rest state.

  19. SURAMIN AS AN INHIBITOR OF SYMPATHETIC EXCITATORY. JUNCTION POTENTIALS: STUDY IN GUINEA PIG ISOLATED VAS DEFERENS

    Directory of Open Access Journals (Sweden)

    M AYATOLLAHI

    2001-06-01

    Full Text Available

    Introduction. Suramin, as a selective P2x-Pourinoceptor antagonist can inhibit the sympathetic excitatory junction potentials (SEJPs. Experiments have shown that the biphasic contractile responses (bcr in smooth muscles of vascular and vas deferens (vds is evoked by cotransmission of ATP and neuradrenaline. Therefore, vds is considered as a model for studying the role of A TP and antagonizing its effect. By using different concentrations of Suramin, its antagonistic effect in phase one of bcr is observed To confirm the purinergic origin of SEJPs, some experiments should be performed electrophysiologically at different concentrations of Suramin.
    Methods. Suramin was dissolved in distilled water and after diluting with physiological salt solution freezed as a stock solution at concentration of 10-1M. After killing and dissecting the albino male guinea pigs (weighing 2S0-300 gm, both testes were pushed up to give out the whole vds. The vds was cleaned from surrounding tissues and cut from epididymic and prostatic ends. vds was maintained at 3SC in physiological salt solution bubbled with 9S percent O2 and 5 percent CO2. Intracellular microelectrodes (with resistance of 20-40 MQ recordings were made from prostatic end of vds.
    Results. The resting membrane potential of the control smooth muscle cells was 67.4±.0.7 mV (n=48. Electrical stimulation at frequency of 0.5 Hz evokes SEJPs which are magnified consistently due to facilitation. Mean magnitude of fully facilitated SEJPs which were evoked from control cells was 8.5±0.8 mV (n=23. Further facilitation was evoked at frequencies of 1 Hz or 2 Hz, because SEJPs were obtained at the threshold limit to begin the action potentials which were 55 mV in most cells. It was difficult to estimate correctly the threshold potential in a cell because disseminated potential might

  20. Network models predict that reduced excitatory fluctuations can give rise to hippocampal network hyper-excitability in MeCP2-null mice.

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    Ernest C Y Ho

    Full Text Available Rett syndrome is a severe pediatric neurological disorder caused by loss of function mutations within the gene encoding methyl CpG-binding protein 2 (MeCP2. Although MeCP2 is expressed near ubiquitously, the primary pathophysiology of Rett syndrome stems from impairments of nervous system function. One alteration within different regions of the MeCP2-deficient brain is the presence of hyper-excitable network responses. In the hippocampus, such responses exist despite there being an overall decrease in spontaneous excitatory drive within the network. In this study, we generated and used mathematical, neuronal network models to resolve this apparent paradox. We did this by taking advantage of previous mathematical modelling insights that indicated that decreased excitatory fluctuations, but not mean excitatory drive, more critically explain observed changes in hippocampal network oscillations from MeCP2-null mouse slices. Importantly, reduced excitatory fluctuations could also bring about hyper-excitable responses in our network models. Therefore, these results indicate that diminished excitatory fluctuations may be responsible for the hyper-excitable state of MeCP2-deficient hippocampal circuitry.

  1. Fear learning increases the number of polyribosomes associated with excitatory and inhibitory synapses in the barrel cortex.

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    Malgorzata Jasinska

    Full Text Available Associative fear learning, resulting from whisker stimulation paired with application of a mild electric shock to the tail in a classical conditioning paradigm, changes the motor behavior of mice and modifies the cortical functional representation of sensory receptors involved in the conditioning. It also induces the formation of new inhibitory synapses on double-synapse spines of the cognate barrel hollows. We studied density and distribution of polyribosomes, the putative structural markers of enhanced synaptic activation, following conditioning. By analyzing serial sections of the barrel cortex by electron microscopy and stereology, we found that the density of polyribosomes was significantly increased in dendrites of the barrel activated during conditioning. The results revealed fear learning-induced increase in the density of polyribosomes associated with both excitatory and inhibitory synapses located on dendritic spines (in both single- and double-synapse spines and only with the inhibitory synapses located on dendritic shafts. This effect was accompanied by a significant increase in the postsynaptic density area of the excitatory synapses on single-synapse spines and of the inhibitory synapses on double-synapse spines containing polyribosomes. The present results show that associative fear learning not only induces inhibitory synaptogenesis, as demonstrated in the previous studies, but also stimulates local protein synthesis and produces modifications of the synapses that indicate their potentiation.

  2. Nutritional state-dependent ghrelin activation of vasopressin neurons via retrograde trans-neuronal-glial stimulation of excitatory GABA circuits.

    Science.gov (United States)

    Haam, Juhee; Halmos, Katalin C; Di, Shi; Tasker, Jeffrey G

    2014-04-30

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal-glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal-glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal-glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis.

  3. The unusual adrenergic-like excitatory action of acetylcholine on the ventricular cardiac muscle of the horned shark, Heterodontus portusjacksoni.

    Science.gov (United States)

    Thompson, A P; O'Shea, J E

    1997-01-01

    The atypical excitatory effect of acetylcholine on cardiac ventricular muscle was investigated in the horned shark, Heterodontus portusjacksoni. Electrically paced ventricular strips produced a massive 391.45% (+/-26.39%) increase in basal force of contraction in response to exogenously applied acetylcholine. The response was similar in nature to that produced by applied adrenaline, which caused a 382.52% (+/-72.47%) increase. The response to acetylcholine was blocked by the muscarinic cholinoceptor antagonist atropine and the competitive beta-adrenoceptor antagonist propranolol and was reduced by bretylium, an agent known to inhibit the release of catecholamines from adrenergic nerves. These findings strongly suggest that acetylcholine mediates a localised release of a catecholamine via muscarinic cholinoceptors in shark heart. A cholinergically controlled catecholamine store has been proposed (cholinergic-adreno complex), implying that elasmobranchs may be capable of finer control of cardiac output than has previously been suspected. This complex may represent a transitional adrenergic state between humoral and neuronal regulation. The spontaneously beating atrium showed no evidence of such an excitatory response to applied acetylcholine but produced an atropine-sensitive slowing, a response typical of other vertebrates.

  4. Neuroprotection via strychnine-sensitive glycine receptors during post-ischemic recovery of excitatory synaptic transmission in the hippocampus.

    Science.gov (United States)

    Tanabe, Mitsuo; Nitta, Azusa; Ono, Hideki

    2010-01-01

    Recent evidence indicates that strychnine-sensitive glycine receptors are located in upper brain regions including the hippocampus. Because of excitatory effects of glycine via facilitation of NMDA-receptor function, however, the net effects of increased extracellular glycine on neuronal excitability in either physiological or pathophysiological conditions are mostly unclear. Here, we addressed the potential neuroprotective effect of either exogenous application of glycine and taurine, which are both strychnine-sensitive glycine-receptor agonists, or an endogenous increase of glycine via blockade of glycine transporter 1 (GlyT1) by assessing their ability to facilitate the functional recovery of field excitatory postsynaptic potentials (fEPSPs) after termination of brief oxygen/glucose deprivation (OGD) in the CA1 region in mouse hippocampal slices. Glycine and taurine promoted restoration of the fEPSPs after reperfusion, but this was never observed in the presence of strychnine. Interestingly, glycine and taurine appeared to generate neuroprotective effects only at their optimum concentration range. By contrast, blockade of GlyT1 by N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine or sarcosine did not elicit significant neuroprotection. These results suggest that activation of strychnine-sensitive glycine receptors potentially produces neuroprotection against metabolic stress such as OGD. However, GlyT1 inhibition is unlikely to elicit a sufficient increase in the extracellular level of glycine to generate neuroprotection.

  5. Pacemaker shift in the gastric antrum of guinea-pigs produced by excitatory vagal stimulation involves intramuscular interstitial cells.

    Science.gov (United States)

    Hirst, G D S; Dickens, E J; Edwards, F R

    2002-06-15

    Intracellular recordings were made from isolated bundles of the circular muscle layer of guinea-pig gastric antrum and the responses produced by stimulating intrinsic nerve fibres were examined. After abolishing the effects of stimulating inhibitory nerve terminals with apamin and L-nitroarginine (NOLA), transmural nerve stimulation often evoked a small amplitude excitatory junction potential (EJP) and invariably evoked a regenerative potential. Neurally evoked regenerative potentials had similar properties to those evoked in the same bundle by direct stimulation. EJPs and neurally evoked regenerative potentials were abolished by hyoscine suggesting that both resulted from the release of acetylcholine and activation of muscarinic receptors. Neurally evoked regenerative potentials, but not EJPs, were abolished by membrane hyperpolarization, caffeine and chloride channel blockers. In the intact antrum, excitatory vagal nerve stimulation increased the frequency of slow waves. Simultaneous intracellular recordings of pacemaker potentials from myenteric interstitial cells (ICC(MY)) and slow waves showed that the onset of each pacemaker potential normally preceded the onset of each slow wave but vagal stimulation caused the onset of each slow wave to precede each pacemaker potential. Together the observations suggest that during vagal stimulation there is a change in the origin of pacemaker activity with slow waves being initiated by intramuscular interstitial cells (ICC(IM)) rather than by ICC(MY).

  6. Primary afferent terminals acting as excitatory interneurons contribute to spontaneous motor activities in the immature spinal cord.

    Science.gov (United States)

    Bos, Rémi; Brocard, Frédéric; Vinay, Laurent

    2011-07-13

    Patterned, spontaneous activity plays a critical role in the development of neuronal networks. A robust spontaneous activity is observed in vitro in spinal cord preparations isolated from immature rats. The rhythmic ventral root discharges rely mainly on the depolarizing/excitatory action of GABA and glycine early during development, whereas at later stages glutamate drive is primarily responsible for the rhythmic activity and GABA/glycine are thought to play an inhibitory role. However, rhythmic discharges mediated by the activation of GABA(A) receptors are recorded from dorsal roots (DRs). In the present study, we used the in vitro spinal cord preparation of neonatal rats to identify the relationship between discharges that are conducted antidromically along DRs and the spontaneous activity recorded from lumbar motoneurons. We show that discharges in DRs precede those in ventral roots and that primary afferent depolarizations (PADs) start earlier than EPSPs in motoneurons. EPSP-triggered averaging revealed that the action potentials propagate not only antidromically in the DR but also centrally and trigger EPSPs in motoneurons. Potentiating GABAergic antidromic discharges by diazepam increased the EPSPs recorded from motoneurons; conversely, blocking DR bursts markedly reduced these EPSPs. High intracellular concentrations of chloride are maintained in primary afferent terminals by the sodium-potassium-chloride cotransporter NKCC1. Blocking these cotransporters by bumetanide decreased both dorsal and ventral root discharges. We conclude that primary afferent fibers act as excitatory interneurons and that GABA, through PADs reaching firing threshold, is still playing a key role in promoting spontaneous activity in neonates.

  7. Excitatory amino acid changes in the brains of rhesus monkeys following selective cerebral deep hypothermia and blood flow occlusion

    Institute of Scientific and Technical Information of China (English)

    Jun Pu; Xiaoqun Niu; Jizong Zhao

    2013-01-01

    Selective cerebral deep hypothermia and blood flow occlusion can enhance brain tolerance to ischemia and hypoxia and reduce cardiopulmonary complications in monkeys. Excitotoxicity induced by the release of a large amount of excitatory amino acids after cerebral ischemia is the major mechanism underlying ischemic brain injury and nerve cell death. In the present study, we used selective cerebral deep hypothermia and blood flow occlusion to block the bilateral common carotid arteries and/or bilateral vertebral arteries in rhesus monkey, followed by reperfusion using Ringer's solution at 4°C. Microdialysis and transmission electron microscope results showed that selective cerebral deep hypothermia and blood flow occlusion inhibited the release of glutamic acid into the extracellular fluid in the brain frontal lobe and relieved pathological injury in terms of the ultrastructure of brain tissues after severe cerebral ischemia. These findings indicate that cerebral deep hypothermia and blood flow occlusion can inhibit cytotoxic effects and attenuate ischemic/ hypoxic brain injury through decreasing the release of excitatory amino acids, such as glutamic acid.

  8. Medial superior olivary neurons receive surprisingly few excitatory and inhibitory inputs with balanced strength and short-term dynamics.

    Science.gov (United States)

    Couchman, Kiri; Grothe, Benedikt; Felmy, Felix

    2010-12-15

    Neurons in the medial superior olive (MSO) process microsecond interaural time differences, the major cue for localizing low-frequency sounds, by comparing the relative arrival time of binaural, glutamatergic excitatory inputs. This coincidence detection mechanism is additionally shaped by highly specialized glycinergic inhibition. Traditionally, it is assumed that the binaural inputs are conveyed by many independent fibers, but such an anatomical arrangement may decrease temporal precision. Short-term depression on the other hand might enhance temporal fidelity during ongoing activity. For the first time we show that binaural coincidence detection in MSO neurons may require surprisingly few but strong inputs, challenging long-held assumptions about mammalian coincidence detection. This study exclusively uses adult gerbils for in vitro electrophysiology, single-cell electroporation and immunohistochemistry to characterize the size and short-term plasticity of inputs to the MSO. We find that the excitatory and inhibitory inputs to the MSO are well balanced both in strength and short-term dynamics, redefining this fastest of all mammalian coincidence detector circuits.

  9. Upregulation of excitatory neurons and downregulation of inhibitory neurons in barrel cortex are associated with loss of whisker inputs

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    Zhang Guanjun

    2013-01-01

    Full Text Available Abstract Loss of a sensory input causes the hypersensitivity in other modalities. In addition to cross-modal plasticity, the sensory cortices without receiving inputs undergo the plastic changes. It is not clear how the different types of neurons and synapses in the sensory cortex coordinately change after input deficits in order to prevent loss of their functions and to be used for other modalities. We studied this subject in the barrel cortices from whiskers-trimmed mice vs. controls. After whisker trimming for a week, the intrinsic properties of pyramidal neurons and the transmission of excitatory synapses were upregulated in the barrel cortex, but inhibitory neurons and GABAergic synapses were downregulated. The morphological analyses indicated that the number of processes and spines in pyramidal neurons increased, whereas the processes of GABAergic neurons decreased in the barrel cortex. The upregulation of excitatory neurons and the downregulation of inhibitory neurons boost the activity of network neurons in the barrel cortex to be high levels, which prevent the loss of their functions and enhances their sensitivity to sensory inputs. These changes may prepare for attracting the innervations from sensory cortices and/or peripheral nerves for other modalities during cross-modal plasticity.

  10. Dendritic Target Region-Specific Formation of Synapses Between Excitatory Layer 4 Neurons and Layer 6 Pyramidal Cells.

    Science.gov (United States)

    Qi, Guanxiao; Feldmeyer, Dirk

    2016-04-01

    Excitatory connections between neocortical layer 4 (L4) and L6 are part of the corticothalamic feedback microcircuitry. Here we studied the intracortical element of this feedback loop, the L4 spiny neuron-to-L6 pyramidal cell connection. We found that the distribution of synapses onto both putative corticothalamic (CT) and corticocortical (CC) L6 pyramidal cells (PCs) depends on the presynaptic L4 neuron type but is independent of the postsynaptic L6 PC type. L4 spiny stellate cells establish synapses on distal apical tuft dendrites of L6 PCs and elicit slow unitary excitatory postsynaptic potentials (uEPSPs) in L6 somata. In contrast, the majority of L4 star pyramidal neurons target basal and proximal apical oblique dendrites of L6 PCs and show fast uEPSPs. Compartmental modeling suggests that the slow uEPSP time course is primarily the result of dendritic filtering. This suggests that the dendritic target specificity of the 2 L4 spiny neuron types is due to their different axonal projection patterns across cortical layers. The preferential dendritic targeting by different L4 neuron types may facilitate the generation of dendritic Ca(2+) or Na(+) action potentials in L6 PCs; this could play a role in synaptic gain modulation in the corticothalamic pathway.

  11. Activation-induced structural change in the GluN1/GluN3A excitatory glycine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Balasuriya, Dilshan; Takahashi, Hirohide; Srivats, Shyam; Edwardson, J. Michael, E-mail: jme1000@cam.ac.uk

    2014-08-08

    Highlights: • We studied the response of the GluN1/GluN3A excitatory glycine receptor to activation. • GluN1 and GluN3A subunits interacted within transfected cells. • The GluN1/GluN3A receptor was functionally active. • Glycine or D-serine caused a ∼1 nm height reduction in bilayer-integrated receptors. • This height reduction was abolished by the glycine antagonist DCKA. - Abstract: Unlike GluN2-containing N-methyl-D-aspartate (NMDA) receptors, which require both glycine and glutamate for activation, receptors composed of GluN1 and GluN3 subunits are activated by glycine alone. Here, we used atomic force microscopy (AFM) imaging to examine the response to activation of the GluN1/GluN3A excitatory glycine receptor. GluN1 and GluN3A subunits were shown to interact intimately within transfected tsA 201 cells. Isolated GluN1/GluN3A receptors integrated into lipid bilayers responded to addition of either glycine or D-serine, but not glutamate, with a ∼1 nm reduction in height of the extracellular domain. The height reduction in response to glycine was abolished by the glycine antagonist 5,7-dichlorokynurenic acid. Our results represent the first demonstration of the effect of activation on the conformation of this receptor.

  12. Excitatory cortical neurons with multipolar shape establish neuronal polarity by forming a tangentially oriented axon in the intermediate zone.

    Science.gov (United States)

    Hatanaka, Yumiko; Yamauchi, Kenta

    2013-01-01

    The formation of axon-dendrite polarity is crucial for neuron to make the proper information flow within the brain. Although the processes of neuronal polarity formation have been extensively studied using neurons in dissociated culture, the corresponding developmental processes in vivo are still unclear. Here, we illuminate the initial steps of morphological polarization of excitatory cortical neurons in situ, by sparsely labeling their neuroepithelial progenitors using in utero electroporation and then examining their neuronal progeny in brain sections and in slice cultures. Morphological analysis showed that an axon-like long tangential process formed in progeny cells in the intermediate zone (IZ). Time-lapse imaging analysis using slice culture revealed that progeny cells with multipolar shape, after alternately extending and retracting their short processes for several hours, suddenly elongated a long process tangentially. These cells then transformed into a bipolar shape, extending a pia-directed leading process, and migrated radially leaving the tangential process behind, which gave rise to an "L-shaped" axon. Our findings suggest that neuronal polarity in these cells is established de novo from a nonpolarized stage in vivo and indicate that excitatory cortical neurons with multipolar shape in the IZ initiate axon outgrowth before radial migration into the cortical plate.

  13. Potentiation of excitatory transmission in substantia gelatinosa neurons of rat spinal cord by inhibition of estrogen receptor alpha

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    Li Kai-Cheng

    2010-12-01

    Full Text Available Abstract Background It has been shown that estrogen is synthesized in the spinal dorsal horn and plays a role in modulating pain transmission. One of the estrogen receptor (ER subtypes, estrogen receptor alpha (ERα, is expressed in the spinal laminae I-V, including substantia gelatinosa (SG, lamina II. However, it is unclear how ERs are involved in the modulation of nociceptive transmission. Results In the present study, a selective ERα antagonist, methyl-piperidino-pyrazole (MPP, was used to test the potential functional roles of spinal ERα in the nociceptive transmission. Using the whole-cell patch-clamp technique, we examined the effects of MPP on SG neurons in the dorsal root-attached spinal cord slice prepared from adult rats. We found that MPP increased glutamatergic excitatory postsynaptic currents (EPSCs evoked by the stimulation of either Aδ- or C-afferent fibers. Further studies showed that MPP treatment dose-dependently increased spontaneous EPSCs frequency in SG neurons, while not affecting the amplitude. In addition, the PKC was involved in the MPP-induced enhancement of synaptic transmission. Conclusions These results suggest that the selective ERα antagonist MPP pre-synaptically facilitates the excitatory synaptic transmission to SG neurons. The nociceptive transmission evoked by Aδ- and C-fiber stimulation could be potentiated by blocking ERα in the spinal neurons. Thus, the spinal estrogen may negatively regulate the nociceptive transmission through the activation of ERα.

  14. Estrous cycle influences excitatory amino acid transport and visceral pain sensitivity in the rat: effects of early-life stress.

    Science.gov (United States)

    Moloney, Rachel D; Sajjad, Jahangir; Foley, Tara; Felice, Valeria D; Dinan, Timothy G; Cryan, John F; O'Mahony, Siobhain M

    2016-01-01

    Early-life stress (ELS) is a recognized risk factor for chronic pain disorders, and females appear to be more sensitive to the negative effects of stress. Moreover, estrous cycle-related fluctuations in estrogen levels have been linked with alternating pain sensitivity. Aberrant central circuitry involving both the anterior cingulate cortex (ACC) and the lumbosacral spinal cord has also been implicated in the modulation of visceral pain in clinical and preclinical studies. Here we further investigate changes in visceral pain sensitivity and central glutamatergic systems in rats with respect to estrous cycle and ELS. We investigated visceral sensitivity in adult female Sprague-Dawley rats, which had undergone maternal separation (MS) in early life or remained non-separated (NS), by performing colorectal distension (CRD). We also assessed excitatory amino acid uptake through excitatory amino acid transporters (EAATs) in the lumbosacral spinal cord and ACC. NS animals in proestrus and estrus exhibited reduced EAAT uptake and decreased threshold to CRD. Moreover, total pain behaviors were increased in these stages. MS rats exhibited lower pain thresholds and higher total pain behaviors to CRD across all stages of the estrous cycle. Interestingly, cortical EAAT function in MS rats was inhibited in the low estrogen state-an effect completely opposite to that seen in NS rats. This data confirms that estrous cycle and ELS are significant factors in visceral sensitivity and fluctuations in EAAT function may be a perpetuating factor mediating central sensitization.

  15. Examining the limits of cellular adaptation bursting mechanisms in biologically-based excitatory networks of the hippocampus.

    Science.gov (United States)

    Ferguson, K A; Njap, F; Nicola, W; Skinner, F K; Campbell, S A

    2015-12-01

    Determining the biological details and mechanisms that are essential for the generation of population rhythms in the mammalian brain is a challenging problem. This problem cannot be addressed either by experimental or computational studies in isolation. Here we show that computational models that are carefully linked with experiment provide insight into this problem. Using the experimental context of a whole hippocampus preparation in vitro that spontaneously expresses theta frequency (3-12 Hz) population bursts in the CA1 region, we create excitatory network models to examine whether cellular adaptation bursting mechanisms could critically contribute to the generation of this rhythm. We use biologically-based cellular models of CA1 pyramidal cells and network sizes and connectivities that correspond to the experimental context. By expanding our mean field analyses to networks with heterogeneity and non all-to-all coupling, we allow closer correspondence with experiment, and use these analyses to greatly extend the range of parameter values that are explored. We find that our model excitatory networks can produce theta frequency population bursts in a robust fashion.Thus, even though our networks are limited by not including inhibition at present, our results indicate that cellular adaptation in pyramidal cells could be an important aspect for the occurrence of theta frequency population bursting in the hippocampus. These models serve as a starting framework for the inclusion of inhibitory cells and for the consideration of additional experimental features not captured in our present network models.

  16. Up-Regulation of the Excitatory Amino Acid Transporters EAAT1 and EAAT2 by Mammalian Target of Rapamycin

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    Abeer Abousaab

    2016-11-01

    Full Text Available Background: The excitatory amino-acid transporters EAAT1 and EAAT2 clear glutamate from the synaptic cleft and thus terminate neuronal excitation. The carriers are subject to regulation by various kinases. The EAAT3 isoform is regulated by mammalian target of rapamycin (mTOR. The present study thus explored whether mTOR influences transport by EAAT1 and/or EAAT2. Methods: cRNA encoding wild type EAAT1 (SLC1A3 or EAAT2 (SLC1A2 was injected into Xenopus oocytes without or with additional injection of cRNA encoding mTOR. Dual electrode voltage clamp was performed in order to determine electrogenic glutamate transport (IEAAT. EAAT2 protein abundance was determined utilizing chemiluminescence. Results: Appreciable IEAAT was observed in EAAT1 or EAAT2 expressing but not in water injected oocytes. IEAAT was significantly increased by coexpression of mTOR. Coexpression of mTOR increased significantly the maximal IEAAT in EAAT1 or EAAT2 expressing oocytes, without significantly modifying affinity of the carriers. Moreover, coexpression of mTOR increased significantly EAAT2 protein abundance in the cell membrane. Conclusions: The kinase mTOR up-regulates the excitatory amino acid transporters EAAT1 and EAAT2.

  17. Responses of Cholinergic and Noncholinergic Renshaw Cell Receptors After Acute and Chronic Exposure to Anticholinesterases.

    Science.gov (United States)

    1983-07-01

    investigation of ventral horn interneurons . The tissue samples were fixed by immersion in 5% phosphate buffered (0.1M, pH 7.4) glutaraldehyde. After 24...burst discharge consistent with its excitatory post synaptic potential ( EPSP ) and the burst, when transmitted, initiates inhibitory recurrent post...synaptic potentials (RIPSP) in membranes of motoneurones and other interneurones (Eccles (1964), Hultborn et al. (1971)). The source for activation of the

  18. Evidence against VIP or substance P being the transmitter in non-cholinergic excitatory nerves supplying the guinea-pig bladder.

    Science.gov (United States)

    Meldrum, L A; Burnstock, G

    1985-06-01

    In the guinea-pig bladder, contractile responses to substance P (0.3 microM) and VIP (3 microM) were unaffected by P2-purinoceptor desensitization with alpha,beta-methylene ATP (3 X 10(-6) M), while the responses to stimulation of the non-cholinergic excitatory nerves (4-16 Hz) were abolished. The evidence presented suggests that ATP or a related purine nucleotide, and not VIP or substance P, is responsible for the non-cholinergic excitatory component of the nerve-mediated response.

  19. The Timing of the Excitatory-to-Inhibitory GABA Switch Is Regulated by the Oxytocin Receptor via KCC2

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    Marianna Leonzino

    2016-04-01

    Full Text Available Oxytocin and its receptor (Oxtr play a crucial role in the postnatal transition of neuronal GABA neurotransmission from excitatory to inhibitory, a developmental process known as the GABA switch. Using hippocampal neurons from Oxtr-null mice, we show that (1 Oxtr is necessary for the correct timing of the GABA switch by upregulating activity of the chloride cotransporter KCC2, (2 Oxtr, in a very early and narrow time window, directly modulates the functional activity of KCC2 by promoting its phosphorylation and insertion/stabilization at the neuronal surface, and (3 in the absence of Oxtr, electrophysiological alterations are recorded in mature neurons, a finding consistent with a reduced level of KCC2 and increased susceptibility to seizures observed in adult Oxtr-null mice. These data identify KCC2 as a key target of oxytocin in postnatal events that may be linked to pathogenesis of neurodevelopmental disorders.

  20. Expression of an insect excitatory toxin, BmK IT, from the scorpion, Buthus martensii Karsch, and its biological activity.

    Science.gov (United States)

    Hao, Chan-juan; Xu, Cheng-gang; Wang, Wei; Chai, Bao-feng; Liang, Ai-hua

    2005-12-01

    An insect excitatory toxin from Buthus martensii Karsch (BmK IT) was cloned into the expression vector, pTWIN1, and expressed into Escherichia coli BL21 (DE3) host cells. The soluble fusion expression of CBD-intein-BmK IT was obtained. The recombinant BmK IT was purified by two anion-exchange chromatography columns and one gel chromatography column. Bioassays were carried out to verify the toxicity of this recombinant toxin. At the end of a 96 h experimental period, 83% of cotton bollworm larvae were killed with an LT(50) value of 58-62 h. Furthermore, the average weight of larvae fed on BmK IT-containing media was approx 4% of that of the control groups. The results indicate that the expressed and purified recombinant BmK IT has biological activity.

  1. Activity-dependent endogenous taurine release facilitates excitatory neurotransmission in the neocortical marginal zone of neonatal rats.

    Science.gov (United States)

    Qian, Taizhe; Chen, Rongqing; Nakamura, Masato; Furukawa, Tomonori; Kumada, Tatsuro; Akita, Tenpei; Kilb, Werner; Luhmann, Heiko J; Nakahara, Daiichiro; Fukuda, Atsuo

    2014-01-01

    In the developing cerebral cortex, the marginal zone (MZ), consisting of early-generated neurons such as Cajal-Retzius cells, plays an important role in cell migration and lamination. There is accumulating evidence of widespread excitatory neurotransmission mediated by γ-aminobutyric acid (GABA) in the MZ. Cajal-Retzius cells express not only GABAA receptors but also α2/β subunits of glycine receptors, and exhibit glycine receptor-mediated depolarization due to high [Cl(-)]i. However, the physiological roles of glycine receptors and their endogenous agonists during neurotransmission in the MZ are yet to be elucidated. To address this question, we performed optical imaging from the MZ using the voltage-sensitive dye JPW1114 on tangential neocortical slices of neonatal rats. A single electrical stimulus evoked an action-potential-dependent optical signal that spread radially over the MZ. The amplitude of the signal was not affected by glutamate receptor blockers, but was suppressed by either GABAA or glycine receptor antagonists. Combined application of both antagonists nearly abolished the signal. Inhibition of Na(+), K(+)-2Cl(-) cotransporter by 20 µM bumetanide reduced the signal, indicating that this transporter contributes to excitation. Analysis of the interstitial fluid obtained by microdialysis from tangential neocortical slices with high-performance liquid chromatography revealed that GABA and taurine, but not glycine or glutamate, were released in the MZ in response to the electrical stimulation. The ambient release of taurine was reduced by the addition of a voltage-sensitive Na(+) channel blocker. Immunohistochemistry and immunoelectron microscopy indicated that taurine was stored both in Cajal-Retzius and non-Cajal-Retzius cells in the MZ, but was not localized in presynaptic structures. Our results suggest that activity-dependent non-synaptic release of endogenous taurine facilitates excitatory neurotransmission through activation of glycine

  2. Pharmacology of morphine and morphine-3-glucuronide at opioid, excitatory amino acid, GABA and glycine binding sites

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    Bartlett, S.E.; Smith, M.T. (Department of Pharmacy, The University of Queensland (Australia)); Dood, P.R. (Clinical Research Centre, Royal Brisbane Hospital Foundation, Brisbane (Australia))

    1994-07-01

    Morphine in high doses and its major metabolite, morphine-3-glucuronide, cause CNS excitation following intrathecal and intracerebroventricular administration by an unknown mechanism. This study investigated whether morphine and morphine-3-glucuronide interact at major excitatory (glutamate), major inhibitory (GABA or glycine), or opioid binding sites. Homogenate binding assays were performed using specific radioligands. At opioid receptors, morphine-3-glucuronide and morphine caused an equipotent sodium shift, consistent with morphine-3-glucuronide behaving as an agonist. This suggests that morphine-3-glucuronide-mediated excitation is not caused by an interaction at opioid receptors. Morphine-3-glucuronide and morphine caused a weak inhibition of the binding of [sup 3]H-MK801 (non-competitive antagonist) and [sup 125]I-ifenprodil (polyamine site antagonist), but at unphysiologically high concentrations. This suggests that CNS excitation would not result from an interaction of morphine-3-glucuronide and high-dose morphine with these sites on the NMDA receptor. Morphine-3-glucuronide and morphine inhibited the binding of [sup 3]H-muscimol (GABA receptor agonist), [sup 3]H-diazepam and [sup 3]H-flunitraxepam (benzodiazepine agonists) binding very weakly, suggesting the excitatory effects of morphine-3-glucuronide and high-dose morphine are not elicited through GABA[sub A] receptors. Morphine-3-glucuronide and high-dose morphine did not prevent re-uptake of glutamate into presynaptic nerve terminals. In addition, morphine-3-glucuronide and morphine did not inhibit the binding of [sup 3]H-strychnine (glycine receptor antagonist) to synaptic membranes prepared from bovine spinal cord. It is concluded that excitation caused by high-dose morphine and morphine-3-glucuronide is not mediated by an interaction with postsynaptic amino acid receptors. (au) (30 refs.).

  3. L-DOPA inhibits excitatory synaptic transmission in the rat nucleus tractus solitarius through release of dopamine.

    Science.gov (United States)

    Ohi, Y; Kodama, D; Haji, A

    2017-09-30

    The mode of action of L-DOPA on excitatory synaptic transmission in second-order neurons of the nucleus tractus solitarius (NTS) was studied using the rat brainstem slices. Superfusion of L-DOPA (10μM) reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) without any effect on the amplitude. A low concentration (1μM) was ineffective on the mEPSCs, and the highest concentration (100μM) exerted a stronger inhibitory effect. L-DOPA (10μM) decreased the amplitude of EPSCs (eEPSCs) evoked by electrical stimulation of the tractus solitarius and increased the paired-pulse ratio. The inhibitory effects of L-DOPA on mEPSCs and eEPSCs were similar to those of dopamine (100μM). The effects of L-DOPA were blocked by a competitive antagonist, L-DOPA methyl ester (100μM) and also by a D2 receptor antagonist, sulpiride (10μM), while those of dopamine were blocked by the latter but not by the former. In reserpine (5mg/kg, s.c.)-treated rats, the effects of L-DOPA on both mEPSCs and eEPSCs were completely abolished, but those of dopamine remained unchanged. The present results suggest a possibility that L-DOPA may induce the release of dopamine from the axon terminals in the NTS and the released dopamine suppresses the glutamatergic transmission through activation of the presynaptic D2 receptors. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. NAD+ Attenuates Bilirubin-Induced Hyperexcitation in the Ventral Cochlear Nucleus by Inhibiting Excitatory Neurotransmission and Neuronal Excitability

    Science.gov (United States)

    Liang, Min; Yin, Xin-Lu; Wang, Lu-Yang; Yin, Wei-Hai; Song, Ning-Ying; Shi, Hai-Bo; Li, Chun-Yan; Yin, Shan-Kai

    2017-01-01

    Nicotinamide adenine dinucleotide (NAD+) is an important molecule with extensive biological functions in various cellular processes, including protection against cell injuries. However, little is known regarding the roles of NAD+ in neuronal excitation and excitotoxicity associated with many neurodegenerative disorders and diseases. Using patch-clamp recordings, we studied its potential effects on principal neurons in the ventral cochlear nucleus (VCN), which is particularly vulnerable to bilirubin excitotoxicity. We found that NAD+ effectively decreased the size of evoked excitatory postsynaptic currents (eEPSCs), increased paired-pulse ratio (PPR) and reversed the effect of bilirubin on eEPSCs, implicating its inhibitory effects on the presynaptic release probability (Pr). Moreover, NAD+ not only decreased the basal frequency of miniature EPSCs (mEPSCs), but also reversed bilirubin-induced increases in the frequency of mEPSCs without affecting their amplitude under either condition. Furthermore, we found that NAD+ decreased the frequency of spontaneous firing of VCN neurons as well as bilirubin-induced increases in firing frequency. Whole-cell current-clamp recordings showed that NAD+ could directly decrease the intrinsic excitability of VCN neurons in the presence of synaptic blockers, suggesting NAD+ exerts its actions in both presynaptic and postsynaptic loci. Consistent with these observations, we found that the latency of the first postsynaptic spike triggered by high-frequency train stimulation of presynaptic afferents (i.e., the auditory nerve) was prolonged by NAD+. These results collectively indicate that NAD+ suppresses presynaptic transmitter release and postsynaptic excitability, jointly weakening excitatory neurotransmission. Our findings provide a basis for the exploration of NAD+ for the prevention and treatment of bilirubin encephalopathy and excitotoxicity associated with other neurological disorders. PMID:28217084

  5. Presynaptic facilitation by tetracaine of glutamatergic spontaneous excitatory transmission in the rat spinal substantia gelatinosa - Involvement of TRPA1 channels.

    Science.gov (United States)

    Piao, Lian-Hua; Fujita, Tsugumi; Yu, Ting; Kumamoto, Eiichi

    2017-02-15

    The amide-type local anesthetic (LA) lidocaine activates transient receptor potential (TRP) ankyrin-1 (TRPA1) channels to facilitate spontaneous l-glutamate release onto spinal substantia gelatinosa (SG) neurons, which play a crucial role in regulating nociceptive transmission. In contrast, the ester-type LA procaine reduces the spontaneous release of l-glutamate in SG neurons. In order to determine whether TRPA1 activation by LAs is specific to amide-types, we examined the actions of tetracaine, another ester-type LA, and other amide-type LAs on glutamatergic spontaneous excitatory transmission in SG neurons by focusing on TRP activation. Whole-cell patch-clamp recordings were performed on SG neurons of adult rat spinal cord slices at a holding potential of -70mV. Bath-applied tetracaine increased spontaneous excitatory postsynaptic current (sEPSC) frequency in a concentration-dependent manner. Tetracaine activity was resistant to the voltage-gated Na(+)-channel blocker tetrodotoxin, the TRP vanilloid-1 antagonist capsazepine, and the TRP melastatin-8 antagonist BCTC, but was inhibited by the non-selective TRP antagonist ruthenium red and the TRPA1 antagonist HC-030031. With respect to amide-type LAs, prilocaine had a tendency to increase sEPSC frequency, while ropivacaine and levobupivacaine reduced the frequency. In conclusion, tetracaine facilitated spontaneous l-glutamate release from nerve terminals by activating TRPA1 channels in the SG, resulting in an increase in the excitability of SG neurons. TRPA1 activation was not specific to amide-type or ester-type LAs. The facilitatory action of LAs may be involved in pain occurring after recovery from spinal anesthesia.

  6. Comparative ultrastructural features of excitatory synapses in the visual and frontal cortices of the adult mouse and monkey.

    Science.gov (United States)

    Hsu, Alexander; Luebke, Jennifer I; Medalla, Maria

    2017-03-03

    The excitatory glutamatergic synapse is the principal site of communication between cortical pyramidal neurons and their targets, a key locus of action of many drugs, and highly vulnerable to dysfunction and loss in neurodegenerative disease. A detailed knowledge of the structure of these synapses in distinct cortical areas and across species is a prerequisite for understanding the anatomical underpinnings of cortical specialization and, potentially, selective vulnerability in neurological disorders. We used serial electron microscopy to assess the ultrastructural features of excitatory (asymmetric) synapses in the layers 2-3 (L2-3) neuropil of visual (V1) and frontal (FC) cortices of the adult mouse and compared findings to those in the rhesus monkey (V1 and lateral prefrontal cortex [LPFC]). Analyses of multiple ultrastructural variables revealed four organizational features. First, the density of asymmetric synapses does not differ between frontal and visual cortices in either species, but is significantly higher in mouse than in monkey. Second, the structural properties of asymmetric synapses in mouse V1 and FC are nearly identical, by stark contrast to the significant differences seen between monkey V1 and LPFC. Third, while the structural features of postsynaptic entities in mouse and monkey V1 do not differ, the size of presynaptic boutons are significantly larger in monkey V1. Fourth, both presynaptic and postsynaptic entities are significantly smaller in the mouse FC than in the monkey LPFC. The diversity of synaptic ultrastructural features demonstrated here have broad implications for the nature and efficacy of glutamatergic signaling in distinct cortical areas within and across species.

  7. Subregion-specific modulation of excitatory input and dopaminergic output in the striatum by tonically activated glycine and GABAA receptors

    Directory of Open Access Journals (Sweden)

    Louise eAdermark

    2011-10-01

    Full Text Available The flow of cortical information through the basal ganglia is a complex spatiotemporal pattern of increased and decreased firing. The striatum is the biggest input nucleus to the basal ganglia and the aim of this study was to assess the role of inhibitory GABAA and glycine receptors in regulating synaptic activity in the dorsolateral (DLS and ventral striatum (nucleus accumbens, nAc. Local field potential recordings from coronal brain slices of juvenile and adult Wistar rats showed that GABAA receptors and strychnine-sensitive glycine receptors are tonically activated and inhibit excitatory input to the DLS and to the nAc. Strychnine-induced disinhibition of glutamatergic transmission was insensitive to the muscarinic receptor inhibitor scopolamine (10 µM, inhibited by the nicotinic acetylcholine receptor antagonist mecamylamine (10 µM and blocked by GABAA receptor inhibitors, suggesting that tonically activated glycine receptors depress excitatory input to the striatum through modulation of cholinergic and GABAergic neurotransmission. As an end-product example of striatal GABAergic output in vivo we measured dopamine release in the DLS and nAc by microdialysis in the awake and freely moving rat. Reversed dialysis of bicuculline (50 μM in perfusate only increased extrasynaptic dopamine levels in the nAc, while strychnine administered locally (200 μM in perfusate decreased dopamine output by 60% in both the DLS and nAc. Our data suggest that GABAA and glycine receptors are tonically activated and modulate striatal transmission in a partially sub-region specific manner.

  8. Computer simulation study of the relationship between the profile of excitatory postsynaptic potential and stimulus-correlated motoneuron firing.

    Science.gov (United States)

    Piotrkiewicz, Maria; Kudina, Lydia; Jakubiec, Michal

    2009-03-01

    This paper shows the results of computer simulation of changes in motoneuron (MN) firing evoked by a repetitively applied synaptic volley that consists of a single excitatory postsynaptic potential (EPSP). Spike trains produced by the threshold-crossing MN model were analyzed as experimental results. Various output functions were applied for analysis; the most useful was a peristimulus time histogram, a special modification of a raster plot and a peristimulus time frequencygram (PSTF). It has been shown that all functions complement each other in distinguishing between the genuine results evoked by the excitatory volley and the secondary results of the EPSP-evoked synchronization. The EPSP rising edge was best reproduced by the PSTF. However, whereas the EPSP rise time could be estimated quite accurately, especially for high EPSP amplitudes at high MN firing rates, the EPSP amplitude estimate was also influenced by factors unrelated to the synaptic volley, such as the afterhyperpolarization duration of the MN or the amplitude of synaptic noise, which cannot be directly assessed in human experiments. Thus, the attempts to scale any estimate of the EPSP amplitude in millivolts appear to be useless. The decaying phase of the EPSP cannot be reproduced accurately by any of the functions. For the short EPSPs, it is extinguished by the generation of an action potential and a subsequent decrease in the MN excitability. For longer EPSPs, it is inseparable from the secondary effects of synchronization. Thus, the methods aimed at extracting information about long-lasting and complex postsynaptic potentials from stimulus-correlated MN firing, should be refined, and the theoretical considerations checked in computer simulations.

  9. Propofol suppresses synaptic responsiveness of somatosensory relay neurons to excitatory input by potentiating GABAA receptor chloride channels

    Directory of Open Access Journals (Sweden)

    Goldstein Peter A

    2005-01-01

    Full Text Available Abstract Propofol is a widely used intravenous general anesthetic. Propofol-induced unconsciousness in humans is associated with inhibition of thalamic activity evoked by somatosensory stimuli. However, the cellular mechanisms underlying the effects of propofol in thalamic circuits are largely unknown. We investigated the influence of propofol on synaptic responsiveness of thalamocortical relay neurons in the ventrobasal complex (VB to excitatory input in mouse brain slices, using both current- and voltage-clamp recording techniques. Excitatory responses including EPSP temporal summation and action potential firing were evoked in VB neurons by electrical stimulation of corticothalamic fibers or pharmacological activation of glutamate receptors. Propofol (0.6 – 3 μM suppressed temporal summation and spike firing in a concentration-dependent manner. The thalamocortical suppression was accompanied by a marked decrease in both EPSP amplitude and input resistance, indicating that a shunting mechanism was involved. The propofol-mediated thalamocortical suppression could be blocked by a GABAA receptor antagonist or chloride channel blocker, suggesting that postsynaptic GABAA receptors in VB neurons were involved in the shunting inhibition. GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs were evoked in VB neurons by electrical stimulation of the reticular thalamic nucleus. Propofol markedly increased amplitude, decay time, and charge transfer of GABAA IPSCs. The results demonstrated that shunting inhibition of thalamic somatosensory relay neurons by propofol at clinically relevant concentrations is primarily mediated through the potentiation of the GABAA receptor chloride channel-mediated conductance, and such inhibition may contribute to the impaired thalamic responses to sensory stimuli seen during propofol-induced anesthesia.

  10. Locomotor rhythm maintenance: electrical coupling among premotor excitatory interneurons in the brainstem and spinal cord of young Xenopus tadpoles.

    Science.gov (United States)

    Li, Wen-Chang; Roberts, Alan; Soffe, Stephen R

    2009-04-15

    Electrical coupling is important in rhythm generating systems. We examine its role in circuits controlling locomotion in a simple vertebrate model, the young Xenopus tadpole, where the hindbrain and spinal cord excitatory descending interneurons (dINs) that drive and maintain swimming have been characterised. Using simultaneous paired recordings, we show that most dINs are electrically coupled exclusively to other dINs (DC coupling coefficients approximately 8.5%). The coupling shows typical low-pass filtering. We found no evidence that other swimming central pattern generator (CPG) interneurons are coupled to dINs or to each other. Electrical coupling potentials between dINs appear to contribute to their unusually reliable firing during swimming. To investigate the role of electrical coupling in swimming, we evaluated the specificity of gap junction blockers (18-beta-GA, carbenoxolone, flufenamic acid and heptanol) in paired recordings. 18-beta-GA at 40-60 mum produced substantial (84%) coupling block but few effects on cellular properties. Swimming episodes in 18-beta-GA were significantly shortened (to approximately 2% of control durations). At the same time, dIN firing reliability fell from nearly 100% to 62% of swimming cycles and spike synchronization weakened. Because dINs drive CPG neuron firing and are critical in maintaining swimming, the weakening of dIN activity could account for the effects of 18-beta-GA on swimming. We conclude that electrical coupling among pre motor reticulospinal and spinal dINs, the excitatory interneurons that drive the swimming CPG in the hatchling Xenopus tadpole, may contribute to the maintenance of swimming as well as synchronization of activity.

  11. Excitatory projections from the amygdala to neurons in the nucleus pontis oralis in the rat: an intracellular study.

    Science.gov (United States)

    Xi, M; Fung, S J; Sampogna, S; Chase, M H

    2011-12-01

    There is a consensus that active (REM) sleep (AS) is controlled by cholinergic projections from the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT) to neurons in the nucleus pontis oralis (NPO) that generate AS (i.e. AS-Generator neurons). The present study was designed to provide evidence that other projections to the NPO, such as those from the amygdala, are also capable of inducing AS. Accordingly, the responses of neurons, recorded intracellularly in the NPO, were examined following stimulation of the ipsilateral central nucleus of the amygdala (CNA) in urethane-anesthetized rats. Single pulse stimulation in the CNA produced an early, fast depolarizing potential (EPSP) in neurons within the NPO. The mean latency to the onset of these excitatory postsynaptic potentials (EPSPs) was 3.6±0.2 ms. A late, small-amplitude inhibitory synaptic potential (IPSP) was present following EPSPs in a portion of the NPO neurons. Following stimulation of the CNA with a train of 8-10 pulses, NPO neurons exhibited a sustained depolarization (5-10 mV) of their resting membrane potential. When single subthreshold intracellular depolarizing current pulses were delivered to NPO neurons, CNA-induced EPSPs were sufficient to promote the discharge of these cells. Stimulation of the CNA with a short train of stimuli induced potent temporal facilitation of EPSPs in NPO neurons. Two forms of synaptic plasticity were revealed by the patterns of response of NPO neurons following stimulation of the CNA: paired-pulse facilitation (PPF) and post-tetanic potentiation (PTP). Six of recorded NPO neurons were identified morphologically with neurobiotin. They were medium to large, multipolar cells with diameters >20 μM, which resemble AS-on cells in the NPO. The present results demonstrate that amygdalar projections are capable of exerting a powerful excitatory postsynaptic drive that activates NPO neurons. Therefore, we suggest that the amygdala is capable of inducing AS via direct

  12. Activity-dependent endogenous taurine release facilitates excitatory neurotransmission in the neocortical marginal zone of neonatal rats

    Directory of Open Access Journals (Sweden)

    Taizhe eQian

    2014-02-01

    Full Text Available In the developing cerebral cortex, the marginal zone (MZ, consisting of early-generated neurons such as Cajal-Retzius cells, plays an important role in cell migration and lamination. There is accumulating evidence of widespread excitatory neurotransmission mediated by γ-aminobutyric acid (GABA in the MZ. Cajal-Retzius cells express not only GABAA receptors but also α2/β subunits of glycine receptors, and exhibit glycine receptor-mediated depolarization due to high [Cl−]i. However, the physiological roles of glycine receptors and their endogenous agonists during neurotransmission in the MZ are yet to be elucidated. To address this question, we performed optical imaging from the MZ using the voltage-sensitive dye JPW1114 on tangential neocortical slices of neonatal rats. A single electrical stimulus evoked an action-potential-dependent optical signal that spread radially over the MZ. The amplitude of the signal was not affected by glutamate receptor blockers, but was suppressed by either GABAA or glycine receptor antagonists. Combined application of both antagonists nearly abolished the signal. Inhibition of Na+, K+-2Cl− cotransporter by 20 µM bumetanide reduced the signal, indicating that this transporter contributes to excitation. Analysis of the interstitial fluid obtained by microdialysis from tangential neocortical slices with high-performance liquid chromatography revealed that GABA and taurine, but not glycine or glutamate, were released in the MZ in response to the electrical stimulation. The ambient release of taurine was reduced by the addition of a voltage-sensitive Na+ channel blocker. Immunohistochemistry and immunoelectron microscopy indicated that taurine was stored both in Cajal-Retzius and non-Cajal-Retzius cells in the MZ, but was not localized in presynaptic structures. Our results suggest that activity-dependent non-synaptic release of endogenous taurine facilitates excitatory neurotransmission through activation of

  13. Effect of helium-neon laser on fast excitatory postsynaptic potential (f-EPSP) of neurons in the isolated rat superior cervical ganglia

    Science.gov (United States)

    Hua, Mo; Ping, He; Ning, Mo

    2002-06-01

    Single electrical stimulation of the cervical sympathetic trunk elicits in the ganglion cells an excitatory postsynaptic potential (EPSP) or multiple EPSPs of varying latencies, among which a fast excitatory postsynaptic potential (f-EPSP) is the main type of ganglionic transmission in the sympathetic neurons. In previous work, we studied the effects of Helium-Neon laser with wavelength 632.8 nm on membrane conductance of neurons with stable f- EPSP in isolated rat superior cervical ganglia. The aim of this study is to further measure the effect of Helium-Neon Laser with wavelength 632.8 nm on fast excitatory postsynaptic potential of postganglionic neurons in the isolated rate superior cervical ganglia by means of intracellular recording techniques. The neurons with fast excitatory postsynaptic potential were irradiated by different power densities (1 and 5 mW/cm2), pulse frequency of 1 Hz laser. Irradiated by the 2 mW/cm2 laser, the amplitude of the f-EPSP could augment (PEPSP could descend and lasted for 3- 8 minutes later.

  14. Propofol enhances the field excitatory postsynaptic potentials in CA1 hippocampal slices of young and aged mice

    Institute of Scientific and Technical Information of China (English)

    Yin Yiqing; William J Middleton; Carlos M.Florez; Peter L.Carlen; Hossam EI-Beheiry

    2014-01-01

    Background Increasing age was shown to decrease the requirements for propfol.However,the mechanisms of ageing-induced potentiation of anesthetic actions have not been clearly explored.The aim of this study is to compare the effects of propofol on the field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices of young and aging mice.Methods Brain slices were prepared from C57BL6 male young (2 months) and aging (>12 months) mice.The dendritic field excitatory postsynaptic potential was recorded from the CA1 stratum radiatum using patch clamp electrophysiological methods.A bipolar concentric stimulating electrode was placed along the Schaffer collateral for othodromic stimulation.The effects of clinically-relevant concentrations of propofol were studied in the young and ageing mouse tissues.Results Propofol application increased the orthodromically evoked fEPSP produced in slices taken from young and older animals.A striking feature in the I/O relationship was the decreased enhancement of the fEPSPs by propofol in slices from older mice.A clinically relevant concentration of propofol,10 μmol/L,showed more significant enhancement in amplitude and area under the curve (AUC) of fEPSP in young compared to tissues from older mice (amplitude:young (24.9±3.4)%,old (4.6±1.6)%; AUC young (30.6±5.4)%,old (2.1±1.7)%).There was no statistically significant difference between the paired-pulse facilitation (PPF) ratios calculated for the responses obtained in tissues from young mice.In slices from older mice,in the presence of 10 μmol/L propofol,PPF was decreased and returned to baseline after washout (baseline 1.21±0.01,propofol:1.16±0.01).Bicuculline (15 μmol/L) blocked the enhancement of propofol on fEPSP in tissues from young and old mice.Conclusion The fEPSP of slices from aging mice demonstrates diminished sensitivity to the enhancing actions of propofol.

  15. Surviving mossy cells enlarge and receive more excitatory synaptic input in a mouse model of temporal lobe epilepsy.

    Science.gov (United States)

    Zhang, Wei; Thamattoor, Ajoy K; LeRoy, Christopher; Buckmaster, Paul S

    2015-05-01

    Numerous hypotheses of temporal lobe epileptogenesis have been proposed, and several involve hippocampal mossy cells. Building on previous hypotheses we sought to test the possibility that after epileptogenic injuries surviving mossy cells develop into super-connected seizure-generating hub cells. If so, they might require more cellular machinery and consequently have larger somata, elongate their dendrites to receive more synaptic input, and display higher frequencies of miniature excitatory synaptic currents (mEPSCs). To test these possibilities pilocarpine-treated mice were evaluated using GluR2-immunocytochemistry, whole-cell recording, and biocytin-labeling. Epileptic pilocarpine-treated mice displayed substantial loss of GluR2-positive hilar neurons. Somata of surviving neurons were 1.4-times larger than in controls. Biocytin-labeled mossy cells also were larger in epileptic mice, but dendritic length per cell was not significantly different. The average frequency of mEPSCs of mossy cells recorded in the presence of tetrodotoxin and bicuculline was 3.2-times higher in epileptic pilocarpine-treated mice as compared to controls. Other parameters of mEPSCs were similar in both groups. Average input resistance of mossy cells in epileptic mice was reduced to 63% of controls, which is consistent with larger somata and would tend to make surviving mossy cells less excitable. Other intrinsic physiological characteristics examined were similar in both groups. Increased excitatory synaptic input is consistent with the hypothesis that surviving mossy cells develop into aberrantly super-connected seizure-generating hub cells, and soma hypertrophy is indirectly consistent with the possibility of axon sprouting. However, no obvious evidence of hyperexcitable intrinsic physiology was found. Furthermore, similar hypertrophy and hyper-connectivity has been reported for other neuron types in the dentate gyrus, suggesting mossy cells are not unique in this regard. Thus

  16. Changes in excitatory and inhibitory circuits of the rat hippocampus 12-14 months after complete forebrain ischemia.

    Science.gov (United States)

    Arabadzisz, D; Freund, T F

    1999-01-01

    Changes in interneuron distribution and excitatory connectivity have been investigated in animals which had survived 12-14 months after complete forebrain ischemia, induced by four-vessel occlusion. Anterograde tracing with Phaseolus vulgaris leucoagglutinin revealed massive Schaffer collateral input even to those regions of the CA1 subfield where hardly any surviving pyramidal cells were found. Boutons of these Schaffer collaterals formed conventional synaptic contacts on dendritic spines and shafts, many of which likely belong to interneurons. Mossy fibres survived the ischemic challenge, however, large mossy terminals showed altered morphology, namely, the number of filopodiae on these terminals decreased significantly. The entorhinal input to the hippocampus did not show any morphological alterations. The distribution of interneurons was investigated by neurochemical markers known to label functionally distinct GABAergic cell populations. In the hilus, spiny interneurons showed a profound decrease in number. This phenomenon was not as obvious in CA3, but the spiny metabotropic glutamate receptor 1alpha-positive non-pyramidal cells, some of which contain calretinin or substance P receptor, disappeared from stratum lucidum of this area. In the CA1 region, somatostatin immunoreactivity disappeared from stratum oriens/lacunosum-moleculare-associated cells, while in metabotropic glutamate receptor 1alpha-stained sections these cells seemed unaffected in number. Other interneurons did not show an obvious decrease in number. In stratum radiatum of the CA1 subfield, some interneuron types had altered morphology: the substance P receptor-positive dendrites lost their characteristic radial orientation, and the metabotropic glutamate receptor 1alpha-expressing cells became extremely spiny. The loss of inhibitory interneurons at the first two stages of the trisynaptic loop coupled with a well-preserved excitatory connectivity among the subfields suggests that

  17. The neurogenesis of P1 and N1: A concurrent EEG/LFP study.

    Science.gov (United States)

    Bruyns-Haylett, Michael; Luo, Jingjing; Kennerley, Aneurin J; Harris, Sam; Boorman, Luke; Milne, Elizabeth; Vautrelle, Nicolas; Hayashi, Yurie; Whalley, Benjamin J; Jones, Myles; Berwick, Jason; Riera, Jorge; Zheng, Ying

    2017-02-01

    It is generally recognised that event related potentials (ERPs) of electroencephalogram (EEG) primarily reflect summed post-synaptic activity of the local pyramidal neural population(s). However, it is still not understood how the positive and negative deflections (e.g. P1, N1 etc) observed in ERP recordings are related to the underlying excitatory and inhibitory post-synaptic activity. We investigated the neurogenesis of P1 and N1 in ERPs by pharmacologically manipulating inhibitory post-synaptic activity in the somatosensory cortex of rodent, and concurrently recording EEG and local field potentials (LFPs). We found that the P1 wave in the ERP and LFP of the supragranular layers is determined solely by the excitatory post-synaptic activity of the local pyramidal neural population, as is the initial segment of the N1 wave across cortical depth. The later part of the N1 wave was modulated by inhibitory post-synaptic activity, with its peak and the pulse width increasing as inhibition was reduced. These findings suggest that the temporal delay of inhibition with respect to excitation observed in intracellular recordings is also reflected in extracellular field potentials (FPs), resulting in a temporal window during which only excitatory post-synaptic activity and leak channel activity are recorded in the ERP and evoked LFP time series. Based on these findings, we provide clarification on the interpretation of P1 and N1 in terms of the excitatory and inhibitory post-synaptic activities of the local pyramidal neural population(s).

  18. Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice.

    Science.gov (United States)

    Inchauspe, Carlota González; Pilati, Nadia; Di Guilmi, Mariano N; Urbano, Francisco J; Ferrari, Michel D; van den Maagdenberg, Arn M J M; Forsythe, Ian D; Uchitel, Osvaldo D

    2015-01-01

    CaV2.1 Ca(2+) channels play a key role in triggering neurotransmitter release and mediating synaptic transmission. Familial hemiplegic migraine type-1 (FHM-1) is caused by missense mutations in the CACNA1A gene that encodes the α1A pore-forming subunit of CaV2.1 Ca(2+) channels. We used knock-in (KI) transgenic mice harbouring the pathogenic FHM-1 mutation R192Q to study inhibitory and excitatory neurotransmission in the principle neurons of the lateral superior olive (LSO) in the auditory brainstem. We tested if the R192Q FHM-1 mutation differentially affects excitatory and inhibitory synaptic transmission, disturbing the normal balance between excitation and inhibition in this nucleus. Whole cell patch-clamp was used to measure neurotransmitter elicited excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in wild-type (WT) and R192Q KI mice. Our results showed that the FHM-1 mutation in CaV2.1 channels has multiple effects. Evoked EPSC amplitudes were smaller whereas evoked and miniature IPSC amplitudes were larger in R192Q KI compared to WT mice. In addition, in R192Q KI mice, the release probability was enhanced compared to WT, at both inhibitory (0.53 ± 0.02 vs. 0.44 ± 0.01, P = 2.10(-5), Student's t-test) and excitatory synapses (0.60 ± 0.03 vs. 0.45 ± 0.02, P = 4 10(-6), Student's t-test). Vesicle pool size was diminished in R192Q KI mice compared to WT mice (68 ± 6 vs 91 ± 7, P = 0.008, inhibitory; 104 ± 13 vs 335 ± 30, P = 10(-6), excitatory, Student's t-test). R192Q KI mice present enhanced short-term plasticity. Repetitive stimulation of the afferent axons caused short-term depression (STD) of E/IPSCs that recovered significantly faster in R192Q KI mice compared to WT. This supports the hypothesis of a gain-of-function of the CaV2.1 channels in R192Q KI mice, which alters the balance of excitatory/inhibitory inputs and could also have implications in the altered cortical excitability responsible for FHM

  19. Association study of polymorphisms in the excitatory amino acid transporter 2 gene (SLC1A2 with schizophrenia

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    Iwata Nakao

    2004-08-01

    Full Text Available Abstract Background The glutamatergic dysfunction hypothesis of schizophrenia suggests that genes involved in glutametergic transmission are candidates for schizophrenic susceptibility genes. We have been performing systematic association studies of schizophrenia with the glutamate receptor and transporter genes. In this study we report an association study of the excitatory amino acid transporter 2 gene, SLC1A2 with schizophrenia. Methods We genotyped 100 Japanese schizophrenics and 100 controls recruited from the Kyushu area for 11 single nucleotide polymorphism (SNP markers distributed in the SLC1A2 region using the direct sequencing and pyrosequencing methods, and examined allele, genotype and haplotype association with schizophrenia.The positive finding observed in the Kyushu samples was re-examined using 100 Japanese schizophrenics and 100 controls recruited from the Aichi area. Results We found significant differences in genotype and allele frequencies of SNP2 between cases and controls (P = 0.013 and 0.008, respectively. After Bonferroni corrections, the two significant differences disappeared. We tested haplotype associations for all possible combinations of SNP pairs. SNP2 showed significant haplotype associations with the disease (P = 9.4 × 10-5, P = 0.0052 with Bonferroni correction, at the lowest in 8 combinations. Moreover, the significant haplotype association of SNP2-SNP7 was replicated in the cumulative analysis of our two sample sets. Conclusion We concluded that at least one susceptibility locus for schizophrenia is probably located within or nearby SLC1A2 in the Japanese population.

  20. Differentiated human midbrain-derived neural progenitor cells express excitatory strychnine-sensitive glycine receptors containing α2β subunits.

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    Florian Wegner

    Full Text Available BACKGROUND: Human fetal midbrain-derived neural progenitor cells (NPCs may deliver a tissue source for drug screening and regenerative cell therapy to treat Parkinson's disease. While glutamate and GABA(A receptors play an important role in neurogenesis, the involvement of glycine receptors during human neurogenesis and dopaminergic differentiation as well as their molecular and functional characteristics in NPCs are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular analyses indicate a predominance of glycine receptor heteromers containing α2β subunits. Intracellular calcium measurements of differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors and not by D-serine-sensitive excitatory glycine receptors. Culturing NPCs with additional glycine, the glycine-receptor antagonist strychnine, or the Na(+-K(+-Cl(- co-transporter 1 (NKCC1-inhibitor bumetanide did not significantly influence cell proliferation and differentiation in vitro. CONCLUSIONS/SIGNIFICANCE: These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation. However, glycine receptors seem to have a limited functional impact on neurogenesis and dopaminergic differentiation of NPCs in vitro.

  1. An Investigation of the Late Excitatory Potentials in the Hand following Transcranial Magnetic Stimulation in Early Alzheimer's Disease.

    Science.gov (United States)

    Balla, Christina; Maertens de Noordhout, Alain; Pepin, Jean Louis

    2014-01-01

    Recent neuroimaging studies in humans support the clinical observations that the motor cortex is affected early in the course of Alzheimer's disease (AD). We measured the silent period (SP) induced by transcranial magnetic stimulation in AD patients in the very early stage of the disease, and we explored whether and in which way the pharmacologic manipulation of the cholinergic system could modify it. An increase in the duration of the SP was observed in AD patients in the early stage in comparison to controls. After 2 months of treatment with donepezil, the duration did not differ significantly from that of normal subjects. The results of our study show a fragmentation and an enlargement of the SP in the presence of multiple late excitatory potentials (LEPs) in early untreated AD patients. These LEPs were also modulated by donepezil. The results suggest an early functional impairment of cholinergic neurotransmission in AD. The disturbance in acetylcholine output in early AD leads to a decrease in excitability of the motor system.

  2. 3D Clustering of GABAergic Neurons Enhances Inhibitory Actions on Excitatory Neurons in the Mouse Visual Cortex

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    Teppei Ebina

    2014-12-01

    Full Text Available Neocortical neurons with similar functional properties assemble into spatially coherent circuits, but it remains unclear how inhibitory interneurons are organized. We applied in vivo two-photon functional Ca2+ imaging and whole-cell recording of synaptic currents to record visual responses of cortical neurons and analyzed their spatial arrangements. GABAergic interneurons were clustered in the 3D space of the mouse visual cortex, and excitatory neurons located within the clusters (insiders had a lower amplitude and sharper orientation tuning of visual responses than outsiders. Inhibitory synaptic currents recorded from the insiders were larger than those of the outsiders. Single, isolated interneurons did not show such a location-tuning/amplitude relationship. The two principal subtypes of interneurons, parvalbumin- and somatostatin-expressing neurons, also formed clusters with only slightly overlapping each other and exhibited a different location-tuning relationship. These findings suggest that GABAergic interneurons and their subgroups form clusters to make their inhibitory function more effective than isolated interneurons.

  3. Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington’s disease model

    KAUST Repository

    Giralt, Albert

    2017-05-30

    The structure and function of spines and excitatory synapses are under the dynamic control of multiple signalling networks. Although tyrosine phosphorylation is involved, its regulation and importance are not well understood. Here we study the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the hippocampus. Hippocampal-related learning and CA1 long-term potentiation are severely impaired in Pyk2-deficient mice and are associated with alterations in NMDA receptors, PSD-95 and dendritic spines. In cultured hippocampal neurons, Pyk2 has autophosphorylation-dependent and -independent roles in determining PSD-95 enrichment and spines density. Pyk2 levels are decreased in the hippocampus of individuals with Huntington and in the R6/1 mouse model of the disease. Normalizing Pyk2 levels in the hippocampus of R6/1 mice rescues memory deficits, spines pathology and PSD-95 localization. Our results reveal a role for Pyk2 in spine structure and synaptic function, and suggest that its deficit contributes to Huntington’s disease cognitive impairments.

  4. Activity-induced long-term potentiation of excitatory synapses in developing zebrafish retina in vivo.

    Science.gov (United States)

    Wei, Hong-ping; Yao, Yuan-yuan; Zhang, Rong-wei; Zhao, Xiao-feng; Du, Jiu-lin

    2012-08-09

    Neural activity-induced long-term potentiation (LTP) of synaptic transmission is believed to be one of the cellular mechanisms underlying experience-dependent developmental refinement of neural circuits. Although it is well established that visual experience and neural activity are critical for the refinement of retinal circuits, whether and how LTP occurs in the retina remain unknown. Using in vivo perforated whole-cell recording and two-photon calcium imaging, we find that both repeated electrical and visual stimulations can induce LTP at excitatory synapses formed by bipolar cells on retinal ganglion cells in larval but not juvenile zebrafish. LTP induction requires the activation of postsynaptic N-methyl-D-aspartate receptors, and its expression involves arachidonic acid-dependent presynaptic changes in calcium dynamics and neurotransmitter release. Physiologically, both electrical and visual stimulation-induced LTP can enhance visual responses of retinal ganglion cells. Thus, LTP exists in developing retinae with a presynaptic locus and may serve for visual experience-dependent refinement of retinal circuits.

  5. The neurotoxin 1-methyl-4-phenylpyridinium (MPP+ alters hippocampal excitatory synaptic transmission by modulation of the GABAergic system

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    YuYing eHuang

    2015-08-01

    Full Text Available The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP induces Parkinson’s disease (PD-like symptoms following administration to mice, monkeys and humans. A common view is that MPTP is metabolized to 1-methyl-4-phenylpyridinium ion (MPP+ to induce its neurodegenerative effects on dopaminergic neurons in the substantia nigra. Moreover, the hippocampus contains dopaminergic fibers, which are projecting from the ventral tegmental area, substantia nigra and pars compacta and contain the whole machinery required for dopamine synthesis making them sensitive to MPTP and MPP+. Here we present data showing that acute bath-application of MPP+ elicited a dose-dependent facilitation followed by a depression of synaptic transmission of hippocampal Schaffer collaterals-CA1 synapses in mice. The effects of MPP+ were not mediated by D1/D5- and D2-like receptor activation. Inhibition of the dopamine transporters (DAT did not prevent but increased the depression of excitatory postsynaptic field potentials. In the search for a possible mechanism, we observed that MPP+ reduced the appearance of polyspikes in population spikes recorded in str. pyramidale and increased the frequency of miniature inhibitory postsynaptic currents. The acute effect of MPP+ on synaptic transmission was attenuated by co-application of a GABAA receptor antagonist. Taking these data together, we suggest that MPP+ affects hippocampal synaptic transmission by enhancing some aspects of

  6. Prenatal stress enhances excitatory synaptic transmission and impairs long-term potentiation in the frontal cortex of adult offspring rats.

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    Joanna Sowa

    Full Text Available The effects of prenatal stress procedure were investigated in 3 months old male rats. Prenatally stressed rats showed depressive-like behavior in the forced swim test, including increased immobility, decreased mobility and decreased climbing. In ex vivo frontal cortex slices originating from prenatally stressed animals, the amplitude of extracellular field potentials (FPs recorded in cortical layer II/III was larger, and the mean amplitude ratio of pharmacologically-isolated NMDA to the AMPA/kainate component of the field potential--smaller than in control preparations. Prenatal stress also resulted in a reduced magnitude of long-term potentiation (LTP. These effects were accompanied by an increase in the mean frequency, but not the mean amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs in layer II/III pyramidal neurons. These data demonstrate that stress during pregnancy may lead not only to behavioral disturbances, but also impairs the glutamatergic transmission and long-term synaptic plasticity in the frontal cortex of the adult offspring.

  7. Cortical excitatory neurons become protected from cell division during neurogenesis in an Rb family-dependent manner.

    Science.gov (United States)

    Oshikawa, Mio; Okada, Kei; Nakajima, Kazunori; Ajioka, Itsuki

    2013-06-01

    Cell cycle dysregulation leads to abnormal proliferation and cell death in a context-specific manner. Cell cycle progression driven via the Rb pathway forces neurons to undergo S-phase, resulting in cell death associated with the progression of neuronal degeneration. Nevertheless, some Rb- and Rb family (Rb, p107 and p130)-deficient differentiating neurons can proliferate and form tumors. Here, we found in mouse that differentiating cerebral cortical excitatory neurons underwent S-phase progression but not cell division after acute Rb family inactivation in differentiating neurons. However, the differentiating neurons underwent cell division and proliferated when Rb family members were inactivated in cortical progenitors. Differentiating neurons generated from Rb(-/-); p107(-/-); p130(-/-) (Rb-TKO) progenitors, but not acutely inactivated Rb-TKO differentiating neurons, activated the DNA double-strand break (DSB) repair pathway without increasing trimethylation at lysine 20 of histone H4 (H4K20), which has a role in protection against DNA damage. The activation of the DSB repair pathway was essential for the cell division of Rb-TKO differentiating neurons. These results suggest that newly born cortical neurons from progenitors become epigenetically protected from DNA damage and cell division in an Rb family-dependent manner.

  8. Differentiated human midbrain-derived neural progenitor cells express excitatory strychnine-sensitive glycine receptors containing α2β subunits.

    Science.gov (United States)

    Wegner, Florian; Kraft, Robert; Busse, Kathy; Härtig, Wolfgang; Ahrens, Jörg; Leffler, Andreas; Dengler, Reinhard; Schwarz, Johannes

    2012-01-01

    Human fetal midbrain-derived neural progenitor cells (NPCs) may deliver a tissue source for drug screening and regenerative cell therapy to treat Parkinson's disease. While glutamate and GABA(A) receptors play an important role in neurogenesis, the involvement of glycine receptors during human neurogenesis and dopaminergic differentiation as well as their molecular and functional characteristics in NPCs are largely unknown. Here we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular analyses indicate a predominance of glycine receptor heteromers containing α2β subunits. Intracellular calcium measurements of differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors and not by D-serine-sensitive excitatory glycine receptors. Culturing NPCs with additional glycine, the glycine-receptor antagonist strychnine, or the Na(+)-K(+)-Cl(-) co-transporter 1 (NKCC1)-inhibitor bumetanide did not significantly influence cell proliferation and differentiation in vitro. These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation. However, glycine receptors seem to have a limited functional impact on neurogenesis and dopaminergic differentiation of NPCs in vitro.

  9. Endogenous excitatory amino acid neurotransmission regulates thyroid-stimulating hormone and thyroid hormone secretion in conscious freely moving male rats.

    Science.gov (United States)

    Arufe, M C; Durán, R; Perez-Vences, D; Alfonso, M

    2002-04-01

    The role of neurotransmission of endogenous excitatory amino acid (EAA) on serum thyroid hormones and thyroid-stimulating hormone (TSH) levels was examined in conscious and freely moving adult male Sprague-Dawley rats. The rats were cannulated at the third ventricle 2 d before the experiments. Several glutamate receptor agonists, such as kainic acid and domoic acid, and antagonists, such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and dizocilpine (MK-801) were administered into the third ventricle. Serum TSH levels were assesed by radioimmunoassay, and serum thyroid hormone levels were assessed by enzyme immunoassay. The results showed that the administration of CNQX and MK-801 produced a decrease in serum levels of TSH and thyroid hormones. The administration of kainic acid and domoic acid increased TSH concentrations, whereas CNQX completely blocked the release of TSH induced by kainic acid and domoic acid. These results suggest the importance of endogenous EAA in the regulation of hormone secretion from the pituitary-thyroid axis, as well as the role of the N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the stimulatory effect of EAAs on the pituitary-thyroid axis.

  10. Effect of helium-neon laser on fast excitatory postsynaptic potential of neurons in the isolated rat superior cervical ganglia

    Science.gov (United States)

    Mo, Hua; He, Ping; Mo, Ning

    2004-08-01

    The aim of this study is to further measure the effect of 632.8-nm helium-neon laser on fast excitatory postsynaptic potential (f-EPSP) of postganglionic neurons in isolated rat superior cervical ganglia by means of intracellular recording techniques. The neurons with f-EPSP were irradiated by different power densities (1-5 mW/cm2) laser. Irradiated by the 2-mW/cm2 laser, the amplitude of the f-EPSP could augment (PEPSP could descend and last for 3-8 minutes. But the amplitude of the f-EPSP of neurons irradiated by the 5-mW/cm2 laser could depress for the irradiating periods. The results show that: 1) the variation of the amplitude of f-EPSP caused by laser is power density-dependent and time-dependent; 2) there exist the second-order phases in the interaction of the helium-neon laser with neurons. These findings may provide certain evidence in explanation of the mechanisms of clinical helium-neon laser therapy.

  11. Nicotinic and muscarinic reduction of unitary excitatory postsynaptic potentials in sensory cortex; dual intracellular recording in vitro.

    Science.gov (United States)

    Levy, Robert B; Reyes, Alex D; Aoki, Chiye

    2006-04-01

    We studied the cholinergic modulation of glutamatergic transmission between neighboring layer 5 regular-spiking pyramidal neurons in somatosensory cortical slices from young rats (P10-P26). Brief bath application of 5-10 microM carbachol, a nonspecific cholinergic agonist, decreased the amplitude of evoked unitary excitatory postsynaptic potentials (EPSPs). This effect was blocked by 1 microM atropine, a muscarinic receptor antagonist. Nicotine (10 microM), in contrast to carbachol, reduced EPSPs in nominally magnesium-free solution but not in the presence of 1 mM Mg+2, indicating the involvement of NMDA receptors. Likewise, when the postsynaptic cell was depolarized under voltage clamp to allow NMDA receptor activation in the presence of 1 mM Mg+2, synaptic currents were reduced by nicotine. Nicotinic EPSP reduction was prevented by the NMDA receptor antagonist D-AP5 (50 microM) and by the nicotinic receptor antagonist mecamylamine (10 microM). Both carbachol and nicotine reduced short-term depression of EPSPs evoked by 10 Hz stimulation, indicating that EPSP reduction happens via reduction of presynaptic glutamate release. In the case of nicotine, several possible mechanisms for NMDAR-dependent EPSP reduction are discussed. As a result of NMDA receptor dependence, nicotinic EPSP reduction may serve to reduce the local spread of cortical excitation during heightened sensory activity.

  12. Optogenetic activation of VGLUT2-expressing excitatory neurons blocks epileptic seizure-like activity in the mouse entorhinal cortex

    Science.gov (United States)

    Yekhlef, Latefa; Breschi, Gian Luca; Taverna, Stefano

    2017-01-01

    We investigated whether an anti-epileptic effect is obtained by selectively activating excitatory neurons expressing ChR2 under the promoter for the synaptic vesicular glutamate transporter 2 (VGLUT2). VGLUT2-expressing cells were optically stimulated while local field potential and whole-cell patch-clamp recordings were performed in mouse entorhinal cortical slices perfused with the proconvulsive compound 4-aminopyridine (4-AP). In control conditions, blue light flashes directly depolarized the majority of putative glutamatergic cells, which in turn synaptically excited GABAergic interneurons. During bath perfusion with 4-AP, photostimuli triggered a fast EPSP-IPSP sequence which was often followed by tonic-clonic seizure-like activity closely resembling spontaneous ictal discharges. The GABAA-receptor antagonist gabazine blocked the progression of both light-induced and spontaneous seizures. Surprisingly, prolonged photostimuli delivered during ongoing seizures caused a robust interruption of synchronous discharges. Such break was correlated with a membrane potential depolarization block in principal cells, while putative GABAergic interneurons changed their firing activity from a burst-like to an irregular single-spike pattern. These data suggest that photostimulation of glutamatergic neurons triggers seizure-like activity only in the presence of an intact GABAergic transmission and that selectively activating the same glutamatergic cells robustly interrupts ongoing seizures by inducing a strong depolarization block, resulting in the disruption of paroxysmal burst-like firing. PMID:28230208

  13. Imaging and analysis of evoked excitatory-postsynaptic-calcium-transients by individual presynaptic-boutons of cultured Aplysia sensorimotor synapse.

    Science.gov (United States)

    Malkinson, Guy; Spira, Micha E

    2010-04-01

    The use of the sensory-motor (SN-MN) synapse of the Aplysia gill withdrawal reflex has contributed immensely to the understanding of synaptic transmission, learning and memory acquisition processes. Whereas the majority of the studies focused on analysis of the presynaptic mechanisms, recent studies indicated that as in mammalian synapses, long term potentiation (LTP) formed by Aplysia SN-MN synapse depends on elevation of the postsynaptic free intracellular calcium concentration ([Ca2+](i)). Consistently, injection of the fast calcium chelator BAPTA to the MN prevents the formation of serotonin-induced LTP. Nevertheless, currently there are no published reports that directly examine and document whether evoked synaptic transmission is associated with transient increase in the postsynaptic [Ca2+](i). In the present study we imaged, for the first time, alterations in the postsynaptic [Ca2+](i) in response to presynaptic stimulation and analyzed the underlying mechanisms. Using live imaging of the postsynaptic [Ca2+](i) while monitoring the EPSP, we found that evoked transmitter release generates excitatory postsynaptic calcium concentration transients (EPSCaTs) by two mechanisms: (a) activation of DNQX-sensitive postsynaptic receptors-gated calcium influx and (b) calcium influx through nitrendipine-sensitive voltage-gated calcium channels (VGCCs). Concomitant confocal imaging of presynaptic boutons and EPSCaTs revealed that approximately 86% of the presynaptic boutons are associated with functional synapses.

  14. Layer-specific processing of excitatory signals in CA1 interneurons depends on postsynaptic M₂ muscarinic receptors.

    Science.gov (United States)

    Zheng, Fang; Seeger, Thomas; Nixdorf-Bergweiler, Barbara E; Alzheimer, Christian

    2011-05-02

    The hippocampus receives a diffuse cholinergic innervation which acts on pre- and postsynaptic sites to modulate neurotransmission and excitability of pyramidal cells and interneurons in an intricate fashion. As one missing piece in this puzzle, we explored how muscarinic receptor activation modulates the somatodendritic processing of glutamatergic input in CA1 interneurons. We performed whole-cell recordings from visually identified interneurons of stratum radiatum (SR) and stratum oriens (SO) and examined the effects of the cholinergic agonist carbachol (CCh) on EPSP-like waveforms evoked by brief glutamate pulses onto their proximal dendrites. In SO interneurons, CCh consistently reduced glutamate-induced postsynaptic potentials (GPSPs) in control rat and mice, but not in M₂ muscarinic receptor knockout mice. By contrast, the overwhelming majority of interneurons recorded in SR of control and M₂ receptor-deficient hippocampi exhibited muscarinic enhancement of GPSPs. Interestingly, the non-responding interneurons were strictly confined to the SR subfield closest to the subiculum. Our data suggest that postsynaptic modulation by acetylcholine of excitatory input onto CA1 interneurons occurs in a stratum-specific fashion, which is determined by the absence or presence of M₂ receptors in their (somato-)dendritic compartments. Thus cholinergic projections might be capable of recalibrating synaptic weights in different inhibitory circuits of the CA1 region.

  15. An Investigation of the Late Excitatory Potentials in the Hand following Transcranial Magnetic Stimulation in Early Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Christina Balla

    2014-11-01

    Full Text Available Background: Recent neuroimaging studies in humans support the clinical observations that the motor cortex is affected early in the course of Alzheimer's disease (AD. Patients and Methods: We measured the silent period (SP induced by transcranial magnetic stimulation in AD patients in the very early stage of the disease, and we explored whether and in which way the pharmacologic manipulation of the cholinergic system could modify it. Results: An increase in the duration of the SP was observed in AD patients in the early stage in comparison to controls. After 2 months of treatment with donepezil, the duration did not differ significantly from that of normal subjects. The results of our study show a fragmentation and an enlargement of the SP in the presence of multiple late excitatory potentials (LEPs in early untreated AD patients. These LEPs were also modulated by donepezil. Conclusions: The results suggest an early functional impairment of cholinergic neurotransmission in AD. The disturbance in acetylcholine output in early AD leads to a decrease in excitability of the motor system.

  16. Effect of helium-neon laser on fast excitatory postsynaptic potential of neurons in the isolated rat superior cervical ganglia

    Institute of Scientific and Technical Information of China (English)

    Hua Mo(莫华); Ping He(何萍); Ning Mo(莫宁)

    2004-01-01

    The aim of this study is to further measure the effect of 632.8-nm helium-neon laser on fast excitatory postsynaptic potential(f-EPSP)of postganglionic neurons in isolated rat superior cervical ganglia by means of intracellular recording techniques.The neurons with f-EPSP were irradiated by different power densities(1 - 5 mW/cm2)laser.Irradiated by the 2-mW/cm2 laser,the amplitude of the f-EPSP could augment(P < 0.05,paired t test)and even cause action potential at the end of the first 1 - 2 minutes,the f-EPSP could descend and last for 3 - 8 minutes.But the amplitude of the f-EPSP of neurons irradiated by the 5-mW/cm2 laser could depress for the irradiating periods.The results show that:1)the variation of the amplitude of f-EPSP caused by laser is power density-dependent and time-dependent; 2)there exist the second-order phases in the interaction of the helium-neon laser with neurons.These findings may provide certain evidence in explanation of the mechanisms of clinical helium-neon laser therapy.

  17. Physiological and chemical analysis of neurotransmitter candidates at a fast excitatory synapse in the jellyfish Cyanea capillata (Cnidaria, Scyphozoa).

    Science.gov (United States)

    Anderson, Peter A V; Trapido-Rosenthal, H G

    2009-12-01

    Motor nerve net (MNN) neurons in the jellyfish Cyanea capillata communicate with one another by way of fast, bidirectional excitatory chemical synapses. As is the case with almost all identified chemical synapses in cnidarians, the identity of the neurotransmitter at these synapses is unclear. MNN neurons are large enough for stable intracellular recordings. This, together with the fact that they can be exposed, providing unlimited access to them and to their synapses, prompted a study of the action of a variety of neurotransmitter candidates, including those typically associated with fast synapses in higher animals. Only the amino acids taurine and beta-alanine produced physiological responses consistent with those of the normal EPSP in these cells. Moreover, chemical analysis revealed that both taurine and beta-alanine are present in the neurons and released by depolarization. These various findings strongly suggest that either or both of these amino acids, or a closely related compound is the neurotransmitter at the fast chemical synapses between MNN neurons.

  18. Excitatory neurotoxic properties of pontamine sky blue make it a useful tool for examining the functions of focal brain parts.

    Science.gov (United States)

    Nagano, Mayuko; Ashidate, Noriko; Yamamoto, Kayo; Ishimizu, Yohko; Saitoh, Sanae; Konishi, Yukiko; Koga, Tomoshige; Fukuda, Hiroyuki

    2004-02-01

    Pontamine sky blue (PSB) is used in brain studies to mark the position of microelectrode and micropipette tips. However, few studies have been made on the effects of PSB on neurons; therefore we examined these effects. When puffed on isolated sensory ganglion cells of rats, PSB increased membrane conductance, depolarized membrane potential, and reduced the amplitude of action potentials. When dripped on frog sympathetic ganglion, much like hexamethonium, PSB decreased the amplitude of compound action potentials of the postganglionic strand. A bath application of PSB to sartorius muscle fibers that had been treated with tetrodotoxin depolarized the membrane potential and increased the frequency and amplitude of miniature end-plate potentials. All these effects were reversible. When injected into the rat's pontine part corresponding to the location of the canine pontine defecation reflex center, PSB produced repetitive colorectal contractions and irreversibly abolished them in response to anal-canal stimulation. The excitatory and blocking effects of PSB and its staining ability make it a useful tool for examining the functions of focal brain parts.

  19. Cocaine cues retain silent traces of an excitatory history after conversion into conditioned inhibitors: 'the ghost in the addict'.

    Science.gov (United States)

    Weiss, Stanley J; Kearns, David N

    2016-04-01

    The present experiment investigated the extent to which the A+/AB- conditioned inhibition procedure could counteract an excitatory drug-related conditioning history. In two groups of rats, a light stimulus was established as a signal for the absence of cocaine. For the History group, the light had previously been a discriminative stimulus (S) that occasioned cocaine self-administration and could thus be classified as a cocaine excitor. In comparison, the No-History group first encountered the light during conditioned inhibition training. During conditioned inhibition training, both groups self-administered cocaine during tone as well as during click Ss, whereas drug seeking was eliminated in click-plus-light, wherein cocaine was not available (A+/AB-). Drug seeking was essentially eliminated in both groups. Nevertheless, on a summation test the light reduced cocaine seeking occasioned by the tone S by 95% in the No-History group, but by less than 50% in the History group. This summation test result showed that the effects of a drug-related history persisted even after the light was converted into an effective conditioned inhibitor on the training baseline through the powerful A+/AB- procedure. Future research should seek procedures that produce even stronger conditioned inhibition that eliminates such residual 'silent' drug excitation, the 'ghost in the addict'.

  20. Age-related changes in cerebellar and hypothalamic function accompany non-microglial immune gene expression, altered synapse organization, and excitatory amino acid neurotransmission deficits

    Science.gov (United States)

    Bonasera, Stephen J.; Arikkath, Jyothi; Boska, Michael D.; Chaudoin, Tammy R.; DeKorver, Nicholas W.; Goulding, Evan H.; Hoke, Traci A.; Mojtahedzedah, Vahid; Reyelts, Crystal D.; Sajja, Balasrinivasa; Schenk, A. Katrin; Tecott, Laurence H.; Volden, Tiffany A.

    2016-01-01

    We describe age-related molecular and neuronal changes that disrupt mobility or energy balance based on brain region and genetic background. Compared to young mice, aged C57BL/6 mice exhibit marked locomotor (but not energy balance) impairments. In contrast, aged BALB mice exhibit marked energy balance (but not locomotor) impairments. Age-related changes in cerebellar or hypothalamic gene expression accompany these phenotypes. Aging evokes upregulation of immune pattern recognition receptors and cell adhesion molecules. However, these changes do not localize to microglia, the major CNS immunocyte. Consistent with a neuronal role, there is a marked age-related increase in excitatory synapses over the cerebellum and hypothalamus. Functional imaging of these regions is consistent with age-related synaptic impairments. These studies suggest that aging reactivates a developmental program employed during embryogenesis where immune molecules guide synapse formation and pruning. Renewed activity in this program may disrupt excitatory neurotransmission, causing significant behavioral deficits. PMID:27689748

  1. Increased Excitatory Synaptic Transmission of Dentate Granule Neurons in Mice Lacking PSD-95-Interacting Adhesion Molecule Neph2/Kirrel3 during the Early Postnatal Period

    Science.gov (United States)

    Roh, Junyeop D.; Choi, Su-Yeon; Cho, Yi Sul; Choi, Tae-Yong; Park, Jong-Sil; Cutforth, Tyler; Chung, Woosuk; Park, Hanwool; Lee, Dongsoo; Kim, Myeong-Heui; Lee, Yeunkum; Mo, Seojung; Rhee, Jeong-Seop; Kim, Hyun; Ko, Jaewon; Choi, Se-Young; Bae, Yong Chul; Shen, Kang; Kim, Eunjoon; Han, Kihoon

    2017-01-01

    Copy number variants and point mutations of NEPH2 (also called KIRREL3) gene encoding an immunoglobulin (Ig) superfamily adhesion molecule have been linked to autism spectrum disorders, intellectual disability and neurocognitive delay associated with Jacobsen syndrome, but the physiological roles of Neph2 in the mammalian brain remain largely unknown. Neph2 is highly expressed in the dentate granule (DG) neurons of the hippocampus and is localized in both dendrites and axons. It was recently shown that Neph2 is required for the formation of mossy fiber filopodia, the axon terminal structure of DG neurons forming synapses with GABAergic neurons of CA3. In contrast, however, it is unknown whether Neph2 also has any roles in the postsynaptic compartments of DG neurons. We here report that, through its C-terminal PDZ domain-binding motif, Neph2 directly interacts with postsynaptic density (PSD)-95, an abundant excitatory postsynaptic scaffolding protein. Moreover, Neph2 protein is detected in the brain PSD fraction and interacts with PSD-95 in synaptosomal lysates. Functionally, loss of Neph2 in mice leads to age-specific defects in the synaptic connectivity of DG neurons. Specifically, Neph2−/− mice show significantly increased spontaneous excitatory synaptic events in DG neurons at postnatal week 2 when the endogenous Neph2 protein expression peaks, but show normal excitatory synaptic transmission at postnatal week 3. The evoked excitatory synaptic transmission and synaptic plasticity of medial perforant pathway (MPP)-DG synapses are also normal in Neph2−/− mice at postnatal week 3, further confirming the age-specific synaptic defects. Together, our results provide some evidence for the postsynaptic function of Neph2 in DG neurons during the early postnatal period, which might be implicated in neurodevelopmental and cognitive disorders caused by NEPH2 mutations. PMID:28381988

  2. Increased Excitatory Synaptic Transmission of Dentate Granule Neurons in Mice Lacking PSD-95-Interacting Adhesion Molecule Neph2/Kirrel3 during the Early Postnatal Period.

    Science.gov (United States)

    Roh, Junyeop D; Choi, Su-Yeon; Cho, Yi Sul; Choi, Tae-Yong; Park, Jong-Sil; Cutforth, Tyler; Chung, Woosuk; Park, Hanwool; Lee, Dongsoo; Kim, Myeong-Heui; Lee, Yeunkum; Mo, Seojung; Rhee, Jeong-Seop; Kim, Hyun; Ko, Jaewon; Choi, Se-Young; Bae, Yong Chul; Shen, Kang; Kim, Eunjoon; Han, Kihoon

    2017-01-01

    Copy number variants and point mutations of NEPH2 (also called KIRREL3) gene encoding an immunoglobulin (Ig) superfamily adhesion molecule have been linked to autism spectrum disorders, intellectual disability and neurocognitive delay associated with Jacobsen syndrome, but the physiological roles of Neph2 in the mammalian brain remain largely unknown. Neph2 is highly expressed in the dentate granule (DG) neurons of the hippocampus and is localized in both dendrites and axons. It was recently shown that Neph2 is required for the formation of mossy fiber filopodia, the axon terminal structure of DG neurons forming synapses with GABAergic neurons of CA3. In contrast, however, it is unknown whether Neph2 also has any roles in the postsynaptic compartments of DG neurons. We here report that, through its C-terminal PDZ domain-binding motif, Neph2 directly interacts with postsynaptic density (PSD)-95, an abundant excitatory postsynaptic scaffolding protein. Moreover, Neph2 protein is detected in the brain PSD fraction and interacts with PSD-95 in synaptosomal lysates. Functionally, loss of Neph2 in mice leads to age-specific defects in the synaptic connectivity of DG neurons. Specifically, Neph2(-/-) mice show significantly increased spontaneous excitatory synaptic events in DG neurons at postnatal week 2 when the endogenous Neph2 protein expression peaks, but show normal excitatory synaptic transmission at postnatal week 3. The evoked excitatory synaptic transmission and synaptic plasticity of medial perforant pathway (MPP)-DG synapses are also normal in Neph2(-/-) mice at postnatal week 3, further confirming the age-specific synaptic defects. Together, our results provide some evidence for the postsynaptic function of Neph2 in DG neurons during the early postnatal period, which might be implicated in neurodevelopmental and cognitive disorders caused by NEPH2 mutations.

  3. Two distinct modes of hypoosmotic medium-induced release of excitatory amino acids and taurine in the rat brain in vivo.

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    Renée E Haskew-Layton

    Full Text Available A variety of physiological and pathological factors induce cellular swelling in the brain. Changes in cell volume activate several types of ion channels, which mediate the release of inorganic and organic osmolytes and allow for compensatory cell volume decrease. Volume-regulated anion channels (VRAC are thought to be responsible for the release of some of organic osmolytes, including the excitatory neurotransmitters glutamate and aspartate. In the present study, we compared the in vivo properties of the swelling-activated release of glutamate, aspartate, and another major brain osmolyte taurine. Cell swelling was induced by perfusion of hypoosmotic (low [NaCl] medium via a microdialysis probe placed in the rat cortex. The hypoosmotic medium produced several-fold increases in the extracellular levels of glutamate, aspartate and taurine. However, the release of the excitatory amino acids differed from the release of taurine in several respects including: (i kinetic properties, (ii sensitivity to isoosmotic changes in [NaCl], and (iii sensitivity to hydrogen peroxide, which is known to modulate VRAC. Consistent with the involvement of VRAC, hypoosmotic medium-induced release of the excitatory amino acids was inhibited by the anion channel blocker DNDS, but not by the glutamate transporter inhibitor TBOA or Cd2+, which inhibits exocytosis. In order to elucidate the mechanisms contributing to taurine release, we studied its release properties in cultured astrocytes and cortical synaptosomes. Similarities between the results obtained in vivo and in synaptosomes suggest that the swelling-activated release of taurine in vivo may be of neuronal origin. Taken together, our findings indicate that different transport mechanisms and/or distinct cellular sources mediate hypoosmotic medium-induced release of the excitatory amino acids and taurine in vivo.

  4. Excitatory synapses on dendritic shafts of the caudal basal amygdala exhibit elevated levels of GABAA receptor α4 subunits following the induction of activity-based anorexia.

    Science.gov (United States)

    Wable, Gauri S; Barbarich-Marsteller, Nicole C; Chowdhury, Tara G; Sabaliauskas, Nicole A; Farb, Claudia R; Aoki, Chiye

    2014-01-01

    Anorexia nervosa (AN) is an eating disorder characterized by self-imposed severe starvation, excessive exercise, and anxiety. The onset of AN is most often at puberty, suggesting that gonadal hormonal fluctuations may contribute to AN vulnerability. Activity-based anorexia (ABA) is an animal model that reproduces some of the behavioral phenotypes of AN, including the paradoxical increase in voluntary exercise following food restriction. The basal amygdala as well as the GABAergic system regulate trait anxiety. We therefore examined the subcellular distribution of GABA receptors (GABARs) in the basal amygdala of female pubertal rats and specifically of their α4 subunits, because expression of α4-containing GABARs is regulated by gonadal hormone fluctuations. Moreover, because these GABARs reduce neuronal excitability through shunting of EPSPs, we quantified the frequency of occurrence of these GABARs adjacent to excitatory synapses. Electron microscopic immunoctychemistry revealed no change in the frequency of association of α4 subunits with excitatory synapses on dendritic spines, whether in the anterior (Bregma -2.8 mm) or caudal (Bregma -3.8 mm) portion of the basal amygdala. Sholl analysis of golgi-stained neurons also revealed no change in the extent of dendritic branching by these densely spiny, pyramidal-like neurons. However, there was an increase of membranous α4 subunits near excitatory synapses on dendritic shafts, specifically in the caudal basal amygdala, and this was accompanied by a rise of α4 subunits intracellularly. Because most dendritic shafts exhibiting excitatory synapses are GABAergic interneurons, the results predict disinhibition, which would increase excitability of the amygdaloid network, in turn augmenting ABA animals' anxiety.

  5. Imbalance of Excitatory/Inhibitory Synaptic Protein Expression in iPSC-derived Neurons from FOXG1+/− Patients and in Foxg1+/− Mice

    Science.gov (United States)

    Patriarchi, Tommaso; Amabile, Sonia; Frullanti, Elisa; Landucci, Elisa; Lo Rizzo, Caterina; Ariani, Francesca; Costa, Mario; Olimpico, Francesco; Hell, Johannes W.; Vaccarino, Flora M.; Renieri, Alessandra; Meloni, Ilaria

    2015-01-01

    Rett Syndrome (RTT) is a severe neurodevelopmental disorder associated with mutations in either MECP2, CDKL5 or FOXG1. The precise molecular mechanisms that lead to the pathogenesis of RTT have yet to be elucidated. We recently reported that expression of GluD1 (orphan Glutamate receptor Delta-1 subunit) is increased in iPSC-derived neurons obtained from patients with mutations in either MECP2 or CDKL5. GluD1 controls synaptic differentiation and shifts the balance between excitatory and inhibitory synapses towards the latter. Thus, an increase in GluD1 might be a critical factor in the etiology of RTT by affecting the excitatory/inhibitory balance in the developing brain. To test this hypothesis, we generated iPSC-derived neurons from FOXG1+/− patients. We analyzed mRNA and protein levels of GluD1 together with key markers of excitatory and inhibitory synapses in these iPSC-derived neurons and in Foxg1+/− mouse fetal (E11.5) and adult (P70) brains. We found strong correlation between iPSC-derived neurons and fetal mouse brains, where GluD1 and inhibitory synaptic markers (GAD67 and GABA AR-α1) were increased, while the levels of a number of excitatory synaptic markers (VGLUT1, GluA1, GluN1, PSD-95) were decreased. In adult mice, GluD1 was decreased along with all GABAergic and glutamatergic markers. Our findings further the understanding of the etiology of RTT by introducing a new pathological event occurring in the brain of FOXG1+/− patients during embryonic development and its time-dependent shift toward a general decrease in brain synapses. PMID:26443267

  6. Developmental changes in electrophysiological properties and a transition from electrical to chemical coupling between excitatory layer 4 neurons in the rat barrel cortex

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    Fliza eValiullina

    2016-01-01

    Full Text Available During development, sensory systems switch from an immature to an adult mode of function along with the emergence of the active cortical states. Here, we used patch-clamp recordings from neocortical slices in vitro to characterize the developmental changes in the basic electrophysiological properties of excitatory L4 neurons and their connectivity before and after the developmental switch, which occurs in the rat barrel cortex in vivo at postnatal day P8. Prior to the switch, L4 neurons had lower resting membrane potentials, higher input resistance, lower membrane capacity, as well as action potentials (APs with smaller amplitudes, longer durations and higher AP thresholds compared to the neurons after the switch. A sustained firing pattern also emerged around the switch. Dual patch-clamp recordings from L4 neurons revealed that recurrent connections between L4 excitatory cells do not exist before and develop rapidly across the switch. In contrast, electrical coupling between these neurons waned around the switch. We suggest that maturation of electrophysiological features, particularly acquisition of a sustained firing pattern, and a transition from the immature electrical to mature chemical synaptic coupling between excitatory L4 neurons, contributes to the developmental switch in the cortical mode of function.

  7. Layer-specific generation and propagation of seizures in slices of developing neocortex: role of excitatory GABAergic synapses.

    Science.gov (United States)

    Rheims, Sylvain; Represa, Alfonso; Ben-Ari, Yehezkel; Zilberter, Yuri

    2008-08-01

    The neonatal period is critical for seizure susceptibility, and neocortical networks are central in infantile epilepsies. We report that application of 4-aminopyridine (4-AP) to immature (P6-P9) neocortical slices generates layer-specific interictal seizures (IISs) that transform after recurrent seizures to ictal seizures (ISs). During IISs, cell-attached recordings show action potentials in interneurons and pyramidal cells in L5/6 and interneurons but not pyramidal neurons in L2/3. However, L2/3 pyramidal neurons also fire during ISs. Using single N-methyl-d-aspartate (NMDA) channel recordings for measuring the cell resting potential (Em), we show that transition from IISs to ISs is associated with a gradual Em depolarization of L2/3 and L5/6 pyramidal neurons that enhances their excitability. Bumetanide, a NKCC1 co-transporter antagonist, inhibits generation of IISs and prevents their transformation to ISs, indicating the role excitatory GABA in epilepsies. Therefore deep layer neurons are more susceptible to seizures than superficial ones. The initiating phase of seizures is characterized by IISs generated in L5/6 and supported by activation of both L5/6 interneurons and pyramidal cells. IISs propagate to L2/3 via activation of L2/3 interneurons but not pyramidal cells, which are mostly quiescent at this phase. In superficial layers, a persistent increase in excitability of pyramidal neurons caused by Em depolarization is associated with a transition from largely confined GABAergic IIS to ictal events that entrain the entire neocortex.

  8. Dendritic HCN channels shape excitatory postsynaptic potentials at the inner hair cell afferent synapse in the mammalian cochlea.

    Science.gov (United States)

    Yi, Eunyoung; Roux, Isabelle; Glowatzki, Elisabeth

    2010-05-01

    Synaptic transmission at the inner hair cell (IHC) afferent synapse, the first synapse in the auditory pathway, is specialized for rapid and reliable signaling. Here we investigated the properties of a hyperpolarization-activated current (I(h)), expressed in the afferent dendrite of auditory nerve fibers, and its role in shaping postsynaptic activity. We used whole cell patch-clamp recordings from afferent dendrites directly where they contact the IHC in excised postnatal rat cochlear turns. Excitatory postsynaptic potentials (EPSPs) of variable amplitude (1-35 mV) were found with 10-90% rise times of about 1 ms and time constants of decay of about 5 ms at room temperature. Current-voltage relations recorded in afferent dendrites revealed I(h). The pharmacological profile and reversal potential (-45 mV) indicated that I(h) is mediated by hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels. The HCN channel subunits HCN1, HCN2, and HCN4 were found to be expressed in afferent dendrites using immunolabeling. Raising intracellular cAMP levels sped up the activation kinetics, increased the magnitude of I(h) and shifted the half activation voltage (V(half)) to more positive values (-104 +/- 3 to -91 +/- 2 mV). Blocking I(h) with 50 microM ZD7288 resulted in hyperpolarization of the resting membrane potential (approximately 4 mV) and slowing the decay of the EPSP by 47%, suggesting that I(h) is active at rest and shortens EPSPs, thereby potentially improving rapid and reliable signaling at this first synapse in the auditory pathway.

  9. Associative plasticity in the human motor cortex is enhanced by concurrently targeting separate muscle representations with excitatory and inhibitory protocols.

    Science.gov (United States)

    Kamke, Marc R; Nydam, Abbey S; Sale, Martin V; Mattingley, Jason B

    2016-04-01

    Paired associative stimulation (PAS) induces changes in the excitability of human sensorimotor cortex that outlast the procedure. PAS typically involves repeatedly pairing stimulation of a peripheral nerve that innervates an intrinsic hand muscle with transcranial magnetic stimulation over the representation of that muscle in the primary motor cortex. Depending on the timing of the stimuli (interstimulus interval of 25 or 10 ms), PAS leads to either an increase (PAS25) or a decrease (PAS10) in excitability. Both protocols, however, have been associated with an increase in excitability of nearby muscle representations not specifically targeted by PAS. Based on these spillover effects, we hypothesized that an additive, excitability-enhancing effect of PAS25 applied to one muscle representation may be produced by simultaneously applying PAS25 or PAS10 to a nearby representation. In different experiments prototypical PAS25 targeting the left thumb representation [abductor pollicis brevis (APB)] was combined with either PAS25 or PAS10 applied to the left little finger representation [abductor digiti minimi (ADM)] or, in a control experiment, with PAS10 also targeting the APB. In an additional control experiment PAS10 targeted both representations. The plasticity effects were quantified by measuring the amplitude of motor evoked potentials (MEPs) recorded before and after PAS. As expected, prototypical PAS25 was associated with an increase in MEP amplitude in the APB muscle. This effect was enhanced when PAS also targeted the ADM representation but only when a different interstimulus timing (PAS10) was used. These results suggest that PAS-induced plasticity is modified by concurrently targeting separate motor cortical representations with excitatory and inhibitory protocols.

  10. The KCl cotransporter, KCC2, is highly expressed in the vicinity of excitatory synapses in the rat hippocampus.

    Science.gov (United States)

    Gulyás, A I; Sík, A; Payne, J A; Kaila, K; Freund, T F

    2001-06-01

    Immunocytochemical visualization of the neuron-specific K+/Cl- cotransporter, KCC2, at the cellular and subcellular level revealed an area- and layer-specific diffuse labelling, and a discrete staining outlining the somata and dendrites of some interneurons in all areas of the rat hippocampus. KCC2 was highly expressed in parvalbumin-containing interneurons, as well as in subsets of calbindin, calretinin and metabotropic glutamate receptor 1a-immunoreactive interneurons. During the first 2 postnatal weeks, an increase of KCC2 staining was observed in the molecular layer of the dentate gyrus, correlating temporally with the arrival of entorhinal cortical inputs. Subcellular localization demonstrated KCC2 in the plasma membranes. Immunoreactivity in principal cells was responsible for the diffuse staining found in the neuropil. In these cells, KCC2 was detected primarily in dendritic spine heads, at the origin of spines and, at a much lower level on the somata and dendritic shafts. KCC2 expression was considerably higher in the somata and dendrites of interneurons, most notably of parvalbumin-containing cells, as well as in the thorny excrescences of CA3 pyramidal cells and in the spines of spiny hilar and stratum lucidum interneurons. The data indicate that KCC2 is highly expressed in the vicinity of excitatory inputs in the hippocampus, perhaps in close association with extrasynaptic GABAA receptors. A high level of excitation is known to lead to a simultaneous net influx of Na+ and Cl-, as evidenced by dendritic swelling. KCC2 located in the same microenvironment may provide a Cl- extrusion mechanism to deal with both ion and water homeostasis in addition to its role in setting the driving force of Cl- currents involved in fast postsynaptic inhibition.

  11. Excitatory amino acid transporter 2 downregulation correlates with thalamic neuronal death following kainic acid-induced status epilepticus in rat.

    Science.gov (United States)

    Sakurai, Masashi; Kurokawa, Haruna; Shimada, Akinori; Nakamura, Kazuhiro; Miyata, Hajime; Morita, Takehito

    2015-02-01

    Recurrent seizures without interictal resumption (status epilepticus) have been reported to induce neuronal death in the midline thalamic region that has functional roles in memory and decision-making; however, the pathogenesis underlying status epilepticus-induced thalamic neuronal death is yet to be determined. We performed histological and immunohistochemical studies as well as cerebral blood flow measurement using 4.7 tesla magnetic resonance imaging spectrometer on midline thalamic region in Sprague-Dawley rats (n = 75, male, 7 weeks after birth, body weight 250-300 g) treated with intraperitoneal injection of kainic acid (10 mg/kg) to induce status epilepticus (n = 55) or normal saline solution (n = 20). Histological study using paraffin-embedded specimens revealed neuronal death showing ischemic-like changes and Fluoro-Jade C positivity with calcium deposition in the midline thalamic region of epileptic rats. The distribution of neuronal death was associated with focal loss of immunoreactivity for excitatory amino acid transporter 2 (EAAT2), stronger immunoreaction for glutamate and increase in number of Iba-1-positive microglial cells showing swollen cytoplasm and long processes. Double immunofluorescence study demonstrated co-expression of interleukin-1 beta (IL-1β) and inducible nitric oxide synthase (iNOS) within microglial cells, and loss of EAAT2 immunoreactivity in reactive astrocytes. These microglial alterations and astrocytic EAAT2 downregulation were also observed in tissue without obvious neuronal death in kainic acid-treated rats. These results suggest the possible role of glutamate excitotoxicity in neuronal death in the midline thalamic region following kainic acid-induced status epilepticus due to astrocytic EAAT2 downregulation following microglial activation showing upregulation of IL-1β and iNOS.

  12. Simultaneous analysis of dendritic spine density, morphology and excitatory glutamate receptors during neuron maturation in vitro by quantitative immunocytochemistry.

    Science.gov (United States)

    Nwabuisi-Heath, Evelyn; LaDu, Mary Jo; Yu, Chunjiang

    2012-06-15

    Alterations in the density and morphology of dendritic spines are characteristic of multiple cognitive disorders. Elucidating the molecular mechanisms underlying spine alterations are facilitated by the use of experimental and analytical methods that permit concurrent evaluation of changes in spine density, morphology and composition. Here, an automated and quantitative immunocytochemical method for the simultaneous analysis of changes in the density and morphology of spines and excitatory glutamate receptors was established to analyze neuron maturation, in vitro. In neurons of long-term neuron-glia co-cultures, spine density as measured by drebrin cluster fluorescence, increased from DIV (days in vitro)10 to DIV18 (formation phase), remained stable from DIV18 to DIV21 (maintenance phase), and decreased from DIV21 to DIV26 (loss phase). The densities of spine-localized NMDAR and AMPAR clusters followed a similar trend. Spine head sizes as measured by the fluorescence intensities of drebrin clusters increased from DIV10 to DIV21 and decreased from DIV21 to DIV26. Changes in the densities of NR1-only, GluR2-only, and NR1+GluR2 spines were measured by the colocalizations of NR1 and GluR2 clusters with drebrin clusters. The densities of NR1-only spines remained stable from the maintenance to the loss phases, while GluR2-only and NR1+GluR2 spines decreased during the loss phase, thus suggesting GluR2 loss as a proximal molecular event that may underlie spine alterations during neuron maturation. This study demonstrates a sensitive and quantitative immunocytochemical method for the concurrent analysis of changes in spine density, morphology and composition, a valuable tool for determining molecular events involved in dendritic spine alterations. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: implications for HIV-1-associated neuropathology.

    Science.gov (United States)

    Yang, Jianming; Hu, Dehui; Xia, Jianxun; Liu, Jianuo; Zhang, Gang; Gendelman, Howard E; Boukli, Nawal M; Xiong, Huangui

    2013-09-01

    A plethora of prior studies has linked HIV-1-infected and immune activated brain mononuclear phagocytes (MP; blood borne macrophages and microglia) to neuronal dysfunction. These are modulated by N-methyl-D-aspartate receptor (NMDAR) antagonists and supporting their relevance for HIV-1-associated nervous system disease. The role of NMDAR subsets in HIV-1-induced neuronal injury, nonetheless, is poorly understood. To this end, we investigated conditioned media from HIV-1gp120-treated human monocyte-derived-macrophages (MDM) for its abilities to affect NMDAR-mediated excitatory postsynaptic currents (EPSC(NMDAR)) in rat hippocampal slices. Bath application of gp120-treated MDM-conditioned media (MCM) produced an increase of EPSC(NMDAR). In contrast, control (untreated) MCM had limited effects on EPSC(NMDAR). Testing NR2A NMDAR (NR2AR)-mediated EPSC (EPSC(NR2AR)) and NR2B NMDAR (NR2BR)-mediated EPSC (EPSC(NR2BR)) for MCM showed significant increased EPSC(NR2BR) when compared to EPSC(NR2AR) enhancement. When synaptic NR2AR-mediated EPSC was blocked by bath application of MK801 combined with low frequency stimulations, MCM retained its ability to enhance EPSC(NMDAR) evoked by stronger stimulations. This suggested that increase in EPSC(NMDAR) was mediated, in part, through extra-synaptic NR2BR. Further analyses revealed that the soluble factors with low (NR2BR but not NR2AR blockers. Taken together, these results indicate that macrophage secretory products induce neuronal injury through extra-synaptic NR2BRs.

  14. A homolog of FHM2 is involved in modulation of excitatory neurotransmission by serotonin in C. elegans.

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    Elena G Govorunova

    Full Text Available The C. elegans eat-6 gene encodes a Na(+, K(+-ATPase alpha subunit and is a homolog of the familial hemiplegic migraine candidate gene FHM2. Migraine is the most common neurological disorder linked to serotonergic dysfunction. We sought to study the pathophysiological mechanisms of migraine and their relation to serotonin (5-HT signaling using C. elegans as a genetic model. In C. elegans, exogenous 5-HT inhibits paralysis induced by the acetylcholinesterase inhibitor aldicarb. We found that the eat-6(ad467 mutation or RNAi of eat-6 increases aldicarb sensitivity and causes complete resistance to 5-HT treatment, indicating that EAT-6 is a component of the pathway that couples 5-HT signaling and ACh neurotransmission. While a postsynaptic role of EAT-6 at the bodywall NMJs has been well established, we found that EAT-6 may in addition regulate presynaptic ACh neurotransmission. We show that eat-6 is expressed in ventral cord ACh motor neurons, and that cell-specific RNAi of eat-6 in the ACh neurons leads to hypersensitivity to aldicarb. Electron microscopy showed an increased number of synaptic vesicles in the ACh neurons in the eat-6(ad467 mutant. Genetic analyses suggest that EAT-6 interacts with EGL-30 Galphaq, EGL-8 phospholipase C and SLO-1 BK channel signaling to modulate ACh neurotransmission and that either reduced or excessive EAT-6 function may lead to increased ACh neurotransmission. Study of the interaction between eat-6 and 5-HT receptors revealed both stimulatory and inhibitory 5-HT inputs to the NMJs. We show that the inhibitory and stimulatory 5-HT signals arise from distinct 5-HT neurons. The role of eat-6 in modulation of excitatory neurotransmission by 5-HT may provide a genetic explanation for the therapeutic effects of the drugs targeting 5-HT receptors in the treatment of migraine patients.

  15. Simultaneously Excitatory and Inhibitory Effects of Transcranial Alternating Current Stimulation Revealed Using Selective Pulse-Train Stimulation in the Rat Motor Cortex.

    Science.gov (United States)

    Khatoun, Ahmad; Asamoah, Boateng; Mc Laughlin, Myles

    2017-09-27

    Transcranial alternating current stimulation (tACS) uses sinusoidal, subthreshold, electric fields to modulate cortical processing. Cortical processing depends on a fine balance between excitation and inhibition and tACS acts on both excitatory and inhibitory cortical neurons. Given this, it is not clear whether tACS should increase or decrease cortical excitability. We investigated this using transcranial current stimulation of the rat (all males) motor cortex consisting of a continuous subthreshold sine wave with short bursts of suprathreshold pulse-trains inserted at different phases to probe cortical excitability. We found that when a low-rate, long-duration, suprathreshold pulse-train was used, subthreshold cathodal tACS decreased cortical excitability and anodal tACS increased excitability. However, when a high-rate, short-duration, suprathreshold pulse-train was used this pattern was inverted. An integrate-and-fire model incorporating biophysical differences between cortical excitatory and inhibitory neurons could predict the experimental data and helped interpret these results. The model indicated that low-rate suprathreshold pulse-trains preferentially stimulate excitatory cortical neurons, whereas high-rate suprathreshold pulse-trains stimulate both excitatory and inhibitory neurons. If correct, this indicates that suprathreshold pulse-train stimulation may be able to selectively control the excitation-inhibition balance within a cortical network. The excitation-inhibition balance then likely plays an important role in determining whether subthreshold tACS will increase or decrease cortical excitability.SIGNIFICANCE STATEMENT Transcranial alternating current stimulation (tACS) is a noninvasive neuromodulation method that uses weak sinusoidal electric fields to modulate cortical activity. In healthy volunteers tACS can modulate perception, cognition, and motor function but the underlying neural mechanism is poorly understood. In this study, using rat motor

  16. Effect of topiramate on partial excitatory amino acids in hippocampal dentate gyrus of rats after alcohol withdrawal

    Institute of Scientific and Technical Information of China (English)

    Qinghua Yang; Guang Wu; Haiying Jiang; Yuanzhe Jin; Songbiao Cui

    2006-01-01

    BACKGROUND: Many researches have indicated that the imbalances of various amino acid transmitters and neurotransmitters in brain are involved in the formation of alcohol withdrawal, especially that glutamic acid is one of the important transmitters for alcohol tolerance in central nervous system.OBJECTIVE: To observe the changes of excitatory amino acids in hippocampal dentate gyrus in rats with long-term alcohol drinking after withdrawal under consciousness, and investigate the therapeutic effect of topiramate on alcohol withdrawal.DESIGN: A randomized control animal experiment.SETTING: Department of Neurology, Affiliated Hospital of Yanbian University.MATERIALS: Thirty male Wistar rats of 4 months old, weighing 300-350 g, were purchased from the Experimental Animal Department, Medical College of Yanbian University. Topiramate was produced by Swish Cilag Company, and the batch number was 02CS063.METHODS: The experiments were carried out in the Department of Physiology, Medical College of Yanbian University from August 2005 to February 2006. ① The rats were divided randomly into three groups: control group (n=10), alcohol group (n=10) and topiramate-treated group (n=10). Rats in the alcohol group and topiramate-treated group were given intragastric perfusion of 500 g/L alcohol (10 mL/kg), once a day for 4 weeks successively, and then those in the topiramate-treated group were treated with 80 mg/kg topiramate at 24 hours after the last perfusion of alcohol, once a day for 3 days successively. Rats in the control group were intragastricly given isovolume saline. ② The withdrawal symptoms were assessed at 6, 30, 48 and 72 hours after the last perfusion of alcohol by using the withdrawal rating scale set by Erden et al,which had four observational indexes of stereotyped behaviors, agitation, tail stiffness and abnormal posture,each index was scored by 5 points, the higher the score, the more obvious the symptoms. ③ The contents of aspartic acid and glutamic acid

  17. Morphological changes associated with the genesis and development of an excitatory glutemergic synapse: An integrated framework model

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    Venkateswaran Nagarajan

    2014-04-01

    Full Text Available The genesis of an excitatory synapse has its inception when a dendritic filopodium makes a tactile contact with a presynaptic specialisation (bouton. The subsequent maturation of the synapse takes place via a series of interrelated biochemical and biophysical signalling pathways which controls the actin polymerisation in the presynaptic and the postsynaptic sites. Although individual models of many of these signalling transductions have been proposed, a holistic model integrating the various signalling pathways to the morphological plasticity associated with the genesis and development of synapses has not. In this poster an attempt has been made towards establishing a framework for an integrated model such as the one aforementioned, encompassing several signalling pathways which control the morphology and the efficacy of the synapse. Predominant pathways include those triggered by NMDA and AMPA receptors, Trkb-BDNF, Integrin and Epherin. Also, steps towards a model that elucidates the change in shape of the synapse carried out by zonal actin polymerisation (ZAP governed by the "wastage" of neurotransmitters during exo cum endocytosis processes and the assimilation of the postsynaptic density (PSD and cell adhesion molecules with emphasis on Neurexin-Neuriligin, have been explored. The cannabinoid receptors in the PAZ have extracellular lipophilic domains. Endocannabinoid receptors are triggered by the retrograde signalling cues which negatively affect the cAMP dependent mechanisms. Apart from this, autoreceptors also pilot a feedback mechanism via secondary messengers with Ca 2+ ion concentration and neurotransmitter concentration in the synaptic cleft as its stakeholders. Feedback signals of autoreceptors which functions in accordance to “Lock and Key Mechanism” plays a vital role in fine-tuning the plasticity of the synapse and in controlling the presynaptic release probability by invoking PKA dependent pathways. In a future continuation

  18. Tracking the expression of excitatory and inhibitory neurotransmission-related proteins and neuroplasticity markers after noise induced hearing loss.

    Directory of Open Access Journals (Sweden)

    Cherylea J Browne

    Full Text Available Excessive exposure to loud noise can damage the cochlea and create a hearing loss. These pathologies coincide with a range of CNS changes including reorganisation of frequency representation, alterations in the pattern of spontaneous activity and changed expression of excitatory and inhibitory neurotransmitters. Moreover, damage to the cochlea is often accompanied by acoustic disorders such as hyperacusis and tinnitus, suggesting that one or more of these neuronal changes may be involved in these disorders, although the mechanisms remain unknown. We tested the hypothesis that excessive noise exposure increases expression of markers of excitation and plasticity, and decreases expression of inhibitory markers over a 32-day recovery period. Adult rats (n = 25 were monaurally exposed to a loud noise (16 kHz, 1/10(th octave band pass (115 dB SPL for 1-hour, or left as non-exposed controls (n = 5. Animals were euthanased at either 0, 4, 8, 16 or 32 days following acoustic trauma. We used Western Blots to quantify protein levels of GABA(A receptor subunit α1 (GABA(Aα1, Glutamic-Acid Decarboxylase-67 (GAD-67, N-Methyl-D-Aspartate receptor subunit 2A (NR2A, Calbindin (Calb1 and Growth Associated Protein 43 (GAP-43 in the Auditory Cortex (AC, Inferior Colliculus (IC and Dorsal Cochlear Nucleus (DCN. Compared to sham-exposed controls, noise-exposed animals had significantly (p<0.05: lower levels of GABA(Aα1 in the contralateral AC at day-16 and day-32, lower levels of GAD-67 in the ipsilateral DCN at day-4, lower levels of Calb1 in the ipsilateral DCN at day-0, lower levels of GABA(Aα1 in the ipsilateral AC at day-4 and day-32. GAP-43 was reduced in the ipsilateral AC for the duration of the experiment. These complex fluctuations in protein expression suggests that for at least a month following acoustic trauma the auditory system is adapting to a new pattern of sensory input.

  19. α-MSH exerts direct postsynaptic excitatory effects on NTS neurons and enhances GABAergic signaling in the NTS.

    Science.gov (United States)

    Mimee, A; Kuksis, M; Ferguson, A V

    2014-03-14

    The central melanocortin system plays an essential role in the regulation of energy balance. While anorexigenic effects of α-melanocyte-stimulating hormone (α-MSH) acting in the nucleus of the solitary tract (NTS), a critical medullary autonomic control center, have been established, the cellular events underlying these effects are less well characterized. In this study, we used whole-cell patch-clamp electrophysiology to examine firstly whether α-MSH exerts direct postsynaptic effects on the membrane potential of rat NTS neurons in slice preparation, and secondly whether α-MSH influences GABAergic signaling in the NTS. In normal artificial cerebrospinal fluid, perfusion of α-MSH (500 nM) resulted in a depolarization in 39% of cells (n=16, mean 6.14±0.54 mV), and a hyperpolarization in 22% of cells (n=9, -6.79±1.02 mV). Studies using tetrodotoxin to block neuronal communication revealed α-MSH exerts direct depolarizing effects on some NTS neurons, and indirect inhibitory effects on others. A third subset of neurons is simultaneously directly depolarized and indirectly hyperpolarized by α-MSH, resulting in a net lack of effect on membrane potential. The inhibitory inputs influenced by α-MSH were identified as GABAergic, as α-MSH increased the frequency, but not amplitude, of inhibitory postsynaptic currents (IPSCs) in 50% of NTS neurons. α-MSH had no effect on the frequency or amplitude of miniature IPSCs. Furthermore, pharmacological blockade of GABAA and GABAB receptors, and physical removal of all synaptic inputs via cellular dissociation, abolished hyperpolarizations induced by α-MSH. We conclude α-MSH exerts direct, postsynaptic excitatory effects on a subset of NTS neurons. By exciting GABAergic NTS neurons and presynaptically enhancing GABAergic signaling, α-MSH also indirectly inhibits other NTS cells. These findings provide critical insight into the cellular events underlying medullary melanocortin anorexigenic effects, and expand the

  20. Inducible expression and pharmacology of the human excitatory amino acid transporter 2 subtype of L-glutamate transporter.

    Science.gov (United States)

    Dunlop, J; Lou, Z; Zhang, Y; McIlvain, H B

    1999-12-01

    1. In this study we have examined the use of the ecdysone-inducible mammalian expression system (Invitrogen) for the regulation of expression of the predominant L-glutamate transporter EAAT2 (Excitatory Amino Acid Transporter) in HEK 293 cells. 2. HEK 293 cells which were stably transformed with the regulatory vector pVgRXR (EcR 293 cells) were used for transfection of the human EAAT2 cDNA using the inducible vector pIND and a clone designated HEK/EAAT2 was selected for further characterization. 3. Na+-dependent L-glutamate uptake activity (3.2 pmol min-1 mg-1) was observed in EcR 293 cells and this was increased approximately 2 fold in the uninduced HEK/EAAT2 cells, indicating a low level of basal EAAT2 activity in the absence of exogenous inducing agent. Exposure of HEK/EAAT2 cells to the ecdysone analogue Ponasterone A (10 microM for 24 h) resulted in a > or = 10 fold increase in the Na+-dependent activity. 4. L-glutamate uptake into induced HEK/EAAT2 cells followed first-order Michaelis-Menten kinetics and Eadie-Hofstee transformation of the saturable uptake data produced estimates of kinetic parameters as follows; Km 52.7+/-7.5 microM, Vmax 3.8+/-0.9 nmol min-1 mg-1 protein. 5. The pharmacological profile of the EAAT2 subtype was characterized using a series of L-glutamate transport inhibitors and the rank order of inhibitory potency was similar to that described previously for the rat homologue GLT-1 and in synaptosomal preparations from rat cortex. 6. Addition of the EAAT2 modulator arachidonic acid resulted in an enhancement (155+/-5% control in the presence of 30 microM) of the L-glutamate transport capacity in the induced HEK/EAAT2 cells. 7. This study demonstrates that the expression of EAAT2 can be regulated in a mammalian cell line using the ecdysone-inducible mammalian expression system.

  1. [Bombesin-mediated non-cholinergic late slow excitatory postsynaptic potentials in guinea pig inferior mesenteric ganglion in vitro].

    Science.gov (United States)

    Kong, De-Hu; Wang, Gang; Wang, Hong-Mei; Ke, Dao-Ping; Hu, Jin-Lan; Zhu, Yan; Huang, Zhen-Xin

    2003-08-25

    The effect of bombesin (BOM) on non-cholinergic excitatory synaptic transmission of the guinea pig inferior mesenteric ganglion (IMG) was investigated by intracellular recording. Repetitive stimulation of the colon nerves (1 ms, 25 Hz, 4 s) elicited a burst of action potentials, which was followed by a long-lasting depolarization in 74.3% (52/70) of the IMG neurons. The depolarization was not blocked by nicotinic (d-tubocurarine, 100 micromol/L) and muscarinic (atropine, 1 micromol/L) antagonists, but was eliminated in a low Ca(2+)/high Mg(2+) Krebs solution, indicating that the depolarization was due to the release of non-cholinergic transmitters. Superfusing the ganglia with BOM (10 micromol/L, 1 min) induced a slow depolarization in 66.5% (109/164) neurons tested. The BOM response was not appreciably changed in low Ca(2+)/high Mg(2+) Krebs solution (n=6, P>0.05), suggesting that BOM depolarized the neurons by acting directly on the postsynaptic membrane rather than via a release of other endogenous depolarizing substances. In a total of 102 cells that exhibited late slow excitatory postsynaptic potential (ls-EPSP), superfusion of the ganglia with BOM produced a membrane depolarization in 82 neurons (80%), while the remaining 20 cells (20%) exhibited no response to BOM. In 18 neurons with ls-EPSP, 4 (22%) neurons were sensitive to both BOM and SP; 6 (33%) and 5 (28%) neurons were only sensitive to BOM and SP, respectively. The remaining 3 (17%) neurons were insensitive to both BOM and SP. Membrane resistance (Rm) had no apparent change in 47.3%, 59.5 % of the neurons tested during the ls-EPSP (n=55) and BOM depolarization (n=84), respectively, but had a marked decrease in 38.2%, 27.4%, and a marked increase in the remaining 14.5%, 13.1% of the neurons. However, when the Rm change accompanying ls-EPSP was compared with that accompanying BOM depolarization (n=20) in the same neuron, the changes in Rm were always parallel. Moreover, ls-EPSP (n=6) and BOM

  2. Astrocyte matricellular proteins that control excitatory synaptogenesis are regulated by inflammatory cytokines and correlate with paralysis severity during experimental autoimmune encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Pennelope K. Blakely

    2015-10-01

    Full Text Available The matricellular proteins, secreted protein acidic and rich in cysteine (SPARC and SPARC-like 1 (SPARCL1, are produced by astrocytes and control excitatory synaptogenesis in the central nervous system. While SPARCL1 directly promotes excitatory synapse formation in vitro and in the developing nervous system in vivo, SPARC specifically antagonizes the synaptogenic actions of SPARCL1. We hypothesized these proteins also help maintain existing excitatory synapses in adult hosts, and that local inflammation in the spinal cord alters their production in a way that dynamically modulates motor synapses and impacts the severity of paralysis during experimental autoimmune encephalomyelitis (EAE in mice. Using a spontaneously remitting EAE model, paralysis severity correlated inversely with both expression of synaptic proteins and the number of synapses in direct contact with the perikarya of motor neurons in spinal grey matter. In both remitting and non-remitting EAE models, paralysis severity also correlated inversely with sparcl1:sparc transcript and SPARCL1:SPARC protein ratios directly in lumbar spinal cord tissue. In vitro, astrocyte production of both SPARCL1 and SPARC was regulated by T cell-derived cytokines, causing dynamic modulation of the SPARCL1:SPARC expression ratio. Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal grey matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE. Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation. This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.

  3. Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus.

    Science.gov (United States)

    Gulyás, A I; Megías, M; Emri, Z; Freund, T F

    1999-11-15

    The least known aspect of the functional architecture of hippocampal microcircuits is the quantitative distribution of synaptic inputs of identified cell classes. The complete dendritic trees of functionally distinct interneuron types containing parvalbumin (PV), calbindin D(28k) (CB), or calretinin (CR) were reconstructed at the light microscopic level to describe their geometry, total length, and laminar distribution. Serial electron microscopic reconstruction and postembedding GABA immunostaining was then used to determine the density of GABA-negative asymmetrical (excitatory) and GABA-positive symmetrical (inhibitory) synaptic inputs on their dendrites, somata, and axon initial segments. The total convergence and the distribution of excitatory and inhibitory inputs were then calculated using the light and electron microscopic data sets. The three populations showed characteristic differences in dendritic morphology and in the density and distribution of afferent synapses. PV cells possessed the most extensive dendritic tree (4300 microm) and the thickest dendrites. CR cells had the smallest dendritic tree (2500 microm) and the thinnest shafts. The density of inputs as well as the total number of excitatory plus inhibitory synapses was several times higher on PV cells (on average, 16,294) than on CB (3839) or CR (2186) cells. The ratio of GABAergic inputs was significantly higher on CB (29.4%) and CR (20.71%) cells than on PV cells (6.4%). The density of inhibitory terminals was higher in the perisomatic region than on the distal dendrites. These anatomical data are essential to understand the distinct behavior and role of these interneuron types during hippocampal activity patterns and represent fundamental information for modeling studies.

  4. Monosynaptic inputs to new neurons in the dentate gyrus

    National Research Council Canada - National Science Library

    Vivar, Carmen; Potter, Michelle C; Choi, Jiwon; Lee, Ji-Young; Stringer, Thomas P; Callaway, Edward M; Gage, Fred H; Suh, Hoonkyo; van Praag, Henriette

    2012-01-01

    Adult hippocampal neurogenesis is considered important for cognition. The integration of newborn dentate gyrus granule cells into the existing network is regulated by afferent neuronal activity of unspecified origin...

  5. The GluR5 subtype of kainate receptor regulates excitatory synaptic transmission in areas CA1 and CA3 of the rat hippocampus.

    Science.gov (United States)

    Vignes, M; Clarke, V R; Parry, M J; Bleakman, D; Lodge, D; Ornstein, P L; Collingridge, G L

    1998-01-01

    Activation of kainate receptors depresses excitatory synaptic transmission in the hippocampus. In the present study, we have utilised a GluR5 selective agonist, ATPA [(RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid], and a GluR5 selective antagonist, LY294486 [(3SR,4aRS,6SR,8aRS)-6-([[(1H-tetrazol-5-y l)methyl]oxy]methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3 -carboxylic acid], to determine whether GluR5 subunits are involved in this effect. ATPA mimicked the presynaptic depressant effects of kainate in the CA1 region of the hippocampus. It depressed reversibly AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor-mediated field excitatory postsynaptic potentials (field EPSPs) with an IC50 value of approximately 0.60 microM. The dual-component excitatory postsynaptic current (EPSC) and the pharmacologically isolated NMDA (N-methyl-D-aspartate) receptor-mediated EPSC were depressed to a similar extent by 2 microM ATPA (61 +/- 7% and 58 +/- 6%, respectively). Depressions were associated with an increase in the paired-pulse facilitation ratio suggesting a presynaptic locus of action. LY294486 (20 microM) blocked the effects of 2 microM ATPA on NMDA receptor-mediated EPSCs in a reversible manner. In area CA3, 1 microM ATPA depressed reversibly mossy fibre-evoked synaptic transmission (by 82 +/- 10%). The effects of ATPA were not accompanied by any changes in the passive properties of CA1 or CA3 neurones. However, in experiments where K+, rather than Cs+, containing electrodes were used, a small outward current was observed. These results show that GluR5 subunits comprise or contribute to a kainate receptor that regulates excitatory synaptic transmission in both the CA1 and CA3 regions of the hippocampus.

  6. 4,4-Dimethyl- and diastereomeric 4-hydroxy-4-methyl-(2S)-glutamate analogues display distinct pharmacological profiles at ionotropic glutamate receptors and excitatory amino acid transporters

    DEFF Research Database (Denmark)

    Bunch, Lennart; Pickering, Darryl S; Gefflaut, Thierry;

    2009-01-01

    this approach has provided important insight into the structure-activity relationships (SAR) for ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs), as well as the excitatory amino acid transporters (EAATs). In this work, three 4,4-disubstituted Glu analogues 1-3, which are hybrid structures......Subtype-selective ligands are of great interest to the scientific community, as they provide a tool for investigating the function of one receptor or transporter subtype when functioning in its native environment. Several 4-substituted (S)-glutamate (Glu) analogues were synthesized, and altogether...

  7. A Quantitative Analysis of Modulation of the Fast Excitatory Postsynaptic Potential of Neurons in Rat Sympathetic Ganglia by a Low-Intensity Laser

    Institute of Scientific and Technical Information of China (English)

    MO Hua; YANG Li-Jian; JIA Ya

    2005-01-01

    @@ We propose a mathematical model which can quantitatively describe the kinetics of postsynaptic membrane potential modulated by a low intensity laser. By virtue of the numerical computation, it is found that the height of peak of fast excitatory postsynaptic potential (f-EPSP) for intermediate laser power density (around 2mW/cm2) is higher than that for both small and large laser power densities, that is, of the f-EPSP peak height changes with the increasing laser power density (up to 5mW/cm2) in non-monotonic behaviour. The theoretical results are qualitatively consistent with the previous experimental data.

  8. Polyclonal antibody against an insect excitatory toxin BmKIT from Buthus Martensii karsch and detection of BmKIT expressed in transgenic cotton

    Institute of Scientific and Technical Information of China (English)

    Hao Chanjuan; Xu Chenggang; Zhang Zhiyun; Liang Aihua

    2008-01-01

    An insect excitatory toxin gene from Buthus martensii Karsch (BmKIT) was cloned into the expression vector, pET-28a. BmKIT was expressed as inclusion bodies in Escherichia coli BL21 (DE3) host cells. The authenticity of in vitro expressed protein was confirmed by Western blot. The inclusion body protein band in SDS-PAGE was excised and the protein, BmKIT, was extracted. Polyclonal antibodies to the purified protein were raised in rabbits. The antibody reacted specifically with the expressed BmKIT and was used to quantify its presence in transgenic cotton.

  9. Primary afferent depolarization and flexion reflexes produced by radiant heat stimulation of the skin.

    Science.gov (United States)

    Burke, R E; Rudomin, P; Vyklický, L; Zajac, F E

    1971-02-01

    1. The reflex effects of pulses of intense radiant heat applied to the skin of the central plantar pad have been studied in unanaesthetized (decerebrate) spinal cats.2. Pad heat pulses produced flexion of the ipsilateral hind limb and increased ipsilateral flexor monosynaptic reflexes, due to post-synaptic excitation of flexor alpha motoneurones. These effects were accompanied by reduction of extensor monosynaptic reflexes and post-synaptic inhibition of extensor motoneurones.3. Ipsilateral (and contralateral) pad heat pulses consistently evoked negative dorsal root potentials (DRPs) as well as increased excitability of both cutaneous and group Ib muscle afferent terminals. The excitability of group Ia afferents was sometimes also increased during pad heat pulses, but to a lesser extent.4. Pad heat pulses produced negative DRPs in preparations in which positive DRP components could be demonstrated following electrical stimulation of both skin and muscle nerves.5. The motor and primary afferent effects of heat pulses always accompanied one another, beginning after the pad surface temperature had reached rather high levels (usually 48-55 degrees C).6. Negative DRPs increased excitability of cutaneous and group Ib afferents, and motoneurone activation produced by pad heat pulses was essentially unmodified when conduction in large myelinated afferents from the central plantar pad was blocked by cooling the posterior tibial nerve trunk.7. It is concluded that adequate noxious activation of cutaneous afferents of small diameter produces primary afferent depolarization in a variety of large diameter afferent fibres, as well as post-synaptic effects in alpha motoneurones.

  10. Effects of changes in glucose concentration on synaptic plasticity in hippocampal slices

    NARCIS (Netherlands)

    Gispen, W.H.; Kamal, A.; Spoelstra, K.; Biessels, G.J.; Urban, I.J.A.

    1999-01-01

    The effects of a low or high concentration of glucose in the perfusion medium on synaptic activity and plasticity were studied in hippocampal slices from rats. Low-glucose medium depressed the field excitatory post-synaptic potentials (fEPSP) significantly, whereas high-glucose medium had little eff

  11. Evidence for a role of CCK as neurotransmitter in the guinea-pig enteric nervous system.

    NARCIS (Netherlands)

    Schutte, I.W.M.; Hollestein, K.B.C.W.; Akkermans, L.M.A.; Kroese, A.B.A.

    1997-01-01

    Intracellular recordings were made of neurons in the myenteric plexus of the guinea-pig distal ileum. Slow excitatory post-synaptic potentials (sEPSPs) were evoked by electrical stimulation of an interganglionic fibre tract. The effect of cholecystokinin (CCK) receptor antagonists on the sEPSPs was

  12. Both pre- and post-synaptic alterations contribute to aberrant cholinergic transmission in superior cervical ganglia of APP(-/-) mice.

    Science.gov (United States)

    Cai, Zhao-Lin; Zhang, Jia-Jia; Chen, Ming; Wang, Jin-Zhao; Xiao, Peng; Yang, Li; Long, Cheng

    2016-11-01

    Though amyloid precursor protein (APP) can potentially be cleaved to generate the pathological amyloid β peptide (Aβ), APP itself plays an important role in regulating neuronal activity. APP deficiency causes functional impairment in cholinergic synaptic transmission and cognitive performance. However, the mechanisms underlying altered cholinergic synaptic transmission in APP knock-out mice (APP(-/-)) are poorly understood. In this study, we conducted in vivo extracellular recording to investigate cholinergic compound action potentials (CAPs) of the superior cervical ganglion (SCG) in APP(-/-) and littermate wild-type (WT) mice. Our results demonstrate that APP not only regulates presynaptic activity, but also affects postsynaptic function at cholinergic synapses in SCG. APP deficiency reduces the number of vesicles in presynaptic terminalsand attenuatesthe amplitude of CAPs, likely due to dysfunction of high-affinity choline transporters. Pharmacological and biochemical examination showed that postsynaptic responsesmediated by α4β2 and α7 nicotinic acetylcholine receptors are reduced in the absence of APP. Our research provides evidences on how APP regulates cholinergic function and therefore may help to identify potential therapeutic targets to treat cholinergic dysfunction associated with Alzheimer's disease pathogenesis.

  13. Activity-dependent increases in local oxygen consumption correlate with post-synaptic currents in the mouse cerebellum in vivo

    DEFF Research Database (Denmark)

    Mathiesen, Claus; Caesar, Kirsten; Thomsen, Kirsten Joan

    2011-01-01

    mitochondrial signaling, but whether this also occurs in the intact brain is unknown. Here we applied a pharmacological approach to dissect the effects of ionic currents and cytosolic Ca2+ rises of neuronal origin on activity-dependent rises in CMRO2. We used two-photon microscopy and current source density...

  14. Activity-dependent increases in local oxygen consumption correlate with post-synaptic currents in the mouse cerebellum in vivo

    DEFF Research Database (Denmark)

    Mathiesen, Claus; Caesar, Kirsten; Thomsen, Kirsten Joan

    2011-01-01

    Evoked neural activity correlates strongly with rises in cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow. Activity-dependent rises in CMRO2 fluctuate with ATP turnover due to ion pumping. In vitro studies suggest that increases in cytosolic Ca2+ stimulate oxidative metabolism vi...

  15. Kindling-induced potentiation of excitatory and inhibitory inputs to hippocampal dentate granule cells. II. Effects of the NMDA antagonist MK-801.

    LENUS (Irish Health Repository)

    Robinson, G B

    1991-10-18

    The effect of the non-competitive N-methyl-D-aspartate antagonist MK-801 on the early development of kindling-induced potentiation was examined in the rabbit hippocampal dentate gyrus. MK-801 (0.5 mg\\/kg) was administered 2 h before each daily kindling stimulation was applied to the perforant path. This treatment continued for the first 10 days of kindling. MK-801 depressed the growth of the afterdischarge duration and suppressed development of behavioral seizures. MK-801 did not block kindling-induced potentiation of either the perforant path-dentate granule cell population spike or excitatory postsynaptic potential. Random impulse train stimulation and non-linear systems analytic techniques were used to examine kindling-induced potentiation of presumed GABAergic recurrent inhibitory circuits. Both the magnitude and duration of kindling-induced response inhibition, to the second of each pair of impulses within the train, were reduced in rabbits pretreated with MK-801. These results suggest that MK-801 differentially affects kindling-induced potentiation of excitatory and inhibitory circuits within the rabbit hippocampal dentate gyrus.

  16. Aβ induces acute depression of excitatory glutamatergic synaptic transmission through distinct phosphatase-dependent mechanisms in rat CA1 pyramidal neurons.

    Science.gov (United States)

    Yao, Wen; Zou, Hao-Jun; Sun, Da; Ren, Si-Qiang

    2013-06-17

    Beta-amyloid peptide (Aβ) has a causal role in the pathophysiology of Alzheimer's disease (AD). Recent studies indicate that Aβ can disrupt excitatory glutamatergic synaptic function at synaptic level. However, the underlying mechanisms remain obscure. In this study, we recorded evoked and spontaneous EPSCs in hippocampal CA1 pyramidal neurons via whole-cell voltage-clamping methods and found that 1 μM Aβ can induce acute depression of basal glutamatergic synaptic transmission through both presynaptic and postsynaptic dysfunction. Moreover, we also found that Aβ-induced both presynaptic and postsynaptic dysfunction can be reversed by the inhibitor of protein phosphatase 2B (PP2B), FK506, whereas only postsynaptic disruption can be ameliorated by the inhibitor of PP1/PP2A, Okadaic acid (OA). These results indicate that PP1/PP2A and PP2B have overlapping but not identical functions in Aβ-induced acute depression of excitatory glutamatergic synaptic transmission of hippocampal CA1 pyramidal neurons.

  17. Activation of mu opioid receptor inhibits the excitatory glutamatergic transmission in the anterior cingulate cortex of the rats with peripheral inflammation.

    Science.gov (United States)

    Zheng, Weihong

    2010-02-25

    Emerging evidence recently indicates that the anterior cingulate cortex is critically involved in the central processing and modulation of noxious stimulus, although the neuroadaptation in the anterior cingulate cortex has not been well documented in the conditions of chronic pain. Meanwhile, the cellular mechanism underlying opiate analgesia in the anterior cingulate cortex remains unclear. To address these issues, the present study was undertaken to explore the adaptation of excitatory glutamatergic transmission and mu opioid receptor-mediated modulation of glutamatergic transmission in the anterior cingulate cortex slices from the complete Freund's adjuvant (CFA)-inflamed rats. The results demonstrated that glutamatergic paired-pulse facilitation was decreased in the anterior cingulate cortex neurons from the CFA-inflamed rats, indicating an enhanced presynaptic glutamate release. In addition, activation of mu opioid receptor significantly inhibited the glutamatergic excitatory postsynaptic currents (EPSCs) in the anterior cingulate cortex neurons, which was attained through the suppression of presynaptic glutamate release. Taken together, these findings provided the evidence for the functional adaptation of central glutamatergic transmission induced by peripheral inflammation, and elucidated the cellular mechanism underlying opiate analgesia in the anterior cingulate cortex.

  18. Cerebellar nuclei neurons show only small excitatory responses to optogenetic olivary stimulation in transgenic mice: in vivo and in vitro studies

    Directory of Open Access Journals (Sweden)

    Huo eLu

    2016-03-01

    Full Text Available To study the olivary input to the cerebellar nuclei (CN we used optogenetic stimulation in transgenic mice expressing channelrhodopsin-2 (ChR2 in olivary neurons. We obtained in vivo extracellular Purkinje cell (PC and CN recordings in anesthetized mice while stimulating the contralateral inferior olive (IO with a blue laser (single pulse, 10 - 50 ms duration. Peri-stimulus histograms were constructed to show the spike rate changes after optical stimulation. Among 29 CN neurons recorded, 15 showed a decrease in spike rate of variable strength and duration, and only 1 showed a transient spiking response. These results suggest that direct olivary input to CN neurons is usually overridden by stronger Purkinje cell inhibition triggered by climbing fiber responses. To further investigate the direct input from the climbing fiber collaterals we also conducted whole cell recordings in brain slices, where we used local stimulation with blue light. Due to the expression of ChR2 in Purkinje cell axons as well as the IO in our transgenic line, strong inhibitory responses could be readily triggered with optical stimulation (13 of 15 neurons. After blocking this inhibition with GABAzine, only in 5 of 13 CN neurons weak excitatory responses were revealed. Therefore our in vitro results support the in vivo findings that the excitatory input to CN neurons from climbing fiber collaterals in adult mice is masked by the inhibition under normal conditions.

  19. Effects of Chronic Dopamine D2R Agonist Treatment and Polysialic Acid Depletion on Dendritic Spine Density and Excitatory Neurotransmission in the mPFC of Adult Rats

    Directory of Open Access Journals (Sweden)

    Esther Castillo-Gómez

    2016-01-01

    Full Text Available Dopamine D2 receptors (D2R in the medial prefrontal cortex (mPFC are key players in the etiology and therapeutics of schizophrenia. The overactivation of these receptors contributes to mPFC dysfunction. Chronic treatment with D2R agonists modifies the expression of molecules implicated in neuronal structural plasticity, synaptic function, and inhibitory neurotransmission, which are also altered in schizophrenia. These changes are dependent on the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM, a plasticity-related molecule, but nothing is known about the effects of D2R and PSA-NCAM on excitatory neurotransmission and the structure of mPFC pyramidal neurons, two additional features affected in schizophrenia. To evaluate these parameters, we have chronically treated adult rats with PPHT (a D2R agonist after enzymatic removal of PSA with Endo-N. Both treatments decreased spine density in apical dendrites of pyramidal neurons without affecting their inhibitory innervation. Endo-N also reduced the expression of vesicular glutamate transporter-1. These results indicate that D2R and PSA-NCAM are important players in the regulation of the structural plasticity of mPFC excitatory neurons. This is relevant to our understanding of the neurobiological basis of schizophrenia, in which structural alterations of pyramidal neurons and altered expression of D2R and PSA-NCAM have been found.

  20. Galanin-induced decreases in nucleus accumbens/striatum excitatory postsynaptic potentials and morphine conditioned place preference require both galanin receptor 1 and galanin receptor 2.

    Science.gov (United States)

    Einstein, Emily B; Asaka, Yukiko; Yeckel, Mark F; Higley, Michael J; Picciotto, Marina R

    2013-05-01

    The neuropeptide galanin has been shown to alter the rewarding properties of morphine. To identify potential cellular mechanisms that might be involved in the ability of galanin to modulate opiate reward, we measured excitatory postsynaptic potentials (EPSPs), using both field and whole-cell recordings from striatal brain slices extracted from wild-type mice and mice lacking specific galanin receptor (GalR) subtypes. We found that galanin decreased the amplitude of EPSPs in both the dorsal striatum and nucleus accumbens. We then performed recordings in slices from knockout mice lacking either the GalR1 or GalR2 gene, and found that the ability of galanin to decrease EPSP amplitude was absent from both mouse lines, suggesting that both receptor subtypes are required for this effect. In order to determine whether behavioral responses to opiates were dependent on the same receptor subtypes, we tested GalR1 and GalR2 knockout mice for morphine conditioned place preference (CPP). Morphine CPP was significantly attenuated in both GalR1 and GalR2 knockout mice. These data suggest that mesolimbic excitatory signaling is significantly modulated by galanin in a GalR1-dependent and GalR2-dependent manner, and that morphine CPP is dependent on the same receptor subtypes.

  1. Pharmacology of Glutamate Transport in the CNS: Substrates and Inhibitors of Excitatory Amino Acid Transporters (EAATs) and the Glutamate/Cystine Exchanger System x c -

    Science.gov (United States)

    Bridges, Richard J.; Patel, Sarjubhai A.

    As the primary excitatory neurotransmitter in the mammalian CNS, l-glutamate participates not only in standard fast synaptic communication, but also contributes to higher order signal processing, as well as neuropathology. Given this variety of functional roles, interest has been growing as to how the extracellular concentrations of l-glutamate surrounding neurons are regulated by cellular transporter proteins. This review focuses on two prominent systems, each of which appears capable of influencing both the signaling and pathological actions of l-glutamate within the CNS: the sodium-dependent excitatory amino acid transporters (EAATs) and the glutamate/cystine exchanger, system x c - (Sx c -). While the family of EAAT subtypes limit access to glutamate receptors by rapidly and efficiently sequestering l-glutamate in neurons and glia, Sxc - provides a route for the export of glutamate from cells into the extracellular environment. The primary intent of this work is to provide an overview of the inhibitors and substrates that have been developed to delineate the pharmacological specificity of these transport systems, as well as be exploited as probes with which to selectively investigate function. Particular attention is paid to the development of small molecule templates that mimic the structural properties of the endogenous substrates, l-glutamate, l-aspartate and l-cystine and how strategic control of functional group position and/or the introduction of lipophilic R-groups can impact multiple aspects of the transport process, including: subtype selectivity, inhibitory potency, and substrate activity.

  2. Does excitatory fronto-extracephalic tDCS lead to improved working memory performance? [v1; ref status: indexed, http://f1000r.es/216

    Directory of Open Access Journals (Sweden)

    Níall Lally

    2013-10-01

    Full Text Available Evidence suggests that excitatory transcranial direct current stimulation (tDCS may improve performance on a wide variety of cognitive tasks. Due to the non-invasive and inexpensive nature of the method, harnessing its potential could be particularly useful for the treatment of neuropsychiatric illnesses involving cognitive dysfunction. However, questions remain regarding the efficacious stimulation parameters. Here, using a double-blind between-subjects design, we explored whether 1 mA excitatory (anodal left dorsolateral prefrontal cortex stimulation with a contralateral extracephalic reference electrode, leads to enhanced working memory performance across two days, relative to sham stimulation. Participants performed the 3-back, a test of working memory, at baseline, and during and immediately following stimulation on two days, separated by 24-48 hours. Active stimulation did not significantly enhance performance versus sham over the course of the experiment. However, exploratory comparisons did reveal a significant effect of stimulation group on performance during the first stimulation phase only, with active stimulation recipients performing better than sham. While these results do not support the hypothesis that dorsolateral prefrontal cortex tDCS boosts working memory, they raise the possibility that its effects may be greatest during early learning stages.

  3. Excitation-Transcription Coupling in Parvalbumin-Positive Interneurons Employs a Novel CaM Kinase-Dependent Pathway Distinct from Excitatory Neurons.

    Science.gov (United States)

    Cohen, Samuel M; Ma, Huan; Kuchibhotla, Kishore V; Watson, Brendon O; Buzsáki, György; Froemke, Robert C; Tsien, Richard W

    2016-04-20

    Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity, and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. We report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca(2+) influx through CaV1 channels triggers CaM nuclear translocation via local Ca(2+) signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca(2+) transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and they are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease.

  4. Transiently increasing cAMP levels selectively in hippocampal excitatory neurons during sleep deprivation prevents memory deficits caused by sleep loss.

    Science.gov (United States)

    Havekes, Robbert; Bruinenberg, Vibeke M; Tudor, Jennifer C; Ferri, Sarah L; Baumann, Arnd; Meerlo, Peter; Abel, Ted

    2014-11-19

    The hippocampus is particularly sensitive to sleep loss. Although previous work has indicated that sleep deprivation impairs hippocampal cAMP signaling, it remains to be determined whether the cognitive deficits associated with sleep deprivation are caused by attenuated cAMP signaling in the hippocampus. Further, it is unclear which cell types are responsible for the memory impairments associated with sleep deprivation. Transgenic approaches lack the spatial resolution to manipulate specific signaling pathways selectively in the hippocampus, while pharmacological strategies are limited in terms of cell-type specificity. Therefore, we used a pharmacogenetic approach based on a virus-mediated expression of a Gαs-coupled Drosophila octopamine receptor selectively in mouse hippocampal excitatory neurons in vivo. With this approach, a systemic injection with the receptor ligand octopamine leads to increased cAMP levels in this specific set of hippocampal neurons. We assessed whether transiently increasing cAMP levels during sleep deprivation prevents memory consolidation deficits associated with sleep loss in an object-location task. Five hours of total sleep deprivation directly following training impaired the formation of object-location memories. Transiently increasing cAMP levels in hippocampal neurons during the course of sleep deprivation prevented these memory consolidation deficits. These findings demonstrate that attenuated cAMP signaling in hippocampal excitatory neurons is a critical component underlying the memory deficits in hippocampus-dependent learning tasks associated with sleep deprivation.

  5. Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors.

    Science.gov (United States)

    Li, Wei; Xu, Xin; Pozzo-Miller, Lucas

    2016-03-15

    Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naïve excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders.

  6. Changes in the response to excitatory antagonists, agonists, and spasmolytic agents in circular colonic smooth muscle strips from patients with diverticulosis.

    Science.gov (United States)

    Alvarez-Berdugo, D; Espín, F; Arenas, C; López, I; Clavé, P; Gallego, D

    2015-11-01

    Colonic samples from asymptomatic diverticulosis (DS) patients presented enhanced electrical field stimulation (EFS)-contractions, in an earlier study of ours, suggesting increased endogenous responses. The aim of this study was to explore changes in excitatory neuromuscular transmission and to assess the pharmacodynamics of spasmolytic agents in DS. Circular muscle strips from sigmoid colon of DS patients (n = 30; 69.5 ± 14.8 years) and controls (n = 32; 64.7 ± 16.2 years) were studied using organ baths to evaluate the direct effect of excitatory agonists (carbachol, neurokinin A [NKA] and substance P [SP]), and the effect of antagonists (atropine and NK2 antagonist GR94800) and spasmolytic drugs (otilonium bromide [OB] and N-butyl-hyoscine) on the contractions induced by EFS-stimulation of excitatory motorneurons. qRT-PCR was also performed to compare mRNA expression of M2 , M3 , NK2 receptors and L-type calcium channels. Contractions to carbachol (Emax : 663.7 ± 305.6% control vs 2698.0 ± 439.5% DS; p < 0.0005) and NKA (Emax : 387.8 ± 35.6% vs 1102.0 ± 190.1%; p < 0.0005) were higher in DS group, without differences for SP. Higher potency for DS patients was observed in the concentration-response curves for atropine (pIC50  = 8.56 ± 0.15 control vs pIC50  = 9.95 ± 0.18 DS group; p < 0.005) and slightly higher for GR94800 (pIC50  = 7.21 ± 0.18 control vs pIC50  = 7.97 ± 0.32 group; p < 0.0001). Lower efficacy (Emax ) and potency (pIC50 ) was observed for spasmolytic drugs in DS, whereas no differences were found regarding the relative expression of the receptors evaluated between groups. The greater response to cholinergic and tachykinergic agonists and greater potency for muscarinic and NK2 antagonists observed in DS might play a role in the spasticity found in diverticular disease. © 2015 John Wiley & Sons Ltd.

  7. New insights into the structure-activity-relationship of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitors UCPH-101 and UCPH-102

    DEFF Research Database (Denmark)

    Hansen, Stinne Wessel; Erichsen, Mette Norman; Huynh, T.H.V.

    2016-01-01

    In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15...... (2-amino-4-([1,1'-biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active...

  8. Pharmacological characterization of human excitatory amino acid transporters EAAT1, EAAT2 and EAAT3 in a fluorescence-based membrane potential assay

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Bräuner-Osborne, Hans

    2004-01-01

    We have expressed the human excitatory amino acid transporters EAAT1, EAAT2 and EAAT3 stably in HEK293 cells and characterized the transporters pharmacologically in a conventional [(3) H]-d-aspartate uptake assay and in a fluorescence-based membrane potential assay, the FLIPR Membrane Potential...... presently available is limited, and that almost all of these are characterized by low potency and a low degree of subtype selectivity, future screening of compound libraries at the EAAT-cell lines in the FMP assay could help identify structurally and pharmacologically novel ligands for the transporters....... of the cell lines in the FMP assay were in good agreement with previous findings in electrophysiology studies of the transporters. The FMP assay was capable of distinguishing between substrates and non-substrate inhibitors and to discriminate between "full" and "partial" substrates at the transporters. Taking...

  9. Contribution of intracolumnar layer 2/3-to-layer 2/3 excitatory connections in shaping the response to whisker deflection in rat barrel cortex.

    Science.gov (United States)

    Sarid, Leora; Feldmeyer, Dirk; Gidon, Albert; Sakmann, Bert; Segev, Idan

    2015-04-01

    This computational study integrates anatomical and physiological data to assess the functional role of the lateral excitatory connections between layer 2/3 (L2/3) pyramidal cells (PCs) in shaping their response during early stages of intracortical processing of a whisker deflection (WD). Based on in vivo and in vitro recordings, and 3D reconstructions of connected pairs of L2/3 PCs, our model predicts that: 1) AMPAR and NMDAR conductances/synapse are 0.52 ± 0.24 and 0.40 ± 0.34 nS, respectively; 2) following WD, connection between L2/3 PCs induces a composite EPSPs of 7.6 ± 1.7 mV, well below the threshold for action potential (AP) initiation; 3) together with the excitatory feedforward L4-to-L2/3 connection, WD evoked a composite EPSP of 16.3 ± 3.5 mV and a probability of 0.01 to generate an AP. When considering the variability in L4 spiny neurons responsiveness, it increased to 17.8 ± 11.2 mV; this 3-fold increase in the SD yielded AP probability of 0.35; 4) the interaction between L4-to-L2/3 and L2/3-to-L2/3 inputs is highly nonlinear; 5) L2/3 dendritic morphology significantly affects L2/3 PCs responsiveness. We conclude that early stages of intracortical signaling of WD are dominated by a combination of feedforward L4-L2/3 and L2/3-L2/3 lateral connections. © The Author 2013. Published by Oxford University Press.

  10. Structure and function of the amygdaloid NPY system: NPY Y2 receptors regulate excitatory and inhibitory synaptic transmission in the centromedial amygdala.

    Science.gov (United States)

    Wood, J; Verma, D; Lach, G; Bonaventure, P; Herzog, H; Sperk, G; Tasan, R O

    2016-09-01

    The amygdala is essential for generating emotional-affective behaviors. It consists of several nuclei with highly selective, elaborate functions. In particular, the central extended amygdala, consisting of the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST) is an essential component actively controlling efferent connections to downstream effectors like hypothalamus and brain stem. Both, CEA and BNST contain high amounts of different neuropeptides that significantly contribute to synaptic transmission. Among these, neuropeptide Y (NPY) has emerged as an important anxiolytic and fear-reducing neuromodulator. Here, we characterized the expression, connectivity and electrophysiological function of NPY and Y2 receptors within the CEA. We identified several NPY-expressing neuronal populations, including somatostatin- and calretinin-expressing neurons. Furthermore, in the main intercalated nucleus, NPY is expressed primarily in dopamine D1 receptor-expressing neurons but also in interspersed somatostatin-expressing neurons. Interestingly, NPY neurons did not co-localize with the Y2 receptor. Retrograde tract tracing experiments revealed that NPY neurons reciprocally connect the CEA and BNST. Functionally, the Y2 receptor agonist PYY3-36, reduced both, inhibitory as well as excitatory synaptic transmission in the centromedial amygdala (CEm). However, we also provide evidence that lack of NPY or Y2 receptors results in increased GABA release specifically at inhibitory synapses in the CEm. Taken together, our findings suggest that NPY expressed by distinct populations of neurons can modulate afferent and efferent projections of the CEA via presynaptic Y2 receptors located at inhibitory and excitatory synapses.

  11. Endogenous kisspeptin tone is a critical excitatory component of spontaneous GnRH activity and the GnRH response to NPY and CART

    Science.gov (United States)

    Verma, Saurabh; Kirigiti, Melissa; Millar, Robert P.; Grove, Kevin L.; Smith, M. Susan

    2014-01-01

    Background/Aims Kisspeptin is the major excitatory regulator of GnRH neurons and is responsible for basal GnRH/LH release and the GnRH/LH surge. Although it is widely assumed, based on mutations in kisspeptin and Kiss1R, that kisspeptin acts to sustain basal GnRH neuronal activity, there have been no studies to investigate whether endogenous basal kisspeptin tone plays a direct role in basal spontaneous GnRH neuronal excitability. It is also of interest to examine possible interactions between endogenous kisspeptin tone and other neuropeptides that have direct effects on GnRH neurons, such as NPY or CART, since the activity of all these neuropeptides changes during states of negative energy balance. Methods Loose cell-attached and whole cell current-clamp patch recordings were made from GnRH-GFP neurons in hypothalamic slices from female and male rats. Results Kisspeptin activated GnRH neurons in a concentration dependent manner with an EC50 of 3.32 ± 0.02 nM. Surprisingly, a kisspeptin antagonist, Peptide 347, suppressed spontaneous activity in GnRH neurons, demonstrating the essential nature of the endogenous kisspeptin tone. Furthermore, inhibition of endogenous kisspeptin tone blocked the direct activation of GnRH cells that occurs in response to antagonism of NPY Y5R or by CART. Conclusions Our electrophysiology studies suggest that basal endogenous kisspeptin tone is not only essential for spontaneous GnRH neuronal firing, but it is also required for the net excitatory effects of other neuropeptides, such as CART or NPY antagonism, on GnRH neurons. Therefore, endogenous kisspeptin tone could serve as the linchpin in GnRH activation or inhibition. PMID:25011649

  12. Up-Regulation of Excitatory Amino Acid Transporters EAAT3 and EAAT4 by Lithium Sensitive Glycogen Synthase Kinase GSK3ß

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    Abeer Abousaab

    2016-12-01

    Full Text Available Background: Cellular uptake of glutamate by the excitatory amino-acid transporters (EAATs decreases excitation and thus participates in the regulation of neuroexcitability. Kinases impacting on neuronal function include Lithium-sensitive glycogen synthase kinase GSK3ß. The present study thus explored whether the activities of EAAT3 and/or EAAT4 isoforms are sensitive to GSK3ß. Methods: cRNA encoding wild type EAAT3 (SLC1A1 or EAAT4 (SLC1A6 was injected into Xenopus oocytes without or with additional injection of cRNA encoding wild type GSK3ß or the inactive mutant K85AGSK3ß. Dual electrode voltage clamp was performed in order to determine glutamate-induced current (IEAAT. Results: Appreciable IEAAT was observed in EAAT3 or EAAT4 expressing but not in water injected oocytes. IEAAT was significantly increased by coexpression of GSK3ß but not by coexpression of K85AGSK3ß. Coexpression of GSK3ß increased significantly the maximal IEAAT in EAAT3 or EAAT4 expressing oocytes, without significantly modifying apparent affinity of the carriers. Lithium (1 mM exposure for 24 hours decreased IEAAT in EAAT3 and GSK3ß expressing oocytes to values similar to IEAAT in oocytes expressing EAAT3 alone. Lithium did not significantly modify IEAAT in oocytes expressing EAAT3 without GSK3ß. Conclusions: Lithium-sensitive GSK3ß is a powerful regulator of excitatory amino acid transporters EAAT3 and EAAT4.

  13. Transmission to interneurons is via slow excitatory synaptic potentials mediated by P2Y(1 receptors during descending inhibition in guinea-pig ileum.

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    Peter D J Thornton

    Full Text Available BACKGROUND: The nature of synaptic transmission at functionally distinct synapses in intestinal reflex pathways has not been fully identified. In this study, we investigated whether transmission between interneurons in the descending inhibitory pathway is mediated by a purine acting at P2Y receptors to produce slow excitatory synaptic potentials (EPSPs. METHODOLOGY/PRINCIPAL FINDINGS: Myenteric neurons from guinea-pig ileum in vitro were impaled with intracellular microelectrodes. Responses to distension 15 mm oral to the recording site, in a separately perfused stimulation chamber and to electrical stimulation of local nerve trunks were recorded. A subset of neurons, previously identified as nitric oxide synthase immunoreactive descending interneurons, responded to both stimuli with slow EPSPs that were reversibly abolished by a high concentration of PPADS (30 μM, P2 receptor antagonist. When added to the central chamber of a three chambered organ bath, PPADS concentration-dependently depressed transmission through that chamber of descending inhibitory reflexes, measured as inhibitory junction potentials in the circular muscle of the anal chamber. Reflexes evoked by distension in the central chamber were unaffected. A similar depression of transmission was seen when the specific P2Y(1 receptor antagonist MRS 2179 (10 μM was in the central chamber. Blocking either nicotinic receptors (hexamethonium 200 μM or 5-HT(3 receptors (granisetron 1 μM together with P2 receptors had no greater effect than blocking P2 receptors alone. CONCLUSIONS/SIGNIFICANCE: Slow EPSPs mediated by P2Y(1 receptors, play a primary role in transmission between descending interneurons of the inhibitory reflexes in the guinea-pig ileum. This is the first demonstration for a primary role of excitatory metabotropic receptors in physiological transmission at a functionally identified synapse.

  14. Reduced striatal acetylcholine efflux in the R6/2 mouse model of Huntington's disease: an examination of the role of altered inhibitory and excitatory mechanisms.

    Science.gov (United States)

    Farrar, Andrew M; Callahan, Joshua W; Abercrombie, Elizabeth D

    2011-12-01

    Huntington's disease (HD) is a genetic neurodegenerative disorder that is characterized by the progressive onset of cognitive, psychiatric, and motor symptoms. In parallel, the neuropathology of HD is characterized by progressive loss of projection neurons in cortex and striatum; striatal cholinergic interneurons are relatively spared. Nonetheless, there is evidence that striatal acetylcholine (ACh) function is altered in HD. The present study is the first to examine striatal ACh function in awake, behaving animals, using the R6/2 mouse model of HD, which is transgenic for exon 1 of the mutant huntingtin gene. Physiological levels of extracellular striatal ACh were monitored in R6/2 mice and wild type controls using in vivo microdialysis. Results indicate that spontaneous ACh release is reduced in R6/2 mice relative to controls. Intrastriatal application of the GABA(A) antagonist bicuculline methiodide (10.0 μM) significantly elevated ACh levels in both R6/2 mice and wild type controls, while overall ACh levels were reduced in the R6/2 mice compared to the wild type group. In contrast, systemic administration of the D(1) dopamine receptor partial agonist, SKF-38393 (10.0mg/kg, IP), elevated ACh levels in control animals, but not R6/2 mice. Taken together, the present results suggest that GABA-mediated inhibition of striatal ACh release is intact in R6/2 mice, further demonstrating that cholinergic interneurons are capable of increased ACh release, whereas D(1) receptor-dependent activation of excitatory inputs to striatal cholinergic interneurons is dysfunctional in R6/2 mice. Reduced levels of extracellular striatal ACh in HD may reflect abnormalities in the excitatory innervation of cholinergic interneurons, which may have implications ACh-dependent processes that are altered in HD, including corticostriatal plasticity.

  15. VIP enhances both pre- and postsynaptic GABAergic transmission to hippocampal interneurones leading to increased excitatory synaptic transmission to CA1 pyramidal cells.

    Science.gov (United States)

    Cunha-Reis, Diana; Sebastião, Ana M; Wirkner, Kerstin; Illes, Peter; Ribeiro, Joaquim Alexandre

    2004-11-01

    Vasoactive intestinal peptide (VIP) is present in the hippocampus in three subtypes of GABAergic interneurones, two of which innervate preferentially other interneurones, responsible for pyramidal cell inhibition. We investigated how pre- and postsynaptic modulation of GABAergic transmission (to both pyramidal cells and interneurones) by VIP could influence excitatory synaptic transmission in the CA1 area of the hippocampus. VIP (0.1-100 nM) increased [(3)H]GABA release from hippocampal synaptosomes (maximum effect at 1 nM VIP; 63.8 +/- 4.0%) but did not change [(3)H]glutamate release. VIP (0.3-30 nM) enhanced synaptic transmission in hippocampal slices (maximum effect at 1 nM VIP; field excitatory postsynaptic potentials (epsp) slope: 23.7 +/- 1.1%; population spike amplitude: 20.3 +/- 1.7%). The action on field epsp slope was fully dependent on GABAergic transmission since it was absent in the presence of picrotoxin (50 microM) plus CGP55845 (1 microM). VIP (1 nM) did not change paired-pulse facilitation but increased paired-pulse inhibition in CA1 pyramidal cells (16.0 +/- 0.9%), reinforcing the involvement of GABAergic transmission in the action of VIP. VIP (1 nM) increased muscimol-evoked inhibitory currents by 36.4 +/- 8.7% in eight out of ten CA1 interneurones in the stratum radiatum. This suggests that VIP promotes increased inhibition of interneurones that control pyramidal cells, leading to disinhibition of synaptic transmission to pyramidal cell dendrites. In conclusion, concerted pre- and postsynaptic actions of VIP lead to disinhibition of pyramidal cell dendrites causing an enhancement of synaptic transmission.

  16. The Abused Inhalant Toluene Differentially Modulates Excitatory and Inhibitory Synaptic Transmission in Deep-Layer Neurons of the Medial Prefrontal Cortex

    Science.gov (United States)

    Beckley, Jacob T; Woodward, John J

    2011-01-01

    Volatile organic solvents such as toluene are voluntarily inhaled for their intoxicating effects. Solvent use is especially prevalent among adolescents, and is associated with deficits in a wide range of cognitive tasks including attention, behavioral control, and risk assessment. Despite these findings, little is known about the effects of toluene on brain areas mediating these behaviors. In this study, whole-cell patch-clamp recordings were used to determine the effect toluene on neurons within the medial PFC, a region critically involved in cognitive function. Toluene had no effect on measures of intrinsic excitability, but enhanced stimulus-evoked γ-amino butyric acid A-mediated inhibitory postsynaptic currents (IPSCs). In the presence of tetrodotoxin (TTX) to block action potentials, toluene increased the frequency and amplitude of miniature IPSCs. In contrast, toluene induced a delayed but persistent decrease in evoked or spontaneous AMPA-mediated excitatory postsynaptic currents (EPSCs). This effect was prevented by an intracellular calcium chelator or by the ryanodine receptor and SERCA inhibitors, dantrolene or thapsigargin, respectively, suggesting that toluene may mobilize intracellular calcium pools. The toluene-induced reduction in AMPA EPSCs was also prevented by a cannabinoid receptor (CB1R) antagonist, and was occluded by the CB1 agonist WIN 55,212-2 that itself induced a profound decrease in AMPA-mediated EPSCs. Toluene had no effect on the frequency or amplitude of miniature EPSCs recorded in the presence of TTX. Finally, toluene dose-dependently inhibited N-methyl--aspartate (NMDA)-mediated EPSCs and the magnitude and reversibility of this effect was CB1R sensitive indicating both direct and indirect actions of toluene on NMDA-mediated responses. Together, these results suggest that the effect of toluene on cognitive behaviors may result from its action on inhibitory and excitatory synaptic transmission of PFC neurons. PMID:21430649

  17. Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.

    Directory of Open Access Journals (Sweden)

    Matthew C Weston

    2014-02-01

    Full Text Available The Pten and Tsc1 genes both encode proteins that repress mechanistic target of rapamycin (mTOR signaling. Disruption of either gene in the brain results in epilepsy and autism-like symptoms in humans and mouse models, therefore it is important to understand the molecular and physiological events that lead from gene disruption to disease phenotypes. Given the similar roles these two molecules play in the regulation of cellular growth and the overlap in the phenotypes that result from their loss, we predicted that the deletion of either the Pten or Tsc1 gene from hippocampal neurons would have similar effects on neuronal morphology and synaptic transmission. Accordingly, we found that loss of either Pten or Tsc1 caused comparable increases in soma size, dendrite length and action potential properties. However, the effects of Pten and Tsc1 loss on synaptic transmission were different. Loss of Pten lead to an increase in both excitatory and inhibitory neurotransmission, while loss of Tsc1 did not affect excitatory neurotransmission and reduced inhibitory transmission by decreasing mIPSC amplitude. Although the loss of Pten or Tsc1 both increased downstream mTORC1 signaling, phosphorylation of Akt was increased in Pten-ko and decreased in Tsc1-ko neurons, potentially accounting for the different effects on synaptic transmission. Despite the different effects at the synaptic level, our data suggest that loss of Pten or Tsc1 may both lead to an increase in the ratio of excitation to inhibition at the network level, an effect that has been proposed to underlie both epilepsy and autism.

  18. Lack of excitatory amino acid-induced effects on calcium fluxes measured with sup 45 Ca sup 2+ in rat cerebral cortex synaptosomes

    Energy Technology Data Exchange (ETDEWEB)

    Simonato, M.; Jope, R.S.; Bianchi, C.; Beani, L. (Univ. of Ferrara (Italy))

    1989-07-01

    Ca{sup 2+} uptake was measured in purified rat cerebral cortex synaptosomes (P3 pellets) using {sup 45}Ca{sup 2+} as a tracer. Ca{sup 2+} influx increased in time, and with an increase in external K+ concentration and temperature. The net (external K+-induced, depolarization-dependent) uptake follows a two-component course. The exponential term, due to the opening of voltage-operated calcium channels (VOC), has a rate constant which increases with an increase in the depolarization level (1.04 versus 0.54 nmol/s/mg protein for 50 mM - versus 15 mM (K+)-dependent net influx). The linear term, due to the Na{sup +}/Ca{sup 2+} exchange system, has a similar rate constant at all depolarization levels (0.16 +/- 0.05 and 0.11 +/- 0.02 nmol/s/mg protein). Excitatory amino acids (glutamate, kainate and n-methyl-d-aspartate-NMDA-) were tested on this preparation at doses ranging between 5 x 10(-5) M and 5 x 10(-3) M and at multiple incubation times, under resting conditions and under two depolarizing conditions (partial depolarization: 15 mM external K{sup +} and maximal depolarization: 50 mM external K+). NMDA was also tested in the absence of Mg{sup 2+}. No effect was detectable under any of these experimental conditions. Hypotheses to interpret these data are discussed. Further studies on other preparations are needed in order to directly investigate the presynaptic effects of excitatory amino acids.

  19. Dopaminergic enhancement of excitatory synaptic transmission in layer II entorhinal neurons is dependent on D₁-like receptor-mediated signaling.

    Science.gov (United States)

    Glovaci, I; Caruana, D A; Chapman, C A

    2014-01-31

    The modulatory neurotransmitter dopamine induces concentration-dependent changes in synaptic transmission in the entorhinal cortex, in which high concentrations of dopamine suppress evoked excitatory postsynaptic potentials (EPSPs) and lower concentrations induce an acute synaptic facilitation. Whole-cell current-clamp recordings were used to investigate the dopaminergic facilitation of synaptic responses in layer II neurons of the rat lateral entorhinal cortex. A constant bath application of 1 μM dopamine resulted in a consistent facilitation of EPSPs evoked in layer II fan cells by layer I stimulation; the size of the facilitation was more variable in pyramidal neurons, and synaptic responses in a small group of multiform neurons were not modulated by dopamine. Isolated inhibitory synaptic responses were not affected by dopamine, and the facilitation of EPSPs was not associated with a change in paired-pulse facilitation ratio. Voltage-clamp recordings of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor-mediated excitatory postsynaptic currents (EPSCs) were facilitated by dopamine, but N-methyl-D-aspartate receptor-mediated currents were not. Bath application of the dopamine D₁-like receptor blocker SCH23390 (50 μM), but not the D₂-like receptor blocker sulpiride (50 μM), prevented the facilitation, indicating that it is dependent upon D₁-like receptor activation. Dopamine D₁ receptors lead to activation of protein kinase A (PKA), and including the PKA inhibitor H-89 or KT 5720 in the recording pipette solution prevented the facilitation of EPSCs. PKA-dependent phosphorylation of inhibitor 1 or the dopamine- and cAMP-regulated protein phosphatase (DARPP-32) can lead to a facilitation of AMPA receptor responses by inhibiting the activity of protein phosphatase 1 (PP1) that reduces dephosphorylation of AMPA receptors, and we found here that inhibition of PP1 occluded the facilitatory effect of dopamine. The dopamine

  20. Monoallelic deletion of the microRNA biogenesis gene Dgcr8 produces deficits in the development of excitatory synaptic transmission in the prefrontal cortex

    Directory of Open Access Journals (Sweden)

    Barker Alison J

    2011-04-01

    Full Text Available Abstract Background Neuronal phenotypes associated with hemizygosity of individual genes within the 22q11.2 deletion syndrome locus hold potential towards understanding the pathogenesis of schizophrenia and autism. Included among these genes is Dgcr8, which encodes an RNA-binding protein required for microRNA biogenesis. Dgcr8 haploinsufficient mice (Dgcr8+/- have reduced expression of microRNAs in brain and display cognitive deficits, but how microRNA deficiency affects the development and function of neurons in the cerebral cortex is not fully understood. Results In this study, we show that Dgcr8+/- mice display reduced expression of a subset of microRNAs in the prefrontal cortex, a deficit that emerges over postnatal development. Layer V pyramidal neurons in the medial prefrontal cortex of Dgcr8+/- mice have altered electrical properties, decreased complexity of basal dendrites, and reduced excitatory synaptic transmission. Conclusions These findings demonstrate that precise microRNA expression is critical for the postnatal development of prefrontal cortical circuitry. Similar defects in neuronal maturation resulting from microRNA deficiency could represent endophenotypes of certain neuropsychiatric diseases of developmental onset.

  1. Characterisation of the effects of ATPA, a GLU(K5) receptor selective agonist, on excitatory synaptic transmission in area CA1 of rat hippocampal slices.

    Science.gov (United States)

    Clarke, V R J; Collingridge, G L

    2002-06-01

    Kainate receptors are involved in a variety of synaptic functions in the CNS including the regulation of excitatory synaptic transmission. Previously we described the depressant action of the GLU(K5) selective agonist (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA) on synaptic transmission in the Schaffer collateral-commissural pathway of rat hippocampal slices. In the present study we report several new features of the actions of ATPA at this synapse. Firstly, the effectiveness of ATPA is developmentally regulated. Secondly, the effects of ATPA decline during prolonged or repeated applications. Thirdly, the effects of ATPA are not mediated indirectly via activation of GABA(A), GABA(B), muscarinic or adenosine A(1) receptors. Fourthly, elevating extracellular Ca(2+) from 2 to 4 mM antagonises the effects of ATPA. Some differences between the actions of ATPA and kainate on synaptic transmission in the Schaffer collateral-commissural pathway are also noted.

  2. Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v)2.1 knockin migraine mice.

    Science.gov (United States)

    Tottene, Angelita; Conti, Rossella; Fabbro, Alessandra; Vecchia, Dania; Shapovalova, Maryna; Santello, Mirko; van den Maagdenberg, Arn M J M; Ferrari, Michel D; Pietrobon, Daniela

    2009-03-12

    Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by mutations in Ca(V)2.1 (P/Q-type) Ca(2+) channels. Knockin mice carrying a FHM1 mutation show increased neuronal P/Q-type current and facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura and may activate migraine headache mechanisms. We studied cortical neurotransmission in neuronal microcultures and brain slices of FHM1 mice. We show gain of function of excitatory neurotransmission due to increased action-potential-evoked Ca(2+) influx and increased probability of glutamate release at pyramidal cell synapses but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses. Using an in vitro model of CSD, we show a causative link between enhanced glutamate release and CSD facilitation. The synapse-specific effect of FHM1 mutations points to disruption of excitation-inhibition balance and neuronal hyperactivity as the basis for episodic vulnerability to CSD ignition in migraine.

  3. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction.

    Science.gov (United States)

    Weissberg, Itai; Wood, Lydia; Kamintsky, Lyn; Vazquez, Oscar; Milikovsky, Dan Z; Alexander, Allyson; Oppenheim, Hannah; Ardizzone, Carolyn; Becker, Albert; Frigerio, Federica; Vezzani, Annamaria; Buckwalter, Marion S; Huguenard, John R; Friedman, Alon; Kaufer, Daniela

    2015-06-01

    Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-β) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-β-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-β inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-β-pathway as a potential strategy for the prevention of PIE. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Reciprocal inhibition of the AMPA and NMDA components of excitatory postsynaptic potentials in field CA1 of the rat hippocampus in vitro.

    Science.gov (United States)

    Bazhenov, A V; Kleshchevnikov, A M

    1999-01-01

    The mutual effects of components of excitatory postsynaptic potentials (EPSP) induced by activation of glutamate receptors sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) were studied on living slices of rat hippocampus. Evoked responses were recorded in the radial layer (stratum radialis) in field CA1 after stimulation of collateral-commissural fibers. The contribution of the NMDA component to the total EPSP was altered by extracellular application of solutions containing different concentrations of magnesium. At low magnesium concentrations, when both components made significant contributions to EPSP, inhibition of one of the components by application of antagonists of the appropriate receptors led to increases in the area of the other component. Thus, the total magnitude of pharmacologically isolated components were significantly greater than the control response (for example, at 0.1 mM magnesium, the sum of the components was 340 +/- 120% of the control two-component EPSP (p EPSP inhibit each other. The mutual inhibition of components may be an important factor affecting the conductivity and plastic properties of central glutamatergic synaptic pathways.

  5. [Reciprocal suppression of the AMPA and NMDA components of the excitatory postsynaptic potentials in the CA1 area of the rat hippocampus in vitro].

    Science.gov (United States)

    Bazhenov, A V; Kleshchevnikov, A M

    1998-01-01

    The interaction between N-methyl-d-aspartate (NMDA)- and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-dependent components of excitatory postsynaptic potentials (EPSP) was studied in rat hippocampal slices. Responses evoked by stimulation of the collateral commissural fibers were recorded in the radial layer of the CA1 area. Contribution of the NMDA component was changed by application of solutions with different concentrations of magnesium. In solutions with low magnesium concentration, when both AMPA and NMDA components contribute significantly to EPSP, suppression of one of the components by application of selective antagonist resulted in increase in the area of another component. Thus, the sum of pharmacologically isolated AMPA and NMDA components was significantly higher than the control EPSP. For example, at 0.1 mM of magnesium in the extracellular solution the sum of the components was 340 +/- 120% of the control EPSP (p EPSP components suppress each other. The mutual suppression of the AMPA and NMDA component of the EPSP can be an important factor which influences the conductivity and plastic properties of central glutamatergic synaptic pathways.

  6. Nicotinic excitatory postsynaptic potentials in hippocampal CA1 interneurons are predominantly mediated by nicotinic receptors that contain α4 and β2 subunits.

    Science.gov (United States)

    Bell, Karen A; Shim, Hoon; Chen, Ching-Kang; McQuiston, A Rory

    2011-12-01

    In the hippocampus, activation of nicotinic receptors that include α4 and β2 subunits (α4β2*) facilitates memory formation. α4β2* receptors may also play a role in nicotine withdrawal, and their loss may contribute to cognitive decline in aging and Alzheimer's disease (AD). However, little is known about their cellular function in the hippocampus. Therefore, using optogenetics, whole cell patch clamping and voltage-sensitive dye (VSD) imaging, we measured nicotinic excitatory postsynaptic potentials (EPSPs) in hippocampal CA1. In a subpopulation of inhibitory interneurons, release of ACh resulted in slow depolarizations (rise time constant 33.2 ± 6.5 ms, decay time constant 138.6 ± 27.2 ms) mediated by the activation of α4β2* nicotinic receptors. These interneurons had somata and dendrites located in the stratum oriens (SO) and stratum lacunosum-moleculare (SLM). Furthermore, α4β2* nicotinic EPSPs were largest in the SLM. Thus, our data suggest that nicotinic EPSPs in hippocampal CA1 interneurons are predominantly mediated by α4β2* nicotinic receptors and their activation may preferentially affect extrahippocampal inputs in SLM of hippocampal CA1.

  7. Calcium Transients in Dendrites of Neocortical Neurons Evoked by Single Subthreshold Excitatory Postsynaptic Potentials via Low-Voltage-Activated Calcium Channels

    Science.gov (United States)

    Markram, Henry; Sakmann, Bert

    1994-05-01

    Simultaneous recordings of membrane voltage and concentration of intracellular Ca2+ ([Ca2+]_i) were made in apical dendrites of layer 5 pyramidal cells of rat neocortex after filling dendrites with the fluorescent Ca2+ indicator Calcium Green-1. Subthreshold excitatory postsynaptic potentials (EPSPs), mediated by the activation of glutamate receptor channels, caused a brief increase in dendritic [Ca2+]_i. This rise in dendritic [Ca2+]_i was mediated by the opening of low-voltage-activated Ca2+ channels in the dendritic membrane. The results provide direct evidence that dendrites do not function as passive cables even at low-frequency synaptic activity; rather, a single subthreshold EPSP changes the dendritic membrane conductance by opening Ca2+ channels and generating a [Ca2+]_i transient that may propagate towards the soma. The activation of these Ca2+ channels at a low-voltage threshold is likely to influence the way in which dendritic EPSPs contribute to the electrical activity of the neuron.

  8. The chronic treatment in vivo of salicylate or morphine alters excitatory effects of subsequent salicylate or morphine tests in vitro in hippocampus area CA1.

    Science.gov (United States)

    Sadegh, Mehdi; Fathollahi, Yaghoub; Semnanian, Saeed

    2013-12-05

    The current practical tests were designed to study in vitro interactions in the field potential between salicylate and morphine analgesics in the hippocampus area CA1 taken from morphine-(7 days) or salicylate (6 days)-treated rats. For this, morphine or salicylate was applied in vitro to the hippocampal slices derived from chronically drug-treated or saline-injected rats and drug-induced changes in evoked field potentials of area CA1 were evaluated. Chronic treatment in vivo of morphine or salicylate had no impact on baseline field EPSP and population spikes (PS) but a leftward shift in fEPSP/PS (E/S) curves and an increase in paired pulse ratio at 10 ms IPI were seen. Acute in vitro salicylate produced a durable PS potentiation in morphine-treated group, whereas an increase in PS of all groups was observed after long-term exposure to in vitro salicylate. Acute in vitro morphine caused a stable PS potentiation in control and salicylate treated groups, but not in morphine treated group. A potentiated fEPSP and a greater PS potentiation in salicylate treated group were observed after long-term exposure to in vitro morphine. It is concluded that the chronic treatment in vivo of salicylate or morphine incites lasting changes in the CA1 circuitry, which alters excitatory effects of subsequent salicylate or morphine tests in vitro in a way that an increase in reactivity or tolerance to the acute salicylate or morphine administration was observed.

  9. Amino Acid Sequence of an Excitatory Insect-selective Toxin (BmK IT) From Venom of the Scorpion Buthus martensi Karsch

    Institute of Scientific and Technical Information of China (English)

    吉永华; P. Mansuelle; 徐科; C. Granier; C. Kopeyan; S. Terakawa; H. Rochat

    1994-01-01

    The insect-selective neurotoxin(BmK IT) of scorpion Buthus martensi Karsch was first reduced and S-alkylated, and then digested by TPCK-trypsin and Staphylococcus aureus V-8 Protease. The enzymatic peptides were purified on TLC-plastic sheet and submitted to determine their amino acid compositions and sequences. The sequence of the 70 amino acid residues of BmK IT was established with reference to the primary structure of AaH IT, another excitatory insect-selective toxin from the venom of North African scorpion Androctonus australis Hector. About 75% of the homologous sequence was found in the molecules of BmK IT and AaH IT. It is obvious that the results contribute toward better understanding of the molecular structure characteristics, structure/activity relationship of scorpion insect-selective toxins, and they can serve as the molecular basis for utilizing the toxins as a tool to clarify molecular mechanism involved in channel gating, and to infer the possibility of developing them as new selective b

  10. Ongoing epileptiform activity in the post-ischemic hippocampus is associated with a permanent shift of the excitatory-inhibitory synaptic balance in CA3 pyramidal neurons.

    Science.gov (United States)

    Epsztein, Jérôme; Milh, Mathieu; Bihi, Rachid Id; Jorquera, Isabel; Ben-Ari, Yehezkel; Represa, Alfonso; Crépel, Valérie

    2006-06-28

    Ischemic strokes are often associated with late-onset epilepsy, but the underlying mechanisms are poorly understood. In the hippocampus, which is one of the regions most sensitive to ischemic challenge, global ischemia induces a complete loss of CA1 pyramidal neurons, whereas the resistant CA3 pyramidal neurons display a long-term hyperexcitability several months after the insult. The mechanisms of this long-term hyperexcitability remain unknown despite its clinical implication. Using chronic in vivo EEG recordings and in vitro field recordings in slices, we now report spontaneous interictal epileptiform discharges in the CA3 area of the hippocampus from post-ischemic rats several months after the insult. Whole-cell recordings from CA3 pyramidal neurons, revealed a permanent reduction in the frequency of spontaneous and miniature GABAergic IPSCs and a parallel increase in the frequency of spontaneous and miniature glutamatergic postsynaptic currents. Global ischemia also induced a dramatic loss of GABAergic interneurons and terminals together with an increase in glutamatergic terminals in the CA3 area of the hippocampus. Altogether, our results show a morpho-functional reorganization in the CA3 network several months after global ischemia, resulting in a net shift in the excitatory-inhibitory balance toward excitation that may constitute a substrate for the generation of epileptiform discharges in the post-ischemic hippocampus.

  11. Piracetam ameliorated oxygen and glucose deprivation-induced injury in rat cortical neurons via inhibition of oxidative stress, excitatory amino acids release and P53/Bax.

    Science.gov (United States)

    He, Zhi; Hu, Min; Zha, Yun-hong; Li, Zi-cheng; Zhao, Bo; Yu, Ling-ling; Yu, Min; Qian, Ying

    2014-05-01

    Our previous work has demonstrated that piracetam inhibited the decrease in amino acid content induced by chronic hypoperfusion, ameliorated the dysfunction of learning and memory in a hypoperfusion rat model, down-regulated P53, and BAX protein, facilitated the synaptic plasticity, and may be helpful in the treatment of vascular dementia. To explore the precise mechanism, the present study further evaluated effects of piracetam on Oxygen and glucose deprivation (OGD)-induced neuronal damage in rat primary cortical cells. The addition of piracetam to the cultured cells 12 h before OGD for 4 h significantly reduced neuronal damage as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and lactate dehydrogenase release experiments. Piracetam also lowered the levels of malondialdehyde, nitrogen monoxidum, and xanthine oxidase which was increased in the OGD cells, and enhanced the activities of superoxide dismutase and glutathione peroxidase, which were decreased in the OGD cells. We also demonstrated that piracetam could decrease glutamate and aspartate release when cortical cells were subjected to OGD. Furthermore, Western blot study demonstrated that piracetam attenuated the increased expression of P53 and BAX protein in OGD cells. These observations demonstrated that piracetam reduced OGD-induced neuronal damage by inhibiting the oxidative stress and decreasing excitatory amino acids release and lowering P53/Bax protein expression in OGD cells.

  12. Effects of glutathione depletion by 2-cyclohexen-1-one on excitatory amino acids-induced enhancement of activator protein-1 DNA binding in murine hippocampus.

    Science.gov (United States)

    Ogita, K; Kitayama, T; Okuda, H; Yoneda, Y

    2001-03-01

    We have investigated the role of glutathione in mechanisms associated with excitatory amino acid signaling to the nuclear transcription factor activator protein-1 (AP1) in the brain using mice depleted of endogenous glutathione by prior treatment with 2-cyclohexen-1-one (CHX). In the hippocampus of animals treated with CHX 2 h before, a significant increase was seen in enhancement of AP1 DNA binding when determined 2 h after the injection of kainic acid (KA) at low doses. The sensitization to KA was not seen in animals injected with CHX 24 h before, in coincidence with the recovery of glutathione contents to the normal levels. By contrast, CHX did not significantly affect the potentiation by NMDA of AP1 binding under any experimental conditions. Prior treatment with CHX resulted in facilitation of behavioral changes induced by KA without affecting those induced by NMDA. These results suggest that endogenous glutathione may be at least in part involved in molecular mechanisms underlying transcriptional control by KA, but not by NMDA, signals of cellular functions.

  13. Postsynaptic potentials mediated by excitatory and inhibitory amino acids in interneurons of stratum pyramidale of the CA1 region of rat hippocampal slices in vitro.

    Science.gov (United States)

    Lacaille, J C

    1991-11-01

    1. Because interneurons of stratum pyramidale partly mediate the feed-forward inhibition of pyramidal cells, intracellular postsynaptic potentials (PSPs) evoked by activation of afferent fibers were examined in 32 nonpyramidal cells of stratum pyramidale of the CA1 region of rat hippocampal slices. 2. Electrical stimulation of stratum radiatum at the CA1-CA3 border elicited, in interneurons, PSPs that were composed of four components: a fast excitatory postsynaptic potential (EPSP), an early inhibitory postsynaptic potential (IPSPA), a late IPSPB, and in some cells a delayed, slower EPSP. These synaptic potentials summated and elicited single action potentials in 57% of cells (17/30) and burst of action potentials (2-10) in the remaining 43%. 3. The fast EPSP was observed in all cells, and the mean stimulation intensity at its threshold was 53.4 microA. Its amplitude increased with membrane hyperpolarization, and it was associated with a 45.4% decrease in cellular input resistance. The fast EPSP always elicited an action potential at short latencies (3.6-6.4 ms poststimulation). It was reversibly reduced by 6-cyano-7-nitroquinoxaline-2,3- dione (CNQX), a blocker of non-N-methyl-D-aspartate (non-NMDA) excitatory amino acid receptors. 4. The IPSPA was observed in 28/32 cells, and the mean intensity of stimulation was 57.6 microA at its threshold. The mean latency of its peak amplitude was 17.4 ms. The mean equilibrium potential (Erev) was -72.8 mV, and it was associated with a 38.9% decrease in cellular input resistance. IPSPA was blocked by the GABAA antagonist bicuculline. 5. The IPSPB was seen in 29/32 cells, and the mean intensity of stimulation at its threshold was 80.3 microA. Its latency to peak was 130.6 ms, its Erev was -107.6 mV, and it was associated with a small (7.6%) decrease in cellular input resistance. IPSPB was blocked by the GABAB antagonist phaclofen. 6. In 11/32 cells a slower EPSP was also observed. Its mean latency to peak was 53.3 ms, and the

  14. Use-dependent shift from inhibitory to excitatory GABAA receptor action in SP-O interneurons in the rat hippocampal CA3 area.

    Science.gov (United States)

    Lamsa, Karri; Taira, Tomi

    2003-09-01

    Cortical inhibitory interneurons set the pace of synchronous neuronal oscillations implicated in synaptic plasticity and various cognitive functions. The hyperpolarizing nature of inhibitory postsynaptic potentials (IPSPs) in interneurons has been considered crucial for the generation of oscillations at beta (15-30 Hz) and gamma (30-100 Hz) frequency. Hippocampal basket cells and axo-axonic cells in stratum pyramidale-oriens (S-PO) play a central role in the synchronization of the local interneuronal network as well as in pacing of glutamatergic principal cell firing. A lack of conventional forms of plasticity in excitatory synapses onto interneurons facilitates their function as stable neuronal oscillators. We have used gramicidin-perforated and whole cell clamp recordings to study properties of GABAAR-mediated transmission in CA3 SP-O interneurons and in CA3 pyramidal cells in rat hippocampal slices during electrical 5- to 100-Hz stimulation and during spontaneous activity. We show that GABAergic synapses onto SP-O interneurons can easily switch their mode from inhibitory to excitatory during heightened activity. This is based on a depolarizing shift in the GABAA reversal potential (EGABA-A), which is much faster and more pronounced in interneurons than in pyramidal cells. We also found that the shift in interneuronal function was frequency dependent, being most prominent at 20- to 40-Hz activation of the GABAergic synapses. After 40-Hz tetanic stimulation (100 pulses), GABAA responses remained depolarizing for approximately 45 s in the interneurons, promoting bursting in the GABAergic network. Hyperpolarizing EGABA-A was restored >60 s after the stimulus train. Similar but spontaneous GABAergic bursting was induced by application of 4-aminopyridine (100 microM) to slices. A shift to depolarizing IPSPs by the GABAAR permeant weak acid anion formate provoked interneuronal population bursting, supporting the role of GABAergic excitation in burst generation

  15. LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes.

    Science.gov (United States)

    Hyzinski-García, María C; Rudkouskaya, Alena; Mongin, Alexander A

    2014-11-15

    In mammals, cellular swelling activates release of small organic osmolytes, including the excitatory amino acids (EAA) glutamate and aspartate, via a ubiquitously expressed volume-regulated chloride/anion channel (VRAC). Pharmacological evidence suggests that VRAC plays plural physiological and pathological roles, including excitotoxic release of glutamate in stroke. However, the molecular identity of this pathway was unknown. Two recent studies discovered that LRRC8 gene family members encode heteromeric VRAC composed of LRRC8A plus LRRC8B-E, which mediate swelling-activated Cl(-) currents and taurine release in human non-neural cells (Z. Qiu et al. Cell 157: 447, 2014; F.K. Voss et al. Science 344: 634, 2014). Here, we tested the contribution of LRRC8A to the EAA release in brain glia. We detected and quantified expression levels of LRRC8A-E in primary rat astrocytes with quantitative RT-PCR and then downregulated LRRC8A with gene-specific siRNAs. In astrocytes exposed to hypo-osmotic media, LRRC8A knockdown dramatically reduced swelling-activated release of the EAA tracer D-[(3)H]aspartate. In parallel HPLC assays, LRRC8A siRNA prevented hypo-osmotic media-induced loss of the endogenous intracellular L-glutamate and taurine. Furthermore, downregulation of LRRC8A completely ablated the ATP-stimulated release of D-[(3)H]aspartate and [(14)C]taurine from non-swollen astrocytes. Overall, these data indicate that LRRC8A is an indispensable component of a permeability pathway that mediates both swelling-activated and agonist-induced amino acid release in brain glial cells. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

  16. Pairing-specific long-term depression of Purkinje cell excitatory postsynaptic potentials results from a classical conditioning procedure in the rabbit cerebellar slice.

    Science.gov (United States)

    Schreurs, B G; Oh, M M; Alkon, D L

    1996-03-01

    1. Using a rabbit cerebellar slice preparation, we stimulated a classical conditioning procedure by stimulating parallel fiber inputs to Purkinje cells with the use of a brief, high-frequency train of eight constant-current pulses 80 ms before climbing fiber inputs to the same Purkinje cell were stimulated with the use of a brief, lower frequency train of three constant-current pulses. In all experiments, we assessed the effects of stimulation by measuring the peak amplitude of Purkinje cell excitatory postsynaptic potentials (EPSPs) to single parallel fiber test pulses. 2. Intradendritically recorded Purkinje cell EPSPs underwent a long-term (> 20 min) reduction in peak amplitude (30%) after paired stimulation of the parallel and climbing fibers but not after unpaired or parallel fiber alone stimulation. We call this phenomenon pairing-specific long-term depression (PSD). 3. Facilitation of the peak amplitude of a second EPSP elicited by a parallel fiber train occurred both before and after paired stimulation suggesting that the locus of depression was not presynaptic. Depression of the peak amplitude of a depolarizing response to focal application of glutamate following pairings of parallel and climbing fiber stimulation added support to a suggested postsynaptic locus of the PSD effect. 4. The application of aniracetam potentiated EPSP peak amplitude by 40%, but these values returned to baseline as a result of pairings. With the removal of aniracetam from the bath 20 min after pairings, normal levels of pairing-specific EPSP depression were observed, indicating that the effect did not result from direct desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. 5. Incubation of slices in the protein kinase inhibitor H-7 potentiated EPSP peak amplitudes slightly (9%), but peak amplitudes returned to baseline levels after pairings. The net reduction in EPSP peak amplitude of classical conditioning.

  17. Comparison of excitatory currents activated by different transmitters on crustacean muscle. II. Glutamate-activated currents and comparison with acetylcholine currents present on the same muscle.

    Science.gov (United States)

    Lingle, C; Auerbach, A

    1983-04-01

    The properties of glutamate-activated excitatory currents on the gm6 muscle from the foregut of the spiny lobsters Panulirus argus and interruptus and the crab Cancer borealis were examined using either noise analysis, analysis of synaptic current decays, or slow iontophoretic currents. The properties of acetylcholine currents activated in nonjunctional regions of the gm6 muscle were also examined. At 12 degrees C and -80 mV, the predominant time constant of power spectra from glutamate-activated current noise was approximately 7 ms and the elementary conductance was approximately 34 pS. At 12 degrees C and -80 mV, the predominant time constant of acetylcholine-activated channels was approximately 11 ms with a conductance of approximately 12 pS. Focally recorded glutamatergic extracellular synaptic currents on the gm6 muscle decayed with time constants of approximately 7-8 ms at 12 degrees C and -80 mV. The decay time constant was prolonged e-fold about every 225-mV hyperpolarization in membrane potential. The Q10 of the time constant of the synaptic current decay was approximately 2.6. The voltage dependence of the steady-state conductance increase activated by iontophoretic application of glutamate has the opposite direction of the steady-state conductance activated by cholinergic agonists when compared on the gm6 muscles. The glutamate-activated conductance increase is diminished with hyperpolarization. The properties of the marine crustacean glutamate channels are discussed in relation to glutamate channels in other organisms and to the acetylcholine channels found on the gm6 muscle and the gm1 muscle of the decapod foregut (Lingle and Auerbach, 1983).

  18. Excitatory amino acid receptor blockade within the caudal pressor area and rostral ventrolateral medulla alters cardiovascular responses to nucleus raphe obscurus stimulation in rats

    Directory of Open Access Journals (Sweden)

    Silva N.F.

    2002-01-01

    Full Text Available Pressor responses elicited by stimulation of the nucleus raphe obscurus (NRO depend on the integrity of the rostral ventrolateral medulla (RVLM. Therefore, to test the participation of excitatory amino acid (EAA receptors in the cardiovascular responses evoked by NRO stimulation (1 ms, 100 Hz, 40-70 µA, for 10 s, the EAA antagonist kynurenic acid (Kyn was microinjected at different sites in the ventrolateral medullar surface (2.7 nmol/200 nl of male Wistar rats (270-320 g, N = 39 and NRO stimulation was repeated. The effects of NRO stimulation were: hypertension (deltaMAP = +43 ± 1 mmHg, P<0.01, bradycardia (deltaHR = -30 ± 7 bpm, P<0.01 and apnea. Bilateral microinjection of Kyn into the RVLM, which did not change baseline parameters, almost abolished the bradycardia induced by NRO stimulation (deltaHR = -61 ± 3 before vs -2 ± 3 bpm after Kyn, P<0.01, N = 7. Unilateral microinjection of Kyn into the CVLM did not change baseline parameters or reduce the pressor response to NRO stimulation (deltaMAP = +46 ± 5 before vs +48 ± 5 mmHg after Kyn, N = 6. Kyn bilaterally microinjected into the caudal pressor area reduced blood pressure and heart rate and almost abolished the pressor response to NRO stimulation (deltaMAP = +46 ± 4 mmHg before vs +4 ± 2 mmHg after Kyn, P<0.01, N = 7. These results indicate that EAA receptors on the medullary ventrolateral surface play a role in the modulation of the cardiovascular responses induced by NRO stimulation, and also suggest that the RVLM participates in the modulation of heart rate responses and that the caudal pressor area modulates the pressor response following NRO stimulation.

  19. Opposing effects of traumatic brain injury on excitatory synaptic function in the lateral amygdala in the absence and presence of preinjury stress.

    Science.gov (United States)

    Klein, Rebecca C; Acheson, Shawn K; Qadri, Laura H; Dawson, Alina A; Rodriguiz, Ramona M; Wetsel, William C; Moore, Scott D; Laskowitz, Daniel T; Dawson, Hana N

    2016-06-01

    Traumatic brain injury (TBI) is a leading cause of death and disability among young adults and is highly prevalent among recently deployed military personnel. Survivors of TBI often experience cognitive and emotional deficits, suggesting that long-term effects of injury may disrupt neuronal function in critical brain regions, including the amygdala, which is involved in emotion and fear memory. Amygdala hyperexcitability has been reported in both TBI and posttraumatic stress disorder patients, yet little is known regarding the effects of combined stress and TBI on amygdala structure and function at the neuronal level. The present study seeks to determine how the long-term effects of preinjury foot-shock stress and TBI interact to influence synaptic plasticity in the lateral amygdala (LA) of adult male C57BL/6J mice by using whole-cell patch clamp electrophysiology 2-3 months postinjury. In the absence of stress, TBI resulted in a significant increase in membrane excitability and spontaneous excitatory postsynaptic currents (sEPSCs) in LA pyramidal-like neurons. Foot-shock stress in the absence of TBI also resulted in increased sEPSC activity. In contrast, when preinjury stress and TBI occurred in combination, sEPSC activity was significantly decreased compared with either condition alone. There were no significant differences in inhibitory activity or total dendritic length among any of the treatment groups. These results demonstrate that stress and TBI may be contributing to amygdala hyperexcitability via different mechanisms and that these pathways may counterbalance each other with respect to long-term pathophysiology in the LA.

  20. Characterization of excitatory and inhibitory neuron activation in the mouse medial prefrontal cortex following palatable food ingestion and food driven exploratory behavior

    Directory of Open Access Journals (Sweden)

    Ronald P Gaykema

    2014-07-01

    Full Text Available The medial prefrontal cortex (mPFC is implicated in aspects of executive function, that include the modulation of attentional and memory processes involved in goal selection. Food-seeking behavior has been shown to involve activation of the mPFC, both during the execution of strategies designed to obtain food and during the consumption of food itself. As these behaviors likely require differential engagement of the prefrontal cortex, we hypothesized that the pattern of neuronal activation would also be behavior dependent. In this study we describe, for the first time, the expression of Fos in different layers and cell types of the infralimbic/dorsal peduncular (IL/DP and prelimbic/anterior cingulate (PL/AC subdivisions of mouse mPFC following both the consumption of palatable food and following exploratory activity of the animal directed at obtaining food reward. While both manipulations led to increases of Fos expression in principal excitatory neurons relative to control, food-directed exploratory activity produced a significantly greater increase in Fos expression than observed in the food intake condition. Consequently, we hypothesized that mPFC interneuron activation would also be differentially engaged by these manipulations. Interestingly, Fos expression patterns differed substantially between treatments and interneuron subtype, illustrating how the differential engagement of subsets of mPFC interneurons depends on the behavioral state. In our experiments, both vasoactive intestinal peptide- and parvalbumin-expressing neurons showed enhanced Fos expression only during the food-dependent exploratory task and not during food intake. Conversely, elevations in arcuate and paraventricular hypothalamic fos expression were only observed following food intake and not following food driven exploration. Our data suggest that activation of select mPFC interneurons may be required to support high cognitive demand states while being dispensable during

  1. Exercise pre‑conditioning alleviates brain damage via excitatory amino acid transporter 2 and extracellular signal‑regulated kinase 1/2 following ischemic stroke in rats.

    Science.gov (United States)

    Wang, Xiao; Zhang, Min; Feng, Rui; Li, Wen-Bin; Ren, Shi-Qing; Zhang, Feng

    2015-02-01

    Previous studies have reported that physical exercise may exert a neuroprotective effect in humans as well as animals. However, the detailed mechanisms underlying the neuroprotective effect of exercise has remained to be elucidated. The aim of the present study was to explore the possible signaling pathways involved in the protective effect of pre‑ischemic treadmill training for ischemic stroke in rats. A total of 36 male Sprague‑Dawley rats were divided at random into three groups as follows (n=12 for each): Sham surgery group; middle cerebral artery occlusion (MCAO) group; and exercise with MCAO group. Following treadmill training for three weeks, the middle cerebral artery was occluded for 90 min in order to induce ischemic stroke, followed by reperfusion. Following 24 h post‑reperfusion, six rats from each group were assessed for neurological deficits and then sacrificed to calculate the infarct volume. The remaining rats (n=6 for each group) were sacrificed and the expression levels of excitatory amino acid transporter 2 (EAAT‑2) and extracellular signal‑regulated kinase 1/2 (ERK1/2) were detected using western blot analysis. The results of the present study demonstrated that rats that underwent pre‑ischemic exercise intervention had a significantly decreased brain infarct volume and neurological deficits; in addition, the pre‑ischemic exercise group showed decreased overexpression of phosphorylated ERK1/2 and increased expression of EAAT‑2 following ischemic stroke. In conclusion, treadmill training exercise prior to ischemic stroke alleviated brain damage in rats via regulation of EAAT‑2 and ERK1/2.

  2. mGluR1 receptors contribute to non-purinergic slow excitatory transmission to submucosal VIP neurons of guinea-pig ileum

    Directory of Open Access Journals (Sweden)

    Jaime Pei Pei Foong

    2009-05-01

    Full Text Available Vasoactive intestinal peptide (VIP immunoreactive secretomotor neurons in the submucous plexus are involved in mediating bacterial toxin-induced hypersecretion leading to diarrhoea. VIP neurons become hyperexcitable after the mucosa is exposed to cholera toxin, which suggests that the manipulation of the excitability of these neurons may be therapeutic. This study used standard intracellular recording methods to systematically characterize slow excitatory postsynaptic potentials (EPSPs evoked in submucosal VIP neurons by different stimulus regimes (1, 3 and 15 pulse 30 Hz stimulation, together with their associated input resistances and pharmacology. All slow EPSPs were associated with a significant increase in input resistance compared to baseline values. Slow EPSPs evoked by a single stimulus were confirmed to be purinergic, however, slow EPSPs evoked by 15 pulse trains were non-purinergic and those evoked by 3 pulse trains were mixed. NK1 or NK3 receptor antagonists did not affect slow EPSPs. The group I mGluR receptor antagonist, PHCCC reduced the amplitude of purinergic and non-purinergic slow EPSPs. Blocking mGluR1 receptors depressed the overall response to 3 and 15 pulse trains, but this effect was inconsistent, while blockade of mGluR5 receptors had no effect on the non-purinergic slow EPSPs. Thus, although other receptors are almost certainly involved, our data indicate that there are at least two pharmacologically distinct types of slow EPSPs in the VIP secretomotor neurons: one mediated by P2Y receptors and the other in part by mGluR1 receptors.

  3. Decrease of aquaporin-4 and excitatory amino acid transporter-2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV-associated neurocognitive disorders.

    Science.gov (United States)

    Xing, Hui Qin; Zhang, Yu; Izumo, Kimiko; Arishima, Shiho; Kubota, Ryuji; Ye, Xiang; Xu, Qiping; Mori, Kazuyasu; Izumo, Shuji

    2017-02-01

    Human immunodeficiency virus (HIV) encephalitis and degeneration of cerebral cortex are established histopathologies of HIV-associated neurocognitive disorders (HAND). We previously reported decreased excitatory amino acid transporter-2 (EAAT-2) and astrocytic apoptosis in cortical degeneration using SIVmac239 and simian-human immunodeficiency virus (SHIV)-infected macaques and human AIDS autopsy cases. In the present study, we added highly pathogenic SIVsm543-3-infected macaques. These animals showed similar degenerative changes in the frontal cortex. Using 11 SIV-infected macaques, three SIVsm543-3, five SIVmac239 and three SHIV, we compared brain pathology caused by three different viruses and further analyzed the pathogenic process of HAND. We noticed vacuolar changes in perivascular processes of astrocytes by electron microscopy, and examined expression of astrocyte-specific protein aquaporin-4 (AQP4) by immunohistochemistry. APQ4 was diffusely positive in the neuropil and perivascular area in control brains. There was patchy or diffuse decrease of AQP4 staining in the neuropil of SIV-infected macaques, which was associated with EAAT-2 staining by double immunostaining. A quantitative analysis demonstrated significant positive correlation between areas of AQP4 and EAAT-2. Some astrocytes express EAAT-2 but not AQP4, and decrease of EAAT-2 expression tended to be less than the decrease of AQP4. Active-caspase-3 immunostaining demonstrated apoptosis of neurons and astrocytes in the area of AQP4/EAAT-2 reduction. These results suggest that AQP4 is damaged first and decrease of EAAT-2 may follow in pathogenesis of cortical degeneration. This is the first demonstration of decrease of AQP4 and its association with EAAT-2 decrease in AIDS brain, suggesting a role in the pathogenesis of HAND. © 2016 Japanese Society of Neuropathology.

  4. Pelviureteral inhibitory reflex and ureteropelvic excitatory reflex: role of the two reflexes in regulation of urine flow from the renal pelvis to the ureter.

    Science.gov (United States)

    Shafik, A

    1997-01-01

    The mechanism by which the ureteropelvic junction (UPJ) regulates the passage of urine from the renal pelvis to the ureter, and prevents urinary backflow from the the ureter to the renal pelvis, is not completely understood. The current communication studies this mechanism in 18 dogs. With the dogs under anesthesia, nephrostomy was done through which two catheters (one pressure and one balloon-tipped) were introduced into the UPJ and the renal pelvis, respectively. Renal pelvis distension with a balloon filled with 1 ml of saline effected a rise of renal pelvic pressure from a mean basal pressure of 4.8 +/- 1.2 cm H2O to 6.9 +/- 2.3 cm H2O (P pelvic balloon (P > 0.05). Renal pelvic distension with 2, 3, and 4 ml caused a significant rise of renal pelvic pressure to 8.4 +/- 2.7 (P 0.05). In contrast, the UPJ showed no significant pressure change upon distension of the locally anesthetized renal pelvis or ureter, respectively. Likewise, the locally anesthetized UPJ exhibited no significant pressure response to renal pelvic or ureteric distension. The study demonstrates that urine might have to accumulate in the renal pelvis up to a certain volume and pressure so as to effect UPJ opening, which occurs at its maximum irrespective of the distending volume. UPJ opening upon renal pelvic distension postulates a reflex relationship which we call "pelviureteral inhibitory reflex." This reflex is believed to regulate the passage of urine from the renal pelvis to the ureter. Ureteric distension closes the UPJ; we call this reflex action the "ureteropelvic excitatory reflex" as it seems to prevent reflux of urine through the UPJ and thus protects the kidney. The concept that the UPJ acts as a physiologic sphincter is put forward.

  5. Schaffer-specific local field potentials reflect discrete excitatory events at gamma frequency that may fire postsynaptic hippocampal CA1 units.

    Science.gov (United States)

    Fernández-Ruiz, Antonio; Makarov, Valeri A; Benito, Nuria; Herreras, Oscar

    2012-04-11

    Information processing and exchange between brain nuclei are made through spike series sent by individual neurons in highly irregular temporal patterns. Synchronization in cell assemblies, proposed as a network language for internal neural representations, still has little experimental support. We use a novel technique to extract pathway-specific local field potentials (LFPs) in the hippocampus to explore the ongoing temporal structure of a single presynaptic input, the CA3 Schaffer pathway, and its contribution to the spontaneous output of CA1 units in anesthetized rat. We found that Schaffer-specific LFPs are composed of a regular succession of pulse-like excitatory packages initiated by spontaneous clustered firing of CA3 pyramidal cells to which individual units contribute variably. A fraction of these packages readily induce firing of CA1 pyramidal cells and interneurons, the so-called Schaffer-driven spikes, revealing the presynaptic origin in the output code of single CA1 units. The output of 70% of CA1 pyramidal neurons contains up to 10% of such spikes. Our results suggest a hierarchical internal operation of the CA3 region based on sequential oscillatory activation of pyramidal cell assemblies whose activity partly gets in the output code at the next station. We conclude that CA1 output may directly reflect the activity of specific ensembles of CA3 neurons. Thus, the fine temporal structure of pathway-specific LFPs, as an accurate readout of the activity of a presynaptic population, is useful in searching for hidden presynaptic code in irregular spikes series of individual neurons and assemblies.

  6. Latent N-methyl-D-aspartate receptors in the recurrent excitatory pathway between hippocampal CA1 pyramidal neurons: Ca(2+)-dependent activation by blocking A1 adenosine receptors.

    Science.gov (United States)

    Klishin, A; Tsintsadze, T; Lozovaya, N; Krishtal, O

    1995-01-01

    When performed at increased external [Ca2+]/[Mg2+] ratio (2.5 mM/0.5 mM), temporary block of A1 adenosine receptors in hippocampus [by 8-cyclopentyltheophylline (CPT)] leads to a dramatic and irreversible change in the excitatory postsynaptic current (EPSC) evoked by Schaffer collateral/commissural (SCC) stimulation and recorded by in situ patch clamp in CA1 pyramidal neurons. The duration of the EPSC becomes stimulus dependent, increasing with increase in stimulus strength. The later occurring component of the EPSC is carried through N-methyl-D-aspartate (NMDA) receptor-operated channels but disappears under either the NMDA antagonist 2-amino-5-phosphonovaleric acid (APV) or the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These findings indicate that the late component of the SCC-evoked EPSC is polysynaptic: predominantly non-NMDA receptor-mediated SCC inputs excite CA1 neurons that recurrently excite each other by predominantly NDMA receptor-mediated synapses. These recurrent connections are normally silent but become active after CPT treatment, leading to enhancement of the late component of the EPSC. The activity of these connections is maintained for at least 2 hr after CPT removal. When all functional NMDA receptors are blocked by dizocilpine maleate (MK-801), subsequent application of CPT leads to a partial reappearance of NMDA receptor-mediated EPSCs evoked by SCC stimulation, indicating that latent NMDA receptors are recruited. Altogether, these findings indicate the existence of a powerful system of NMDA receptor-mediated synaptic contacts in SCC input to hippocampal CA1 pyramidal neurons and probably also in reciprocal connections between these neurons, which in the usual preparation are kept latent by activity of A1 receptors. PMID:8618915

  7. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1997-01-01

    We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation......)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments......, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation...

  8. Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors.

    Science.gov (United States)

    Murray, Katherine C; Stephens, Marilee J; Rank, Michelle; D'Amico, Jessica; Gorassini, Monica A; Bennett, David J

    2011-08-01

    Sensory afferent transmission and associated spinal reflexes are normally inhibited by serotonin (5-HT) derived from the brain stem. Spinal cord injury (SCI) that eliminates this 5-HT innervation leads to a disinhibition of sensory transmission and a consequent emergence of unusually long polysynaptic excitatory postsynaptic potentials (EPSPs) in motoneurons. These EPSPs play a critical role in triggering long polysynaptic reflexes (LPRs) that initiate muscles spasms. In the present study we examined which 5-HT receptors modulate the EPSPs and whether these receptors adapt to a loss of 5-HT after chronic spinal transection in rats. The EPSPs and associated LPRs recorded in vitro in spinal cords from chronic spinal rats were consistently inhibited by 5-HT(1B) or 5-HT(1F) receptor agonists, including zolmitriptan (5-HT(1B/1D/1F)) and LY344864 (5-HT(1F)), with a sigmoidal dose-response relation, from which we computed the 50% inhibition (EC(50)) and potency (-log EC(50)). The potencies of 5-HT receptor agonists were highly correlated with their binding affinity to 5-HT(1B) and 5-HT(1F) receptors, and not to other 5-HT receptors. Zolmitriptan also inhibited the LPRs and general muscle spasms recorded in vivo in the awake chronic spinal rat. The 5-HT(1B) receptor antagonists SB216641 and GR127935 and the inverse agonist SB224289 reduced the inhibition of LPRs by 5-HT(1B) agonists (zolmitriptan). However, when applied alone, SB224289, SB216641, and GR127935 had no effect on the LPRs, indicating that 5-HT(1B) receptors do not adapt to chronic injury, remaining silent, without constitutive activity. The reduction in EPSPs with zolmitriptan unmasked a large glycine-mediated inhibitory postsynaptic current (IPSC) after SCI. This IPSC and associated chloride current reversed at -73 mV, slightly below the resting membrane potential. Zolmitriptan did not change motoneuron properties. Our results demonstrate that 5-HT(1B/1F) agonists, such as zolmitriptan, can restore inhibition

  9. Sensitivity of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials and synaptic plasticity to TCN 201 and TCN 213 in rat hippocampal slices.

    Science.gov (United States)

    Izumi, Yukitoshi; Zorumski, Charles F

    2015-02-01

    Whereas ifenprodil has been used as a selective GluN1/GluN2B (NR1/NR2B, B-type) receptor antagonist to distinguish between GluN2B (NR2B) and GluN2A (NR2A)-containing N-methyl-d-aspartate receptors (NMDARs), TCN 201 (3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide) and TCN 213 [N-(cyclohexylmethyl)-2-[{5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio]acetamide] have been found to be selective GluN1/GluN2A (NR1/NR2A, A-type) antagonists. Based on the premise that A- and B-types are major synaptic NMDARs, we examined whether inhibition of NMDAR excitatory postsynaptic potentials (EPSPs) by the TCN compounds and ifenprodil are complementary. Contrary to this prediction, inhibition of NMDAR EPSPs by the TCN compounds and ifenprodil were largely overlapping in the CA1 region of hippocampal slices from 30-day-old rats. After partial inhibition by ifenprodil, TCN compounds produced little further suppression of NMDAR EPSPs. Similarly, after partial inhibition by TCN compounds ifenprodil failed to further suppress NMDAR EPSPs. However, low micromolar d-2-amino-5-phosphonovalerate, a competitive NMDAR antagonist, which alone only partially inhibits NMDAR EPSPs, markedly suppresses residual NMDAR responses in the presence of ifenprodil or the TCNs, suggesting that low 2-amino-5-phosphonovalerate antagonizes both ifenprodil- and TCN-insensitive synaptic NMDARs. These observations can be most readily interpreted if ifenprodil and TCNs act on a similar population of synaptic NMDARs. Recent lines of evidence suggest that the majority of hippocampal synaptic NMDARs are triheteromers. If so, modulation of GluN2A, and not just GluN2B NMDARs, could dampen long-term depression (LTD). Indeed, both TCNs, like ifenprodil, blocked LTD, suggesting the involvement of ifenprodil- and TCN-sensitive NMDARs in LTD induction. However, the TCNs plus ifenprodil failed to inhibit long-term potentiation (LTP), suggesting that neither ifenprodil- nor TCN

  10. Novel class of amino acid antagonists at non-N-methyl-D-aspartic acid excitatory amino acid receptors. Synthesis, in vitro and in vivo pharmacology, and neuroprotection

    Energy Technology Data Exchange (ETDEWEB)

    Krogsgaard-Larsen, P.; Ferkany, J.W.; Nielsen, E.O.; Madsen, U.; Ebert, B.; Johansen, J.S.; Diemer, N.H.; Bruhn, T.; Beattie, D.T.; Curtis, D.R. (Royal Danish School of Pharmacy, Copenhagen (Denmark))

    1991-01-01

    The isoxazole amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) (1), which is a highly selective agonist at the AMPA subtype of excitatory amino acid (EAA) receptors, has been used as a lead for the development of two novel EAA receptor antagonists. One of the compounds, 2-amino-3-(3-(carboxymethoxy)-5-methylisoxazol-4-yl)propionic acid (AMOA, 7), was synthesized via O-alkylation by ethyl chloroacetate of the amino acid protected AMPA derivative 4. The other compound, 2-amino-3-(2-(3-hydroxy-5-methylisoxazol-4-yl)-methyl-5-methyl-3-+ ++oxoisoxazolin -4-yl)propionic acid (AMNH, 14) was synthesized with use of 4-(chloromethyl)-3-methoxy-5-methylisoxazole (8) as the starting material. The intermediate 4-(chloromethyl)-2-(3-methoxy-5-methylisoxazol-4-yl)methyl-5-me thylisoxazolin- 3-one (11) was converted into the acetamidomalonate (12), which was stepwise deprotected to give 14. Compounds 7 and 14 were stable in aqueous solution at pH values close to physiological pH. Neither 7 nor 14 showed detectable affinities for the receptor, ion channel, or modulatory sites of the N-methyl-D-aspartic acid (NMDA) receptor complex. Quantitative receptor autoradiographic and conventional binding techniques were used to study the affinities of 7 and 14 for non-NMDA receptor sites. Both compounds were inhibitors of the binding of (3H)AMPA (IC50 = 90 and 29 microM, respectively). Compounds 14 and 7 were both very weak inhibitors of the high-affinity binding of radioactive kainic acid ((3H)KAIN). Compound 14, but not 7, was, however, shown to be an inhibitor of low-affinity (3H)KAIN binding as determined in the presence of 100 mM calcium chloride. In the rat cortical slice preparation, 7 was shown to antagonize excitation induced by 1 with some selectivity, whereas 14 proved to be a rather selective antagonist of KAIN-induced excitation.

  11. Functional properties of heteromeric P2X(1/5) receptors expressed in HEK cells and excitatory junction potentials in guinea-pig submucosal arterioles.

    Science.gov (United States)

    Surprenant, A; Schneider, D A; Wilson, H L; Galligan, J J; North, R A

    2000-07-01

    P2X receptors are ATP-gated cation channels; they form as homomers or heteromers from a family of seven related subunits. In particular, heteromeric channels comprising P2X(2) and P2X(3) subunits, or P2X(1) and P2X(5) subunits, show distinctive physiological and pharmacological properties in heterologous expression systems. There is substantial evidence that one of the native P2X receptors in sensory neurones corresponds to the P2X(2/3) heteromer, but there is no evidence for P2X(1/5) heteromers in native tissue. We recorded currents in response to activation of heteromeric P2X(1/5) receptors expressed in HEK293 cells to characterize further their functional properties. The ATP concentration-response curve had a threshold concentration of 1 nM, and a Hill slope of one. TNP-ATP was a weak partial agonist, and a non-competitive antagonist which inhibited maximal ATP currents by 60%. Increasing or decreasing pH from 7.3 shifted the ATP concentration-response curves to the right by fivefold and decreased the maximum current by 40%. Calcium permeability was lower than that observed for other P2X receptors (P(Ca)/P(Na) ratio=1.1). The nanomolar sensitivity of this receptor revealed a steady release of ATP from HEK293 cells, providing an extracellular concentration which ranged from 3 to 300 nM. Noradrenaline (0.3-30 microM) increased ATP-evoked currents by 35%; this facilitation occurred within 20 ms. We also recorded excitatory junction potentials (EJPs) from guinea-pig submucosal arterioles. EJPs were inhibited by suramin and PPADS (IC(50)s of 0.2 microM and 20 microM) but TNP-ATP (0.1-10 microM) inhibited EJPs by <30%. Noradrenaline (0.3-30 microM in the presence of phentolamine and propranolol) decreased EJPs in control preparations but facilitated EJPs by 5-20% in submucosal arterioles from reserpinized guinea-pigs. These properties are discussed in relation to P2X receptors underlying EJPs at autonomic neuroeffector junctions.

  12. Presynaptic alpha-7 nicotinic acetylcholine receptors modulate excitatory synaptic transmission in hippocampal neurons%突触前α7烟碱受体对海马神经元兴奋性突触传递的调控

    Institute of Scientific and Technical Information of China (English)

    刘振伟; 杨胜; 张永祥; 刘传缋

    2003-01-01

    The effects of presynaptic nicotinic acetylcholine receptors (nAChRs) on excitatory synaptic transmission in CA1 pyramidal neurons of the rat hippocampus were examined by blind whole-cell patch clamp recording from hippocampal slice preparations. Local application of the nAChRs agonist dimethylphenyl-piperazinium iodide (DMPP) did not induce a postsynaptic current response in CA1 pyramidal cells. However, DMPP enhanced the frequency and amplitude of spontaneous excitatory postsynaptic current (sEPSC) in these cells in a dose-dependent manner. This enhancement was blocked by the selective nicotinic α-7 receptor antagonist α-bungarotoxin, but not by the antagonist mecamylamine, hexamethonium or dihyhro3-erythroidine. The frequency of miniature excitatory postsynaptic current (mEPSC) in CA1 pyramidal neurons was also increased by application of DMPP, indicating a presynaptic site of action of the agonist. Taken together, these results suggest that activation of presynaptic nAChRs in CA1 pyramidal neurons, which contain α-7 subunits, potentiates presynaptic glutamate release and consequently modulate excitatory synaptic transmission in the hippocampus.%采用盲法膜片钳技术观察突触前烟碱受体(nicotinic acetylcholine receptors,nAChRs)对海马脑片CA1区锥体神经元兴奋性突触传递的调控作用.结果显示,nAChRs激动剂碘化二甲基苯基哌嗪(dimethylphenyl-piperazinium iodide,DMPP)不能在CA1区锥体神经元上诱发出烟碱电流.DMPP对CA1区锥体神经元自发兴奋性突触后电流(spontaneous excitatory postsynaptic current,sEPSC)具有明显的增频和增幅作用,并呈现明显的浓度依赖关系.DMPP对微小兴奋性突触后电流(miniature excitatory postsynaptic current,mEPSC)具有增频作用,但不具有增幅作用.上述DMPP增强突触传递的作用不能被nAChRs拮抗剂美加明、六烃季铵和双氢-β-刺桐丁所阻断,但可被α-银环蛇毒素阻断.上述结果提示,海马脑片CA1

  13. Presynaptic inhibition by neuropeptide Y in rat hippocampal slice in vitro is mediated by a Y2 receptor.

    OpenAIRE

    Colmers, W. F.; Klapstein, G. J.; A. Fournier; St-Pierre, S.; Treherne, K. A.

    1991-01-01

    1. The action of analogues and C-terminal fragments of neuropeptide Y (NPY) was examined on excitatory synaptic transmission in area CA1 of the rat hippocampal slice in vitro, by use of intracellular and extracellular recordings, to determine by agonist profile the NPY receptor subtype mediating presynaptic inhibition. 2. Neither NPY, analogues nor fragments of NPY affected the passive or active properties of the post-synaptic CA1 pyramidal neurones, indicating their action is at a presynapti...

  14. Enlarged dendritic spines and pronounced neophobia in mice lacking the PSD protein RICH2

    OpenAIRE

    Sarowar, Tasnuva; Grabrucker, Stefanie; Föhr, Karl; Mangus, Katharina; Eckert, Matti; Bockmann, Juergen; Boeckers, Tobias M.; Andreas M. Grabrucker

    2016-01-01

    Background The majority of neurons within the central nervous system receive their excitatory inputs via small, actin-rich protrusions called dendritic spines. Spines can undergo rapid morphological alterations according to synaptic activity. This mechanism is implicated in learning and memory formation as it is ultimately altering the number and distribution of receptors and proteins at the post-synaptic membrane, thereby regulating synaptic input. The Rho-family GTPases play an important ro...

  15. Long Term Depression in the CA1 field is associated with a transient decrease in Pre-and Post-synaptic PKC substrate phosphorylation

    NARCIS (Netherlands)

    Gispen, W.H.; Ramakers, G.J.A.; Heinen, K.; Graan, P.N.E. de

    2000-01-01

    Induction of homosynaptic long term depression (LTD) in the CA1 field of the hippocampus is thought to require activation of N-methyl-D-aspartate receptors, an elevation of postsynaptic Ca2+ levels, and a subsequent increase in phosphatase activity. To investigate the spatial and temporal changes in

  16. Serotonin stimulates lateral habenula via activation of the post-synaptic serotonin 2/3 receptors and transient receptor potential channels.

    Science.gov (United States)

    Zuo, Wanhong; Zhang, Yong; Xie, Guiqin; Gregor, Danielle; Bekker, Alex; Ye, Jiang-Hong

    2016-02-01

    There is growing interest on the role of the lateral habenula (LHb) in depression, because it closely and bilaterally connects with the serotoninergic raphe nuclei. The LHb sends glutamate efferents to the raphe nuclei, while it receives serotoninergic afferents, and expresses a high density of serotonin (5-HT) receptors. Recent studies suggest that 5-HT receptors exist both in the presynaptic and postsynaptic sites of LHb neurons, and activation of these receptors may have different effects on the activity of LHb neurons. The current study focused on the effect of 5-HT on the postsynaptic membrane. We found that 5-HT initiated a depolarizing inward current (I((5-HTi))) and accelerated spontaneous firing in ∼80% of LHb neurons in rat brain slices. I((5-HTi)) was also induced by the 5-HT uptake blocker citalopram, indicating activity of endogenous 5-HT. I((5-HTi)) was diminished by 5-HT(2/3) receptor antagonists (ritanserin, SB-200646 or ondansetron), and activated by the selective 5-HT(2/3) agonists 1-(3-Chlorophenyl) piperazine hydrochloride or 1-(3-Chlorophenyl) biguanide hydrochloride. Furthermore, I((5-HTi)) was attenuated by 2-Aminoethyl diphenylborinate, a blocker of transient receptor potential channels, and an IP3 receptor inhibitor, indicating the involvement of transient receptor potential channels. These results demonstrate that the reciprocal connection between the LHb and the 5-HT system highlights a key role for 5-HT stimulation of LHb neurons that may be important in the pathogenesis of depression.

  17. Estrogen regulates excitatory amino acid carrier 1 (EAAC1) expression through sphingosine kinase 1 (SphK1) transacting FGFR-mediated ERK signaling in rat C6 astroglial cells.

    Science.gov (United States)

    Huang, C; Yuan, P; Wu, J; Huang, J

    2016-04-05

    Excitatory amino acid carrier 1 (EAAC1) is one important subtype of the excitatory amino acid transporters (EAATs), and its absence can increase the vulnerability to oxidative stress in neural tissue. Enhanced expression of EAAC1 can provide neuroprotection in multiple disorders, including ischemia and multiple sclerosis. However, the mechanism regulating EAAC1 expression is not fully understood. Using rat C6 astroglial cells, which specifically express EAAC1, we found that 17β-estradiol (E2) and (±)-1-[(3aR(∗),4S(∗),9bS(∗))-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone (G1), an agonist of the G-protein-coupled estrogen receptor (GPR30), strongly increased EAAC1 protein levels and protected cells from hydrogen peroxide (H2O2) toxicity. We further found that E2/G1 activated sphingosine kinase 1 (SphK1) via GPR30, resulting in the transcription of fibroblast growth factor 2 (FGF2), which stimulated its receptor (FGFR) and led to the phosphorylation of FGFR substrate 2α (FRS2α). This triggered downstream ERK1/2 signaling for the expression of EAAC1. Both the knockdown of FGF2 by siRNA and the pharmacological suppression of the FGFR-ERK cascade abolished the E2/G1 effect on EAAC1 expression. Overall, our work characterizes a signaling pathway by which E2 transactivates FGFR-ERK to induce EAAC1 expression in an FGF2-dependent manner. This occurs through SphK1 activation via GPR30 and leads to a resistance to H2O2 toxicity. This signal transduction pathway may provide novel insights into our understanding of the neuroprotective effects of E2 and may reveal new therapeutic targets or drugs for regulating the oxidative toxicity effects of various neurological diseases.

  18. Structure–Activity Relationship Study of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and Absolute Configurational Assignment Using Infrared and Vibrational

    DEFF Research Database (Denmark)

    Huynh, Tri H.V.; Shim, Irene; Bohr, Henrik

    2012-01-01

    The excitatory amino acid transporters (EAATs) play essential roles in regulating the synaptic concentration of the neurotransmitter glutamate in the mammalian central nervous system. To date, five subtypes have been identified, named EAAT1–5 in humans, and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5 i...

  19. Whole-Brain Monosynaptic Afferent Inputs to Basal Forebrain Cholinergic System

    Science.gov (United States)

    Hu, Rongfeng; Jin, Sen; He, Xiaobin; Xu, Fuqiang; Hu, Ji

    2016-01-01

    The basal forebrain cholinergic system (BFCS) robustly modulates many important behaviors, such as arousal, attention, learning and memory, through heavy projections to cortex and hippocampus. However, the presynaptic partners governing BFCS activity still remain poorly understood. Here, we utilized a recently developed rabies virus-based cell-type-specific retrograde tracing system to map the whole-brain afferent inputs of the BFCS. We found that the BFCS receives inputs from multiple cortical areas, such as orbital frontal cortex, motor cortex, and insular cortex, and that the BFCS also receives dense inputs from several subcortical nuclei related to motivation and stress, including lateral septum, central amygdala, paraventricular nucleus of hypothalamus, dorsal raphe, and parabrachial nucleus. Interestingly, we found that the BFCS receives inputs from the olfactory areas and the entorhinal–hippocampal system. These results greatly expand our knowledge about the connectivity of the mouse BFCS and provided important preliminary indications for future exploration of circuit function. PMID:27777554

  20. A mRNA molecule encoding truncated excitatory amino acid carrier 1 (EAAC1) protein (EAAC2) is transcribed from an independent promoter but not an alternative splicing event

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Glutamate transporter EAAC1 removes excitatory neurotransmitter in central nervous system, and alsoabsorbs glutamate in epithelia of intestine, kidney, liver and heart for normal cell growth. When a mousecDNA was screened using EAAC1 cDNA fragment as probe in our lab, a transcript (GenBank U75214)encoding an EAAC1 protein with 148 residues truncated at N-terminal was cloned and named as EAAC2.Sequence analysis shows that EAAC2 has it's own start code and unique 5'UTR that is different from that ofEAAC1. A mouse genomic library was screened and a positive clone including EAAC1 CDS was sequenced(GenBank AF 322393) and indicates that normal EAAC1 transcript (GenBank U73521) is transcribed from10 exons in terms of exon I, II, III, IV, V, VI, VII, VIII, IX, X, and EAAC2 transcript is consisted by exonsfrom IV to IX as same as that of EAAC1 and with its unique exonβ upstream to exon IV and exon δdownstream to IX. EAAC2 transcript has a cluster of transcriptional start sites not overlapping with thetranscriptional start sites of EAAC1. These results indicate that EAAC2 is transcribed from an independentpromoter but not an alternative splicing event.