WorldWideScience

Sample records for abnormal synaptic transmission

  1. Calcium channel blockade attenuates abnormal synaptic transmission in the dentate gyrus elicited by entorhinal amyloidopathy.

    Gholami Pourbadie, Hamid; Naderi, Nima; Janahmadi, Mahyar; Mehranfard, Nasrin; Motamedi, Fereshteh

    2016-10-01

    Entorhinal-hippocampal network is one of the earliest circuits which is affected by Alzheimer's disease (AD). There are numerous data providing the evidence of synaptic deficit in the dentate gyrus (DG) of AD animal model. However, there is little known about how entorhinal cortex (EC) amyloidophaty affects each excitatory and/or inhibitory transmission in the early stage of AD. On the other hand, it is believed that calcium dyshomeostasis has a critical role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on excitatory or inhibitory post synaptic currents (EPSC and IPSC, respectively) in the DG granule cells and then the possible neuroprotective action of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were examined. The amyloid beta (Aβ) 1-42 was injected bilaterally into the EC of male rats and one week later, synaptic currents in the DG granule cells were assessed by whole cell patch clamp. EPSCs were evoked by stimulating the perforant pathway. Voltage clamp recording showed profound decrease of evoked EPSC amplitude and paired pulse facilitation in the DG granule cells of Aβ treated rats. Furthermore, AMPA/NMDA ratio was significantly decreased in the Aβ treated animals. On the other hand, amplitude of IPSC currents was significantly increased in the DG granule cells of these animals. These modifications of synaptic currents were partially reversed by daily intracerebroventricular administration of isradipine or nimodipine. In conclusion, our results suggest that Aβ in the EC triggers decreased excitatory transmission in the DG with substantial decrement in AMPA currents, leading to a prominent activity of inhibitory circuits and increased inhibition of granule cells which may contribute to the development of AD-related neurological deficits in AD and treatment by CCBs could preserve normal synaptic transmission against Aβ toxicity. PMID:27240164

  2. Astrocytes Potentiate Synaptic Transmission

    Nadkarni, Suhita

    2005-03-01

    A recent experimental study shows that astrocytes, a subtype of glia, are able to influence the spontaneous activity in the brain via calcium dependent glutamate release. We model the coupling mechanism between an astrocyte and a neuron based on experimental data. This coupling is dynamic and bi-directional, such that the modulations in intracellular calcium concentrations in astrocytes affect neuronal excitability and vice versa via a glutamatergic pathway. We demonstrate through simple neural-glial circuits that increases in the intracellular calcium concentration in astrocytes nearby can enhance spontaneous activity in a neuron, a significant mechanism said to be involved in plasticity and learning. The pattern of this marked increase in spontaneous firing rate in our model quantitatively follows that observed in the experiment. Further, depending on the type of synaptic connections diverging from the neuron, it can either inhibit or excite the ensuing dynamics and potentiate synaptic transmission, thus reinstating the integral role played by astrocytes in normal neuronal dynamics.

  3. Lateral regulation of synaptic transmission by astrocytes.

    Covelo, A; Araque, A

    2016-05-26

    Fifteen years ago the concept of the "tripartite synapse" was proposed to conceptualize the functional view that astrocytes are integral elements of synapses. The signaling exchange between astrocytes and neurons within the tripartite synapse results in the synaptic regulation of synaptic transmission and plasticity through an autocrine form of communication. However, recent evidence indicates that the astrocyte synaptic regulation is not restricted to the active tripartite synapse but can be manifested through astrocyte signaling at synapses relatively distant from active synapses, a process termed lateral astrocyte synaptic regulation. This phenomenon resembles the classical heterosynaptic modulation but is mechanistically different because it involves astrocytes and its properties critically depend on the morphological and functional features of astrocytes. Therefore, the functional concept of the tripartite synapse as a fundamental unit must be expanded to include the interaction between tripartite synapses. Through lateral synaptic regulation, astrocytes serve as an active processing bridge for synaptic interaction and crosstalk between synapses with no direct neuronal connectivity, supporting the idea that neural network function results from the coordinated activity of astrocytes and neurons. PMID:25732135

  4. Modeling synaptic transmission of the tripartite synapse

    Nadkarni, Suhita; Jung, Peter

    2007-03-01

    The tripartite synapse denotes the junction of a pre- and postsynaptic neuron modulated by a synaptic astrocyte. Enhanced transmission probability and frequency of the postsynaptic current-events are among the significant effects of the astrocyte on the synapse as experimentally characterized by several groups. In this paper we provide a mathematical framework for the relevant synaptic interactions between neurons and astrocytes that can account quantitatively for both the astrocytic effects on the synaptic transmission and the spontaneous postsynaptic events. Inferred from experiments, the model assumes that glutamate released by the astrocytes in response to synaptic activity regulates store-operated calcium in the presynaptic terminal. This source of calcium is distinct from voltage-gated calcium influx and accounts for the long timescale of facilitation at the synapse seen in correlation with calcium activity in the astrocytes. Our model predicts the inter-event interval distribution of spontaneous current activity mediated by a synaptic astrocyte and provides an additional insight into a novel mechanism for plasticity in which a low fidelity synapse gets transformed into a high fidelity synapse via astrocytic coupling.

  5. Data-Driven Modeling of Synaptic Transmission and Integration

    Rothman, Jason S.; Silver, R. Angus

    2014-01-01

    In this chapter, we describe how to create mathematical models of synaptic transmission and integration. We start with a brief synopsis of the experimental evidence underlying our current understanding of synaptic transmission. We then describe synaptic transmission at a particular glutamatergic synapse in the mammalian cerebellum, the mossy fiber to granule cell synapse, since data from this well-characterized synapse can provide a benchmark comparison for how well synaptic properties are ca...

  6. Synaptic Transmission An Information-Theoretic Perspective

    Manwani, A

    1998-01-01

    Here we analyze synaptic transmission from an information-theoretic perspective. We derive closed-form expressions for the lower-bounds on the capacity of a simple model of a cortical synapse under two explicit coding paradigms. Under the ``signal estimation'' paradigm, we assume the signal to be encoded in the mean firing rate of a Poisson neuron. The performance of an optimal linear estimator of the signal then provides a lower bound on the capacity for signal estimation. Under the ``signal detection'' paradigm, the presence or absence of the signal has to be detected. Performance of the optimal spike detector allows us to compute a lower bound on the capacity for signal detection. We find that single synapses (for empirically measured parameter values) transmit information poorly but significant improvement can be achieved with a small amount of redundancy.

  7. Wnt signaling pathway improves central inhibitory synaptic transmission in a mouse model of Duchenne muscular dystrophy.

    Fuenzalida, Marco; Espinoza, Claudia; Pérez, Miguel Ángel; Tapia-Rojas, Cheril; Cuitino, Loreto; Brandan, Enrique; Inestrosa, Nibaldo C

    2016-02-01

    The dystrophin-associated glycoprotein complex (DGC) that connects the cytoskeleton, plasma membrane and the extracellular matrix has been related to the maintenance and stabilization of channels and synaptic receptors, which are both essential for synaptogenesis and synaptic transmission. The dystrophin-deficient (mdx) mouse model of Duchenne muscular dystrophy (DMD) exhibits a significant reduction in hippocampal GABA efficacy, which may underlie the altered synaptic function and abnormal hippocampal long-term plasticity exhibited by mdx mice. Emerging studies have implicated Wnt signaling in the modulation of synaptic efficacy, neuronal plasticity and cognitive function. We report here that the activation of the non-canonical Wnt-5a pathway and Andrographolide, improves hippocampal mdx GABAergic efficacy by increasing the number of inhibitory synapses and GABA(A) receptors or GABA release. These results indicate that Wnt signaling modulates GABA synaptic efficacy and could be a promising novel target for DMD cognitive therapy. PMID:26626079

  8. Synaptic unreliability facilitates information transmission in balanced cortical populations

    Gatys, Leon A.; Ecker, Alexander S.; Tchumatchenko, Tatjana; Bethge, Matthias

    2015-06-01

    Synaptic unreliability is one of the major sources of biophysical noise in the brain. In the context of neural information processing, it is a central question how neural systems can afford this unreliability. Here we examine how synaptic noise affects signal transmission in cortical circuits, where excitation and inhibition are thought to be tightly balanced. Surprisingly, we find that in this balanced state synaptic response variability actually facilitates information transmission, rather than impairing it. In particular, the transmission of fast-varying signals benefits from synaptic noise, as it instantaneously increases the amount of information shared between presynaptic signal and postsynaptic current. Furthermore we show that the beneficial effect of noise is based on a very general mechanism which contrary to stochastic resonance does not reach an optimum at a finite noise level.

  9. Defective glycinergic synaptic transmission in zebrafish motility mutants

    Hiromi Hirata

    2010-01-01

    Full Text Available Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR β subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch once’ mutants, including beo and sho, and report the identification of a new α2 subunit that revises the phylogeny of zebrafish GlyRs.

  10. Understanding complexities of synaptic transmission in medically intractable seizures: A paradigm of epilepsy research

    Jyotirmoy Banerjee

    2013-01-01

    Full Text Available Investigating the changes associated with the development of epileptic state in humans is complex and requires a multidisciplinary approach. Understanding the intricacies of medically intractable epilepsy still remains a challenge for neurosurgeons across the world. A significant number of patients who has undergone resective brain surgery for epilepsy still continue to have seizures. The reason behind this therapy resistance still eludes us. Thus to develop a cure for the difficult to treat epilepsy, we need to comprehensively study epileptogenesis. Although various animal models are developed but none of them replicate the pathological conditions in humans. So the ideal way to understand epileptogenecity is to examine the tissue resected for the treatment of intractable epilepsy. Advanced imaging and electrical localization procedures are utilized to establish the epileptogenic zone in epilepsy patients. Further molecular and cytological studies are required for the microscopic analysis of brain samples collected from the epileptogenic focus. As alterations in inhibitory as well as excitatory synaptic transmission are key features of epilepsy, understanding the regulation of neurotransmission in the resected surgery zone is of immense importance. Here we summarize various modalities of in vitro slice analysis from the resected brain specimen to understand the changes in GABAergic and glutamatergic synaptic transmission in epileptogenic zone. We also review evidence pertaining to the proposed role of nicotinic receptors in abnormal synaptic transmission which is one of the major causes of epileptiform activity. Elucidation of current concepts in regulation of synaptic transmission will help develop therapies for epilepsy cases that cannot me managed pharmacologically.

  11. MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity

    Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity. - Highlights: → I.p. MPTP-injection mediates death of dopaminergic neurons. → I.p. MPTP-injection depletes DA and DOPAC in striatum and hippocampus. → I.p. MPTP-injection does not alter basal synaptic transmission. → Reduction of LTP and enhancement of LTD after i.p. MPTP-injection. → Attenuation of NMDA-receptors mediated

  12. Recent advances in understanding synaptic abnormalities in Rett syndrome

    Michael Johnston; Blue, Mary E.; Sakkubai Naidu

    2015-01-01

    Rett syndrome is an extremely disabling X-linked nervous system disorder that mainly affects girls in early childhood and causes autism-like behavior, severe intellectual disability, seizures, sleep disturbances, autonomic instability, and other disorders due to mutations in the MeCP2 (methyl CpG-binding protein 2) transcription factor. The disorder targets synapses and synaptic plasticity and has been shown to disrupt the balance between glutamate excitatory synapses and GABAergic inhibitory...

  13. How do astrocytes shape synaptic transmission? Insights from electrophysiology

    Nathalie Rouach

    2013-10-01

    Full Text Available A major breakthrough in neuroscience has been the realization in the last decades that the dogmatic view of astroglial cells as being merely fostering and buffering elements of the nervous system is simplistic. A wealth of investigations now shows that astrocytes actually participate in the control of synaptic transmission in an active manner. This was first hinted by the intimate contacts glial processes make with neurons, particularly at the synaptic level, and evidenced using electrophysiological and calcium imaging techniques. Calcium imaging has provided critical evidence demonstrating that astrocytic regulation of synaptic efficacy is not a passive phenomenon. However, given that cellular activation is not only represented by calcium signaling, it is also crucial to assess concomitant mechanisms. We and others have used electrophysiological techniques to simultaneously record neuronal and astrocytic activity, thus enabling the study of multiple ionic currents and in depth investigation of neuro-glial dialogues. In the current review, we focus on the input such approach has provided in the understanding of astrocyte-neuron interactions underlying control of synaptic efficacy.

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

    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.

  15. Convergent evidence for abnormal striatal synaptic plasticity in dystonia

    Peterson, David A.; Sejnowski, Terrence J.; Poizner, Howard

    2009-01-01

    Dystonia is a functionally disabling movement disorder characterized by abnormal movements and postures. Although substantial recent progress has been made in identifying genetic factors, the pathophysiology of the disease remains a mystery. A provocative suggestion gaining broader acceptance is that some aspect of neural plasticity may be abnormal. There is also evidence that, at least in some forms of dystonia, sensorimotor “use” may be a contributing factor. Most empirical evidence of abno...

  16. Cellular and molecular mechanisms of chemical synaptic transmission.

    Millhorn, D E; Bayliss, D A; Erickson, J T; Gallman, E A; Szymeczek, C L; Czyzyk-Krzeska, M; Dean, J B

    1989-12-01

    During the last decade much progress has been made in understanding the cellular and molecular mechanisms by which nerve cells communicate with each other and nonneural (e.g., muscle) target tissue. This review is intended to provide the reader with an account of this work. We begin with an historical overview of research on cell-to-cell communication and then discuss recent developments that, in some instances, have led to dramatic changes in the concept of synaptic transmission. For instance, the finding that single neurons often contain multiple messengers (i.e., neurotransmitters) invalidated the long-held theory (i.e., Dale's Law) that individual neurons contain and release one and only one type of neurotransmitter. Moreover, the last decade witnessed the inclusion of an entire group of compounds, the neuropeptides, as messenger molecules. Enormous progress has also been made in elucidating postsynaptic receptor complexes and biochemical intermediaries involved in synaptic transmission. Here the development of recombinant DNA technology has made it possible to clone and determine the molecular structure for a number of receptors. This information has been used to gain insight into how these receptors function either as a ligand-gated channel or as a G protein-linked ligand recognition molecule. Perhaps the most progress made during this era was in understanding the molecular linkage of G protein-linked receptors to intramembranous and cytoplasmic macromolecules involved in signal amplification and transduction. We conclude with a brief discussion of how synaptic transmission leads to immediate alterations in the electrical activity and, in some cases, to a change in phenotype by altering gene expression. These alterations in cellular behavior are believed to be mediated by phosphoproteins, the final biochemical product of signal transduction. PMID:2575357

  17. Abnormal Changes of Synaptic Excitability in Migraine with Aura

    Siniatchkin, Michael; Sendacki, Mascha; Moeller, Friederike;

    2012-01-01

    Migraine patients are characterized by altered cortical excitability and information processing between attacks. The relationship between these abnormalities is still poorly understood. In this study, visual evoked potentials (VEP) and proton magnetic resonance spectroscopy were recorded simultan......Migraine patients are characterized by altered cortical excitability and information processing between attacks. The relationship between these abnormalities is still poorly understood. In this study, visual evoked potentials (VEP) and proton magnetic resonance spectroscopy were recorded....../Cr) than healthy subjects. In healthy subjects, excitatory (anodal) tDCS caused an increase and inhibitory (cathodal) tDCS a decrease in the Glx/Cr ratio. Subsequent photic stimulation (PS) reversed the changes in Glx/Cr ratios, which returned back to baseline, demonstrating homeostatic-like metaplasticity...

  18. Porcupine Controls Hippocampal AMPAR Levels, Composition, and Synaptic Transmission

    Nadine Erlenhardt

    2016-02-01

    Full Text Available AMPA receptor (AMPAR complexes contain auxiliary subunits that modulate receptor trafficking and gating. In addition to the transmembrane AMPAR regulatory proteins (TARPs and cornichons (CNIH-2/3, recent proteomic studies identified a diverse array of additional AMPAR-associated transmembrane and secreted partners. We systematically surveyed these and found that PORCN and ABHD6 increase GluA1 levels in transfected cells. Knockdown of PORCN in rat hippocampal neurons, which express it in high amounts, selectively reduces levels of all tested AMPAR complex components. Regulation of AMPARs is independent of PORCN’s membrane-associated O-acyl transferase activity. PORCN knockdown in hippocampal neurons decreases AMPAR currents and accelerates desensitization and leads to depletion of TARP γ-8 from AMPAR complexes. Conditional PORCN knockout mice also exhibit specific changes in AMPAR expression and gating that reduce basal synaptic transmission but leave long-term potentiation intact. These studies define additional roles for PORCN in controlling synaptic transmission by regulating the level and composition of hippocampal AMPAR complexes.

  19. Recent advances in understanding synaptic abnormalities in Rett syndrome [version 1; referees: 2 approved

    Michael Johnston

    2015-12-01

    Full Text Available Rett syndrome is an extremely disabling X-linked nervous system disorder that mainly affects girls in early childhood and causes autism-like behavior, severe intellectual disability, seizures, sleep disturbances, autonomic instability, and other disorders due to mutations in the MeCP2 (methyl CpG-binding protein 2 transcription factor. The disorder targets synapses and synaptic plasticity and has been shown to disrupt the balance between glutamate excitatory synapses and GABAergic inhibitory synapses. In fact, it can be argued that Rett syndrome is primarily a disorder of synaptic plasticity and that agents that can correct this imbalance may have beneficial effects on brain development. This review briefly summarizes the link between disrupted synaptic plasticity mechanisms and Rett syndrome and early clinical trials that aim to target these abnormalities to improve the outcome for these severely disabled children.

  20. Extracellular ATP Hydrolysis Inhibits Synaptic Transmission by Increasing pH Buffering in the Synaptic Cleft

    Vroman, Rozan; Klaassen, Lauw J.; Howlett, Marcus H C; Cenedese, Valentina; Klooster, Jan; Sjoerdsma, Trijntje; Kamermans, Maarten

    2014-01-01

    A slow mechanism of retinal synaptic inhibition involves hydrolysis of ATP released from pannexin 1 channels (from the tips of horizontal cell dendrites); the resulting protons and phosphates acidify the synaptic cleft, which inhibits neurotransmitter release.

  1. SNAP-29-mediated Modulation of Synaptic Transmission in Cultured Hippocampal Neurons*

    Pan, Ping-Yue; Cai, Qian; Lin, Lin; Lu, Pei-Hua; Duan, Shumin; Sheng, Zu-Hang

    2005-01-01

    Identifying the molecules that regulate both the recycling of synaptic vesicles and the SNARE components required for fusion is critical for elucidating the molecular mechanisms underlying synaptic plasticity. SNAP-29 was initially isolated as a syntaxin-binding and ubiquitously expressed protein. Previous studies have suggested that SNAP-29 inhibits SNARE complex disassembly, thereby reducing synaptic transmission in cultured superior cervical ganglion neurons in an activity-dependent manner...

  2. Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex

    Schärer, Yan-Ping Zhang; Shum, Jennifer; Moressis, Anastasios; Friedrich, Rainer W.

    2012-01-01

    Dopamine (DA) is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homolog of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell recordin...

  3. Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex

    Friedrich, Rainer W.

    2012-01-01

    Dopamine (DA) is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homologue of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell record...

  4. Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.

    Jaramillo, Thomas C; Speed, Haley E; Xuan, Zhong; Reimers, Jeremy M; Liu, Shunan; Powell, Craig M

    2016-03-01

    Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3(e4-9) KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3(e4-9) heterozygous (HET) and Shank3(e4-9) KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3(e4-9) KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3(e4-9) KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3(e4-9) HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3(e4-9) KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3(e4-9) mutant mouse model of autism. Autism Res 2016, 9: 350-375. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID:26559786

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

    Carlsen, Eva Maria Meier; Perrier, Jean-Francois Marie

    2014-01-01

    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...

  6. Salvia miltiorrhiza Bunge Blocks Ethanol-Induced Synaptic Dysfunction through Regulation of NMDA Receptor-Dependent Synaptic Transmission.

    Park, Hye Jin; Lee, Seungheon; Jung, Ji Wook; Lee, Young Choon; Choi, Seong-Min; Kim, Dong Hyun

    2016-07-01

    Consumption of high doses of ethanol can lead to amnesia, which often manifests as a blackout. These blackouts experienced by ethanol consumers may be a major cause of the social problems associated with excess ethanol consumption. However, there is currently no established treatment for preventing these ethanol-induced blackouts. In this study, we tested the ethanol extract of the roots of Salvia miltiorrhiza (SM) for its ability to mitigate ethanol-induced behavioral and synaptic deficits. To test behavioral deficits, an object recognition test was conducted in mouse. In this test, ethanol (1 g/kg, i.p.) impaired object recognition memory, but SM (200 mg/kg) prevented this impairment. To evaluate synaptic deficits, NMDA receptor-mediated excitatory postsynaptic potential (EPSP) and long-term potentiation (LTP) in the mouse hippocampal slices were tested, as they are known to be vulnerable to ethanol and are associated with ethanol-induced amnesia. SM (10 and 100 μg/ml) significantly ameliorated ethanol-induced long-term potentiation and NMDA receptor-mediated EPSP deficits in the hippocampal slices. Therefore, these results suggest that SM prevents ethanol-induced amnesia by protecting the hippocampus from NMDA receptor-mediated synaptic transmission and synaptic plasticity deficits induced by ethanol. PMID:27257009

  7. Archaerhodopsin Selectively and Reversibly Silences Synaptic Transmission through Altered pH.

    El-Gaby, Mohamady; Zhang, Yu; Wolf, Konstantin; Schwiening, Christof J; Paulsen, Ole; Shipton, Olivia A

    2016-08-23

    Tools that allow acute and selective silencing of synaptic transmission in vivo would be invaluable for understanding the synaptic basis of specific behaviors. Here, we show that presynaptic expression of the proton pump archaerhodopsin enables robust, selective, and reversible optogenetic synaptic silencing with rapid onset and offset. Two-photon fluorescence imaging revealed that this effect is accompanied by a transient increase in pH restricted to archaerhodopsin-expressing boutons. Crucially, clamping intracellular pH abolished synaptic silencing without affecting the archaerhodopsin-mediated hyperpolarizing current, indicating that changes in pH mediate the synaptic silencing effect. To verify the utility of this technique, we used trial-limited, archaerhodopsin-mediated silencing to uncover a requirement for CA3-CA1 synapses whose afferents originate from the left CA3, but not those from the right CA3, for performance on a long-term memory task. These results highlight optogenetic, pH-mediated silencing of synaptic transmission as a spatiotemporally selective approach to dissecting synaptic function in behaving animals. PMID:27524609

  8. Regulation of Synaptic Transmission and Plasticity by Neuronal Nicotinic Acetylcholine Receptors

    McKay, Bruce E.; Placzek, Andon N; Dani, John A.

    2007-01-01

    Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and participate in a variety of physiological functions. Recent advances have revealed roles of nAChRs in the regulation of synaptic transmission and synaptic plasticity, particularly in the hippocampus and midbrain dopamine centers. In general, activation of nAChRs causes membrane depolarization and directly and indirectly increases the intracellular calcium concentration. Thus, when nAChRs ...

  9. Differential regulation of synaptic transmission by pre- and postsynaptic SK channels in the spinal locomotor network.

    Nanou, Evanthia; Alpert, Michael H; Alford, Simon; El Manira, Abdeljabbar

    2013-06-01

    The generation of activity in the central nervous system requires precise tuning of cellular properties and synaptic transmission. Neural networks in the spinal cord produce coordinated locomotor movements. Synapses in these networks need to be equipped with multiple mechanisms that regulate their operation over varying regimes to produce locomotor activity at different frequencies. Using the in vitro lamprey spinal cord, we explored whether Ca(2+) influx via different routes in postsynaptic soma and dendrites and in presynaptic terminals can activate apamin-sensitive Ca(2+)-activated K(+) (SK) channels and thereby shape synaptic transmission. We show that postsynaptic SK channels are tightly coupled to Ca(2+) influx via NMDA receptors. Activation of these channels by synaptically induced NMDA-dependent Ca(2+) transients restrains the time course of the synaptic current and the amplitude of the synaptic potential. In addition, presynaptic SK channels are activated by Ca(2+) influx via voltage-gated channels and control the waveform of the action potential and the resulting Ca(2+) dynamics in the axon terminals. The coupling of SK channels to different Ca(2+) sources, pre- and postsynaptically, acts as a negative feedback mechanism to shape synaptic transmission. Thus SK channels can play a pivotal role in setting the dynamic range of synapses and enabling short-term plasticity in the spinal locomotor network. PMID:23554432

  10. Astrocytes gate synaptic transmission from unmyelinated sensory afferents

    Perrier, Jean-Francois Marie; Christensen, Rasmus Kordt; Delgado-Lezama, R.;

    2015-01-01

    Maternal immune activation (MIA) is known to affect neuronal precursor gene expression, proliferation and differentiation, and has been shown in mice to produce abnormal phenotypes resembling human neurodevelopmental disorders, particularly schizophrenia and autism. The relative contributions of ...

  11. Disruption of LGI1–linked synaptic complex causes abnormal synaptic transmission and epilepsy

    Fukata, Yuko; Lovero, Kathryn L.; Iwanaga, Tsuyoshi; Watanabe, Atsushi; Yokoi, Norihiko; Tabuchi, Katsuhiko; Shigemoto, Ryuichi; Nicoll, Roger A.; Fukata, Masaki

    2010-01-01

    Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1−/−) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, b...

  12. Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection.

    Buzhdygan, Tetyana; Lisinicchia, Joshua; Patel, Vipulkumar; Johnson, Kenneth; Neugebauer, Volker; Paessler, Slobodan; Jennings, Kristofer; Gelman, Benjamin

    2016-06-01

    The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients with effective suppression of virus replication by combination antiretroviral therapy (cART). Several neurotransmitter systems were reported to be abnormal in HIV-infected patients, including the inhibitory GABAergic system, which mediates fine-tuning of neuronal processing and plays an essential role in cognitive functioning. To elucidate the role of abnormal GABAergic transmission in HAND, the expression of GABAergic markers was measured in 449 human brain specimens from HIV-infected patients with and without HAND. Using real-time polymerase chain reaction, immunoblotting and immunohistochemistry we found that the GABAergic markers were significantly decreased in most sectors of cerebral neocortex, the neostriatum, and the cerebellum of HIV-infected subjects. Low GABAergic expression in frontal neocortex was correlated significantly with high expression of endothelial cell markers, dopamine receptor type 2 (DRD2L), and preproenkephalin (PENK) mRNAs, and with worse performance on tasks of verbal fluency. Significant associations were not found between low GABAergic mRNAs and HIV-1 RNA concentration in the brain, the history of cART, or HIV encephalitis. Pathological evidence of neurodegeneration of the affected GABAergic neurons was not present. We conclude that abnormally low expression of GABAergic markers is prevalent in HIV-1 infected patients. Interrelationships with other neurotransmitter systems including dopaminergic transmission and with endothelial cell markers lend added support to suggestions that synaptic plasticity and cerebrovascular anomalies are involved with HAND in virally suppressed patients. PMID:26829944

  13. [Histochemical findings of and fine structural changes in motor endplates in diseases with neuromuscular transmission abnormalities].

    Yoshimura, Toshiro; Motomura, Masakatsu; Tsujihata, Mitsuhiro

    2011-07-01

    We herein review the histochemical findings and fine structural changes of motor endplates associated with diseases causing neuromuscular transmission abnormalities. In anti-acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG), type 2 fiber atrophy is observed, and the motor endplates show a reduction in the nerve terminal area, simplification of the postsynaptic membrane, decreased number of acetylcholine receptors, and deposition of immune complexes. In anti-MuSK antibody-positive MG, the fine structure shows a decrease in the postsynaptic membrane length, but the secondary synaptic cleft is preserved. There is no decrease in the number of AChRs, and there are no deposits of immune complexes at the motor endplates. Patients with Lambert-Eaton myasthenic syndrome show type 2 fiber atrophy, their motor endplates show a decrease in both the mean postsynaptic area and postsynaptic membrane length in the brachial biceps muscle. Congenital myasthenic syndrome with episodic apnea is characterized only by small-sized synaptic vesicles; the postsynaptic area is preserved. In subjects with congenital myasthenic syndrome with acetylcholinesterase deficiency, quantitative electron microscopy reveals a significant decrease in the nerve terminal size and presynaptic membrane length; further, the Schwann cell processes extend into the primary synaptic cleft, and partially or completely occlude the presynaptic membrane. The postsynaptic folds are degenerated, and associated with pinocytotic vesicles and labyrinthine membranous networks. Patients with slow-channel congenital myasthenia syndrome show type 1 fiber predominance, and their junctional folds are typically degenerated with widened synaptic space and loss of AChRs. Patients with AChR deficiency syndrome caused by recessive mutations in AChR subunits also show type 1 fiber predominance, and while most junctional folds are normal, some are simplified and have smaller than normal endplates. Rapsin and Mu

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

    Jean-François Perrier

    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

  15. 3D ESTIMATION OF SYNAPTIC VESICLE DISTRIBUTIONS IN SERIAL SECTION TRANSMISSION ELECTRON MICROSCOPY

    Khanmohammadi, Mahdieh; Darkner, Sune; Nava, Nicoletta;

    directly. It is hypothesized that in a rat model of behavioral stress the vesicles distribution varies. We propose methods for estimating the 3-dimensional distribution of synaptic vesicles from the active zone through serial section transmission electron microscope images (ssTEM) from Sprague-Dawley rat...

  16. Nicotine uses neuron-glia communication to enhance hippocampal synaptic transmission and long-term memory.

    Mónica López-Hidalgo

    Full Text Available Nicotine enhances synaptic transmission and facilitates long-term memory. Now it is known that bi-directional glia-neuron interactions play important roles in the physiology of the brain. However, the involvement of glial cells in the effects of nicotine has not been considered until now. In particular, the gliotransmitter D-serine, an endogenous co-agonist of NMDA receptors, enables different types of synaptic plasticity and memory in the hippocampus. Here, we report that hippocampal long-term synaptic plasticity induced by nicotine was annulled by an enzyme that degrades endogenous D-serine, or by an NMDA receptor antagonist that acts at the D-serine binding site. Accordingly, both effects of nicotine: the enhancement of synaptic transmission and facilitation of long-term memory were eliminated by impairing glial cells with fluoroacetate, and were restored with exogenous D-serine. Together, these results show that glial D-serine is essential for the long-term effects of nicotine on synaptic plasticity and memory, and they highlight the roles of glial cells as key participants in brain functions.

  17. Enhanced Synaptic Transmission at the Squid Giant Synapse by Artificial Seawater Based on Physically Modified Saline

    Kerry D Walton

    2014-02-01

    Full Text Available Superfusion of the squid giant synapse with artificial seawater (ASW based on isotonic saline containing oxygen nanobubbles (RNS60 ASW generates an enhancement of synaptic transmission. This was determined by examining the postsynaptic response to single and repetitive presynaptic spike activation, spontaneous transmitter release, and presynaptic voltage clamp studies. In the presence of RNS60 ASW single presynaptic stimulation elicited larger postsynaptic potentials (PSP and more robust recovery from high frequency stimulation than in control ASW. Analysis of postsynaptic noise revealed an increase in spontaneous transmitter release with modified noise kinetics in RNS60 ASW. Presynaptic voltage clamp demonstrated an increased EPSP, without an increase in presynaptic ICa⁺⁺ amplitude during RNS60 ASW superfusion. Synaptic release enhancement reached stable maxima within 5 to 10 minutes of RNS60 ASW superfusion and was maintained for the entire recording time, up to one hour. Electronmicroscopic morphometry indicated a decrease in synaptic vesicle density and the number at active zones with an increase in the number of clathrin-coated vesicles and large endosome-like vesicles near junctional sites. Block of mitochondrial ATP synthesis by presynaptic injection of oligomycin reduced spontaneous release and prevented the synaptic noise increase seen in RNS60 ASW. After ATP block the number of vesicles at the active zone and clathrin-coated vesicles was reduced, with an increase in large vesicles. The possibility that RNS60 ASW acts by increasing mitochondrial ATP synthesis was tested by direct determination of ATP levels in both presynaptic and postsynaptic structures. This was implemented using luciferin/luciferase photon emission, which demonstrated a marked increase in ATP synthesis following RNS60 administration. It is concluded that RNS60 positively modulates synaptic transmission by up-regulating ATP synthesis, thus leading to synaptic

  18. Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex

    Rainer W. Friedrich

    2012-10-01

    Full Text Available Dopamine (DA is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homologue of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell recordings revealed no obvious effects of DA on membrane potential or input resistance in the majority of Dp neurons. Electrical stimulation of the olfactory tracts produced a complex sequence of synaptic currents in Dp neurons. DA selectively decreased inhibitory currents with little or no effect on excitatory components. Multiphoton calcium imaging showed that population responses of Dp neurons to olfactory tract stimulation or odor application were enhanced by DA, consistent with its effect on inhibitory synaptic transmission. These effects of DA were blocked by an antagonist of D2-like receptors. DA therefore disinhibits and reorganizes sensory responses in Dp. This modulation may affect sensory perception and could be involved in the experience-dependent modification of odor representations.

  19. From synaptically localized to volume transmission by nitric oxide.

    Garthwaite, John

    2016-01-01

    Nitric oxide (NO) functions widely as a transmitter/diffusible second messenger in the central nervous system, exerting physiological effects in target cells by binding to specialized guanylyl cyclase-coupled receptors, resulting in cGMP generation. Despite having many context-dependent physiological roles and being implicated in numerous disease states, there has been a lack of clarity about the ways that NO operates at the cellular and subcellular levels. Recently, several approaches have been used to try to gain a more concrete, quantitative understanding of this unique signalling pathway. These approaches have included analysing the kinetics of NO receptor function, real-time imaging of cellular NO signal transduction in target cells, and the use of ultrasensitive detector cells to record NO as it is being generated from native sources in brain tissue. The current picture is that, when formed in a synapse, NO is likely to act only very locally, probably mostly within the confines of that synapse, and to exist only in picomolar concentrations. Nevertheless, closely neighbouring synapses may also be within reach, raising the possibility of synaptic crosstalk. By engaging its enzyme-coupled receptors, the low NO concentrations are able to stimulate physiological (submicromolar) increases in cGMP concentration in an activity-dependent manner. When many NO-emitting neurones or synapses are active simultaneously in a tissue region, NO can act more like a volume transmitter to influence, and perhaps coordinate, the behaviour of cells within that region, irrespective of their identity and anatomical connectivity. PMID:26486504

  20. Morphological and Functional Abnormalities in Mitochondria Associated with Synaptic Degeneration in Prion Disease

    Sisková, Zuzana; Mahad, Don Joseph; Pudney, Carianne; Campbell, Graham; Cadogan, Mark; Asuni, Ayodeji; O'Connor, Vincent; Perry, Victor Hugh

    2010-01-01

    Synaptic and dendritic pathology is a well-documented component of prion disease. In common with other neurodegenerative diseases that contain an element of protein misfolding, little is known about the underlying mechanisms of synaptic degeneration. In particular, in prion disease the relationship between synaptic malfunction, degeneration, and mitochondria has been neglected. We investigated a wide range of mitochondrial parameters, including changes in mitochondrial density, inner membrane...

  1. In vivo synaptic transmission and morphology in mouse models of Tuberous sclerosis, Fragile X syndrome, Neurofibromatosis type 1 and Costello syndrome.

    Rob Willemsen

    2015-07-01

    Full Text Available Defects in the rat sarcoma viral oncogene homolog (Ras/extracellular-signal-regulated kinase (ERK and the phosphatidylinositol 3-kinase (PI3K-mammalian target of rapamycin (mTOR signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB of the auditory brainstem, in mouse models of Tuberous sclerosis (TSC, Fragile X syndrome (FXS, Neurofibromatosis type 1 (NF1 and Costello syndrome (CS. Calyces from both Tsc1+/- and from Fmr1 knock-out (KO mice showed increased volume and surface area compared to wild-type (WT controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1+/- mice the average delay between EPSPs and APs was slightly smaller compared to wild-type controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission.

  2. Effects of prostaglandin E2 on synaptic transmission in the rat spinal trigeminal subnucleus caudalis.

    Mizutani, Yuka; Ohi, Yoshiaki; Kimura, Satoko; Miyazawa, Ken; Goto, Shigemi; Haji, Akira

    2015-11-01

    The spinal trigeminal subnucleus caudalis (Vc) receives preferentially nociceptive afferent signals from the orofacial area. Nociceptive stimuli to the orofacial area induce cyclooxygenase both peripherally and centrally, which can synthesize a major prostanoid prostaglandin E2 (PGE2) that implicates in diverse physiological functions. To clarify the roles of centrally-synthesized PGE2 in nociception, effects of exogenous PGE2 on synaptic transmission in the Vc neurons were investigated in the rat brainstem slice. Spontaneously occurring excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) were recorded, respectively, under pharmacological blockade of inhibitory and excitatory transmission by whole-cell patch-clamp mode. Perfusion of PGE2 (1-5 μM) increased the frequency of sIPSCs in a concentration-dependent manner but had no significant effect on the amplitude. Similarly to the effects on sIPSCs, PGE2 increased the sEPSC frequency without any effect on the amplitude. These facilitatory effects of PGE2 on spontaneous synaptic transmissions were blocked by an EP1 antagonist SC19220 but not by an EP4 antagonist AH23848. Electrical stimulation of the trigeminal tract evoked short latency EPSCs (eEPSCs) in the Vc neurons. PGE2 (5 μM) was ineffective on the eEPSCs. The present study demonstrated that PGE2 facilitated spontaneous synaptic transmissions in the Vc neurons through activating the presynaptic EP1 receptors but had no effect on the trigeminal tract-mediated excitatory transmission. These results suggest that centrally-synthesized PGE2 modifies the synaptic transmission in the Vc region, thereby contributing to the processing of nociceptive signals originated from the orofacial area. PMID:26320551

  3. Kismet positively regulates glutamate receptor localization and synaptic transmission at the Drosophila neuromuscular junction.

    Rupa Ghosh

    Full Text Available The Drosophila neuromuscular junction (NMJ is a glutamatergic synapse that is structurally and functionally similar to mammalian glutamatergic synapses. These synapses can, as a result of changes in activity, alter the strength of their connections via processes that require chromatin remodeling and changes in gene expression. The chromodomain helicase DNA binding (CHD protein, Kismet (Kis, is expressed in both motor neuron nuclei and postsynaptic muscle nuclei of the Drosophila larvae. Here, we show that Kis is important for motor neuron synaptic morphology, the localization and clustering of postsynaptic glutamate receptors, larval motor behavior, and synaptic transmission. Our data suggest that Kis is part of the machinery that modulates the development and function of the NMJ. Kis is the homolog to human CHD7, which is mutated in CHARGE syndrome. Thus, our data suggest novel avenues of investigation for synaptic defects associated with CHARGE syndrome.

  4. Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures

    Koizumi, Schuichi; Fujishita, Kayoko; Tsuda, Makoto; Shigemoto-Mogami, Yukari; Inoue, Kazuhide

    2003-09-01

    Originally ascribed passive roles in the CNS, astrocytes are now known to have an active role in the regulation of synaptic transmission. Neuronal activity can evoke Ca2+ transients in astrocytes, and Ca2+ transients in astrocytes can evoke changes in neuronal activity. The excitatory neurotransmitter glutamate has been shown to mediate such bidirectional communication between astrocytes and neurons. We demonstrate here that ATP, a primary mediator of intercellular Ca2+ signaling among astrocytes, also mediates intercellular signaling between astrocytes and neurons in hippocampal cultures. Mechanical stimulation of astrocytes evoked Ca2+ waves mediated by the release of ATP and the activation of P2 receptors. Mechanically evoked Ca2+ waves led to decreased excitatory glutamatergic synaptic transmission in an ATP-dependent manner. Exogenous application of ATP does not affect postsynaptic glutamatergic responses but decreased presynaptic exocytotic events. Finally, we show that astrocytes exhibit spontaneous Ca2+ waves mediated by extracellular ATP and that inhibition of these Ca2+ responses enhanced excitatory glutamatergic transmission. We therefore conclude that ATP released from astrocytes exerts tonic and activity-dependent down-regulation of synaptic transmission via presynaptic mechanisms.

  5. GluN3A promotes NMDA spiking by enhancing synaptic transmission in Huntington's disease models.

    Mahfooz, Kashif; Marco, Sonia; Martínez-Turrillas, Rebeca; Raja, Mathan K; Pérez-Otaño, Isabel; Wesseling, John F

    2016-09-01

    Age-inappropriate expression of juvenile NMDA receptors (NMDARs) containing GluN3A subunits has been linked to synapse loss and death of spiny projection neurons of the striatum (SPNs) in Huntington's disease (HD). Here we show that suppressing GluN3A expression prevents a multivariate synaptic transmission phenotype that precedes morphological signs at early prodromal stages. We start by confirming that afferent fiber stimulation elicits larger synaptic responses mediated by both AMPA receptors and NMDARs in SPNs in the YAC128 mouse model of HD. We then show that the enhancement mediated by both is fully prevented by suppressing GluN3A expression. Strong fiber-stimulation unexpectedly elicited robust NMDAR-mediated electrogenic events (termed "upstates" or "NMDA spikes"), and the effective threshold for induction was more than 2-fold lower in YAC128 SPNs because of the enhanced synaptic transmission. The threshold could be restored to control levels by suppressing GluN3A expression or by applying the weak NMDAR blocker memantine. However, the threshold was not affected by preventing glutamate spillover from synaptic clefts. Instead, long-lasting NMDAR responses interpreted previously as activation of extrasynaptic receptors by spilled-over glutamate were caused by NMDA spikes occurring in voltage clamp mode as escape potentials. Together, the results implicate GluN3A reactivation in a broad spectrum of early-stage synaptic transmission deficits in YAC128 mice; question the current concept that NMDAR mislocalization is the pathological trigger in HD; and introduce NMDA spikes as a new candidate mechanism for coupling NMDARs to neurodegeneration. PMID:27072890

  6. Compartment-Specific Modulation of GABAergic Synaptic Transmission by TRPV1 Channels in the Dentate Gyrus

    Chávez, Andrés E.; Hernández, Vivian M.; Rodenas-Ruano, Alma; Chan, C. Savio; Castillo, Pablo E.

    2014-01-01

    The transient receptor potential TRPV1 or vanilloid receptor is a nonselective ligand-gated channel highly expressed in primary sensory neurons where it mediates nociception. TRPV1 is also expressed in the brain where its activation depresses excitatory synaptic transmission. Whether TRPV1 also regulates inhibitory synapses in the brain is unclear. Here, using a combination of pharmacology, electrophysiology, and an in vivo knockdown strategy, we report that TRPV1 activation by capsaicin or b...

  7. Energy demand of synaptic transmission at the hippocampal Schaffer-collateral synapse

    Liotta, Agustin; Rösner, Jörg; Huchzermeyer, Christine; Wojtowicz, Anna; Kann, Oliver; Schmitz, Dietmar; Heinemann, Uwe; Kovács, Richard

    2012-01-01

    Neuroenergetic models of synaptic transmission predicted that energy demand is highest for action potentials (APs) and postsynaptic ion fluxes, whereas the presynaptic contribution is rather small. Here, we addressed the question of energy consumption at Schaffer-collateral synapses. We monitored stimulus-induced changes in extracellular potassium, sodium, and calcium concentration while recording partial oxygen pressure (pO2) and NAD(P)H fluorescence. Blockade of postsynaptic receptors reduc...

  8. PGE2 DEPRESSES SOLITARY TRACT-MEDIATED SYNAPTIC TRANSMISSION IN THE NTS

    Laaris, Nora; Weinreich, Daniel

    2007-01-01

    Prostaglandin E2 (PGE2) is a prototypical inflammatory mediator that excites and sensitizes cell bodies (Kwong and Lee, 2002; 2005) and peripheral nerve terminals (Ho et al. 2000) of primary vagal sensory neurons. Nearly all central nerve terminals of vagal afferents are in the nucleus tractus solitarius (NTS), where they operate with a high probability of release (Doyle and Andresen, 2001). We studied the effect of PGE2 on synaptic transmission between tractus solitarius afferent nerve termi...

  9. Hemichannel composition and electrical synaptic transmission: molecular diversity and its implications for electrical rectification

    Palacios-Prado, Nicolás; Huetteroth, Wolf; Pereda, Alberto E.

    2014-01-01

    Unapposed hemichannels (HCs) formed by hexamers of gap junction proteins are now known to be involved in various cellular processes under both physiological and pathological conditions. On the other hand, less is known regarding how differences in the molecular composition of HCs impact electrical synaptic transmission between neurons when they form intercellular heterotypic gap junctions (GJs). Here we review data indicating that molecular differences between apposed HCs at electrical synaps...

  10. Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures

    Koizumi, Schuichi; Fujishita, Kayoko; Tsuda, Makoto; Shigemoto-Mogami, Yukari; Inoue, Kazuhide

    2003-01-01

    Originally ascribed passive roles in the CNS, astrocytes are now known to have an active role in the regulation of synaptic transmission. Neuronal activity can evoke Ca2+ transients in astrocytes, and Ca2+ transients in astrocytes can evoke changes in neuronal activity. The excitatory neurotransmitter glutamate has been shown to mediate such bidirectional communication between astrocytes and neurons. We demonstrate here that ATP, a primary mediator of intercellular Ca2+ signaling among astroc...

  11. Differential regulation of synaptic transmission by pre- and postsynaptic SK channels in the spinal locomotor network

    Nanou, Evanthia; Alpert, Michael H.; Alford, Simon; El Manira, Abdeljabbar

    2013-01-01

    The generation of activity in the central nervous system requires precise tuning of cellular properties and synaptic transmission. Neural networks in the spinal cord produce coordinated locomotor movements. Synapses in these networks need to be equipped with multiple mechanisms that regulate their operation over varying regimes to produce locomotor activity at different frequencies. Using the in vitro lamprey spinal cord, we explored whether Ca2+ influx via different routes in postsynaptic so...

  12. Adult Onset-hypothyroidism has Minimal Effects on Synaptic Transmission in the Hippocampus of Rats Independent of Hypothermia

    Introduction: Thyroid hormones (TH) influence central nervous system (CNS) function during development and in adulthood. The hippocampus, a brain area critical for learning and memory is sensitive to TH insufficiency. Synaptic transmission in the hippocampus is impaired following...

  13. First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression.

    Cummings, Damian M; Liu, Wenfei; Portelius, Erik; Bayram, Sevinç; Yasvoina, Marina; Ho, Sui-Hin; Smits, Hélène; Ali, Shabinah S; Steinberg, Rivka; Pegasiou, Chrysia-Maria; James, Owain T; Matarin, Mar; Richardson, Jill C; Zetterberg, Henrik; Blennow, Kaj; Hardy, John A; Salih, Dervis A; Edwards, Frances A

    2015-07-01

    Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-β. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloid-β peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloid-β peptides in a mouse model of increasing amyloid-β ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloid-β peptides were above the limit of detection, including amyloid-β40, amyloid-β38 and amyloid-β42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-β levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-β40 rose by ∼7-fold, but amyloid-β42 rose by 25-fold, increasing the amyloid-β42:amyloid-β40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P < 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P < 0.001, n = 7). Hence synaptic changes occur when the amyloid-β levels and amyloid-β42:amyloid-β40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly

  14. Novel nootropic dipeptide Noopept increases inhibitory synaptic transmission in CA1 pyramidal cells.

    Kondratenko, Rodion V; Derevyagin, Vladimir I; Skrebitsky, Vladimir G

    2010-05-31

    Effects of newly synthesized nootropic and anxiolytic dipeptide Noopept on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) significantly increased the frequency of spike-dependant spontaneous IPSCs whereas spike-independent mIPSCs remained unchanged. It was suggested that Noopept mediates its effect due to the activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion. PMID:20382202

  15. Forskolin Enhances Synaptic Transmission in Rat Dorsal Striatum through NMDA Receptors and PKA in Different Phases

    Cho, Hyeong Seok; Lee, Hyun Ho; Choi, Se Joon; Kim, Ki Jung; Jeun, Seung Hyun; Li, Qing-Zhong; Sung, Ki-Wug

    2008-01-01

    The effect of forskolin on corticostriatal synaptic transmission was examined by recording excitatory postsynaptic currents (EPSCs) in rat brain slices using the whole-cell voltage-clamp technique. Forskolin produced a dose-dependent increase of corticostriatal EPSCs (1, 3, 10, and 30 µM) immediately after its treatment, and the increase at 10 and 30 µM was maintained even after its washout. When the brain slices were pre-treated with (DL)-2-amino-5-phosphonovaleric acid (AP-V, 100 µM), an NM...

  16. Tuning synaptic transmission in the hippocampus by stress: The CRH system

    Yuncai eChen

    2012-04-01

    Full Text Available To enhance survival, an organism needs to remember--and learn from--threatening or stressful events. This fact necessitates the presence of mechanisms by which stress can influence synaptic transmission in brain regions, such as hippocampus, that subserve learning and memory. A major focus of this series of monographs is on the role and actions of adrenal-derived hormones, corticosteroids, and of brain-derived neurotransmitters, on synaptic function in the stressed hippocampus. Here we focus on the contribution of hippocampus-intrinsic, stress-activated CRH-CRH receptor signaling to the function and structure of hippocampal synapses. CRH is expressed in interneurons of adult hippocampus, and is released from axon terminals during stress. The peptide exerts time- and dose-dependent effects on learning and memory via modulation of synaptic function and plasticity. Whereas physiological levels of CRH, acting over seconds to minutes, augment memory processes, exposure to presumed severe-stress levels of the peptide results in spine retraction and loss of synapses over more protracted time-frames. Loss of dendritic spines (and hence of synapses takes place through actin cytoskeleton collapse downstream of CRHR1 receptors that reside within excitatory synapses on spine heads. Chronic exposure to stress levels of CRH may promote dying-back (atrophy of spine-carrying dendrites. Thus, the acute effects of CRH may contribute to stress-induced adaptive mechanisms, whereas chronic or excessive exposure to the peptide may promote learning problems and premature cognitive decline.

  17. Synaptic abnormalities in a Drosophila model of Alzheimer’s disease

    Siddhita D. Mhatre

    2014-03-01

    Full Text Available Alzheimer’s disease (AD is an age-related neurodegenerative disease characterized by memory loss and decreased synaptic function. Advances in transgenic animal models of AD have facilitated our understanding of this disorder, and have aided in the development, speed and efficiency of testing potential therapeutics. Recently, we have described the characterization of a novel model of AD in the fruit fly, Drosophila melanogaster, where we expressed the human AD-associated proteins APP and BACE in the central nervous system of the fly. Here we describe synaptic defects in the larval neuromuscular junction (NMJ in this model. Our results indicate that expression of human APP and BACE at the larval NMJ leads to defective larval locomotion behavior, decreased presynaptic connections, altered mitochondrial localization in presynaptic motor neurons and decreased postsynaptic protein levels. Treating larvae expressing APP and BACE with the γ-secretase inhibitor L-685,458 suppresses the behavioral defects as well as the pre- and postsynaptic defects. We suggest that this model will be useful to assess and model the synaptic dysfunction normally associated with AD, and will also serve as a powerful in vivo tool for rapid testing of potential therapeutics for AD.

  18. Cationic influences upon synaptic transmission at the hair cell-afferent fiber synapse of the frog

    Cochran, S. L.

    1995-01-01

    The concentrations of inorganic cations (K+, Na+, and Ca2+) bathing the isolated frog labyrinth were varied in order to assess their role in influencing and mediating synaptic transmission at the hair cell-afferent fiber synapse. Experiments employed intracellular recordings of synaptic activity from VIIIth nerve afferents. Recordings were digitized continuously at 50 kHz, and excitatory postsynaptic potentials were detected and parameters quantified by computer algorithms. Particular attention was focused on cationic effects upon excitatory postsynaptic potential frequency of occurrence and excitatory postsynaptic potential amplitude, in order to discriminate between pre- and postsynaptic actions. Because the small size of afferents preclude long term stable recordings, alterations in cationic concentrations were applied transiently and their peak effects on synaptic activity were assessed. Increases in extracellular K+ concentration of a few millimolar produced a large increase in the frequency of occurrence of excitatory postsynaptic potentials with little change in amplitude, indicating that release of transmitter from the hair cell is tightly coupled to its membrane potential. Increasing extracellular Na+ concentration resulted in an increase in excitatory postsynaptic potential amplitude with no significant change in excitatory postsynaptic potential frequency of occurrence, suggesting that the transmitter-gated subsynaptic channel conducts Na+ ions. Decreases in extracellular Ca2+ concentration had little effect upon excitatory postsynaptic potential frequency, but increased excitatory postsynaptic potential frequency and amplitude. These findings suggest that at higher concentrations Ca2+ act presynaptically to prevent transmitter release and postsynaptically to prevent Na+ influx during the generation of the excitatory postsynaptic potential. The influences of these ions on synaptic activity at this synapse are remarkably similar to those reported at the

  19. Phospholipase A2 activation enhances inhibitory synaptic transmission in rat substantia gelatinosa neurons.

    Liu, Tao; Fujita, Tsugumi; Nakatsuka, Terumasa; Kumamoto, Eiichi

    2008-03-01

    Phospholipase A(2) (PLA(2)) activation enhances glutamatergic excitatory synaptic transmission in substantia gelatinosa (SG) neurons, which play a pivotal role in regulating nociceptive transmission in the spinal cord. By using melittin as a tool to activate PLA(2), we examined the effect of PLA(2) activation on spontaneous inhibitory postsynaptic currents (sIPSCs) recorded at 0 mV in SG neurons of adult rat spinal cord slices by use of the whole cell patch-clamp technique. Melittin enhanced the frequency and amplitude of GABAergic and glycinergic sIPSCs. The enhancement of GABAergic but not glycinergic transmission was largely depressed by Na(+) channel blocker tetrodotoxin or glutamate-receptor antagonists (6-cyano-7-nitroquinoxaline-2,3-dione and/or dl-2-amino-5-phosphonovaleric acid) and also in a Ca(2+)-free Krebs solution. The effects of melittin on glycinergic sIPSC frequency and amplitude were dose-dependent with an effective concentration of approximately 0.7 microM for half-maximal effect and were depressed by PLA(2) inhibitor 4-bromophenacyl bromide or aristolochic acid. The melittin-induced enhancement of glycinergic transmission was depressed by lipoxygenase inhibitor nordihydroguaiaretic acid but not cyclooxygenase inhibitor indomethacin. These results indicate that the activation of PLA(2) in the SG enhances GABAergic and glycinergic inhibitory transmission in SG neurons. The former action is mediated by glutamate-receptor activation and neuronal activity increase, possibly the facilitatory effect of PLA(2) activation on excitatory transmission, whereas the latter action is due to PLA(2) and subsequent lipoxygenase activation and is independent of extracellular Ca(2+). It is suggested that PLA(2) activation in the SG could enhance not only excitatory but also inhibitory transmission, resulting in the modulation of nociception. PMID:18216222

  20. Mitochondria-Targeted Antioxidant SS31 Prevents Amyloid Beta-Induced Mitochondrial Abnormalities and Synaptic Degeneration in Alzheimer's Disease.

    Calkins, Marcus J; Manczak, Maria; Reddy, P Hemachandra

    2012-01-01

    In neuronal systems, the health and activity of mitochondria and synapses are tightly coupled. For this reason, it has been postulated that mitochondrial abnormalities may, at least in part, drive neurodegeneration in conditions such as Alzheimer's disease (AD). Mounting evidence from multiple Alzheimer's disease cell and mouse models and postmortem brains suggest that loss of mitochondrial integrity may be a key factor that mediates synaptic loss. Therefore, the prevention or rescue of mitochondrial dysfunction may help delay or altogether prevent AD-associated neurodegeneration. Since mitochondrial health is heavily dependent on antioxidant defenses, researchers have begun to explore the use of mitochondria-targeted antioxidants as therapeutic tools to prevent neurodegenerative diseases. This review will highlight advances made using a model mitochondria-targeted antioxidant peptide, SS31, as a potential treatment for AD. PMID:23226091

  1. M-type potassium channels modulate Schaffer collateral-CA1 glutamatergic synaptic transmission.

    Sun, Jianli; Kapur, Jaideep

    2012-08-15

    Previous studies have suggested that muscarinic receptor activation modulates glutamatergic transmission. M-type potassium channels mediate the effects of muscarinic activation in the hippocampus, and it has been proposed that they modulate glutamatergic synaptic transmission. We tested whether M1 muscarinic receptor activation enhances glutamatergic synaptic transmission via the inhibition of the M-type potassium channels that are present in Schaffer collateral axons and terminals. Miniature excitatory postsynaptic currents (mEPSCs) were recorded from CA1 pyramidal neurons. The M1 receptor agonist, NcN-A-343, increased the frequency of mEPSCs, but did not alter their amplitude. The M-channel blocker XE991 and its analogue linopirdine also increased the frequency of mEPSCs. Flupirtine, which opens M-channels, had the opposite effect. XE991 did not enhance mEPSCs frequency in a calcium-free external medium. Blocking P/Q- and N-type calcium channels abolished the effect of XE991 on mEPSCs. These data suggested that the inhibition of M-channels increases presynaptic calcium-dependent glutamate release in CA1 pyramidal neurons. The effects of these agents on the membrane potentials of presynaptic CA3 pyramidal neurons were studied using current clamp recordings; activation of M1 receptors and blocking M-channels depolarized neurons and increased burst firing. The input resistance of CA3 neurons was increased by the application of McN-A-343 and XE991; these effects were consistent with the closure of M-channels. Muscarinic activation inhibits M-channels in CA3 pyramidal neurons and its efferents – Schaffer collateral, which causes the depolarization, activates voltage-gated calcium channels, and ultimately elevates the intracellular calcium concentration to increase the release of glutamate on CA1 pyramidal neurons. PMID:22674722

  2. Altered neuronal intrinsic properties and reduced synaptic transmission of the rat's medial geniculate body in salicylate-induced tinnitus.

    Yan-Yan Su

    Full Text Available Sodium salicylate (NaSal, an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB, an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS paradigm. NaSal (1.4 mM decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.

  3. A Computational Model to Investigate Astrocytic Glutamate Uptake Influence on Synaptic Transmission and Neuronal Spiking

    Sushmita Lakshmi Allam

    2012-10-01

    Full Text Available Over the past decades, our view of astrocytes has switched from passive support cells to active processing elements in the brain. The current view is that astrocytes shape neuronal communication and also play an important role in many neurodegenerative diseases. Despite the growing awareness of the importance of astrocytes, the exact mechanisms underlying neuron-astrocyte communication and the physiological consequences of astrocytic-neuronal interactions remain largely unclear. In this work, we define a modeling framework that will permit to address unanswered questions regarding the role of astrocytes. Our computational model of a detailed glutamatergic synapse facilitates the analysis of neural system responses to various stimuli and conditions that are otherwise difficult to obtain experimentally, in particular the readouts at the sub-cellular level. In this paper, we extend a detailed glutamatergic synaptic model, to include astrocytic glutamate transporters. We demonstrate how these glial transporters, responsible for the majority of glutamate uptake, modulate synaptic transmission mediated by ionotropic AMPA and NMDA receptors at glutamatergic synapses. Furthermore, we investigate how these local signaling effects at the synaptic level are translated into varying spatio-temporal patterns of neuron firing. Paired pulse stimulation results reveal that the effect of astrocytic glutamate uptake is more apparent when the input inter-spike interval is sufficiently long to allow the receptors to recover from desensitization. These results suggest an important functional role of astrocytes in spike timing dependent processes and demand further investigation of the molecular basis of certain neurological diseases specifically related to alterations in astrocytic glutamate uptake, such as epilepsy.

  4. Melatonin receptor activation increases glutamatergic synaptic transmission in the rat medial lateral habenula.

    Evely, Katherine M; Hudson, Randall L; Dubocovich, Margarita L; Haj-Dahmane, Samir

    2016-05-01

    Melatonin (MLT) is secreted from the pineal gland and mediates its physiological effects through activation of two G protein-coupled receptors, MT1 and MT2 . These receptors are expressed in several brain areas, including the habenular complex, a pair of nuclei that relay information from forebrain to midbrain and modulate a plethora of behaviors, including sleep, mood, and pain. However, so far, the precise mechanisms by which MLT control the function of habenula neurons remain unknown. Using whole cell recordings from male rat brain slices, we examined the effects of MLT on the excitability of medial lateral habenula (MLHb) neurons. We found that MLT had no significant effects on the intrinsic excitability of MLHb neurons, but profoundly increased the amplitude of glutamate-mediated evoked excitatory post-synaptic currents (EPSC). The increase in strength of glutamate synapses onto MLHb neurons was mediated by an increase in glutamate release. The MLT-induced increase in glutamatergic synaptic transmission was blocked by the competitive MT1 /MT2 receptor antagonist luzindole (LUZ). These results unravel a potential cellular mechanism by which MLT receptor activation enhances the excitability of MLHb neurons. The MLT-mediated control of glutamatergic inputs to the MLHb may play a key role in the modulation of various behaviors controlled by the habenular complex. PMID:26799638

  5. Regulation and restoration of motoneuronal synaptic transmission during neuromuscular regeneration in the pulmonate snail Helisoma trivolvis.

    Turner, M B; Szabo-Maas, T M; Poyer, J C; Zoran, M J

    2011-08-01

    Regeneration of motor systems involves reestablishment of central control networks, reinnervation of muscle targets by motoneurons, and reconnection of neuromodulatory circuits. Still, how these processes are integrated as motor function is restored during regeneration remains ill defined. Here, we examined the mechanisms underlying motoneuronal regeneration of neuromuscular synapses related to feeding movements in the pulmonate snail Helisoma trivolvis. Neurons B19 and B110, although activated during different phases of the feeding pattern, innervate similar sets of muscles. However, the percentage of muscle fibers innervated, the efficacy of excitatory junction potentials, and the strength of muscle contractions were different for each cell's specific connections. After peripheral nerve crush, a sequence of transient electrical and chemical connections formed centrally within the buccal ganglia. Neuromuscular synapse regeneration involved a three-phase process: the emergence of spontaneous synaptic transmission (P1), the acquisition of evoked potentials of weak efficacy (P2), and the establishment of functional reinnervation (P3). Differential synaptic efficacy at muscle contacts was recapitulated in cell culture. Differences in motoneuronal presynaptic properties (i.e., quantal content) were the basis of disparate neuromuscular synapse function, suggesting a role for retrograde target influences. We propose a homeostatic model of molluscan motor system regeneration. This model has three restoration events: (1) transient central synaptogenesis during axonal outgrowth, (2) intermotoneuronal inhibitory synaptogenesis during initial neuromuscular synapse formation, and (3) target-dependent regulation of neuromuscular junction formation. PMID:21876114

  6. A transducible nuclear/nucleolar protein, mLLP, regulates neuronal morphogenesis and synaptic transmission

    Yu, Nam-Kyung; Kim, Hyoung F.; Shim, Jaehoon; Kim, Somi; Kim, Dae Won; Kwak, Chuljung; Sim, Su-Eon; Choi, Jun-Hyeok; Ahn, Seohee; Yoo, Juyoun; Choi, Sun-Lim; Jang, Deok-Jin; Lim, Chae-Seok; Lee, Yong-Seok; Kang, Chulhun; Choi, Soo Young; Kaang, Bong-Kiun

    2016-01-01

    Cell-permeable proteins are emerging as unconventional regulators of signal transduction and providing a potential for therapeutic applications. However, only a few of them are identified and studied in detail. We identify a novel cell-permeable protein, mouse LLP homolog (mLLP), and uncover its roles in regulating neural development. We found that mLLP is strongly expressed in developing nervous system and that mLLP knockdown or overexpression during maturation of cultured neurons affected the neuronal growth and synaptic transmission. Interestingly, extracellular addition of mLLP protein enhanced dendritic arborization, demonstrating the non-cell-autonomous effect of mLLP. Moreover, mLLP interacts with CCCTC-binding factor (CTCF) as well as transcriptional machineries and modulates gene expression involved in neuronal growth. Together, these results illustrate the characteristics and roles of previously unknown cell-permeable protein mLLP in modulating neural development. PMID:26961175

  7. High-frequency electroacupuncture evidently reinforces hippocampal synaptic transmission in Alzheimer's disease rats

    Li, Wei; Kong, Li-hong; Wang, Hui; Shen, Feng; Wang, Ya-wen; Zhou, Hua; Sun, Guo-jie

    2016-01-01

    The frequency range of electroacupuncture in treatment of Alzheimer's disease in rats is commonly 2–5 Hz (low frequency) and 50–100 Hz (high frequency). We established a rat model of Alzheimer's disease by injecting β-amyloid 1–42 (Aβ1–42) into the bilateral hippocampal dentate gyrus to verify which frequency may be better suited in treatment. Electroacupuncture at 2 Hz or 50 Hz was used to stimulate Baihui (DU20) and Shenshu (BL23) acupoints. The water maze test and electrophysiological studies demonstrated that spatial memory ability was apparently improved, and the ranges of long-term potentiation and long-term depression were increased in Alzheimer's disease rats after electroacupuncture treatment. Moreover, the effects of electroacupuncture at 50 Hz were better than that at 2 Hz. These findings suggest that high-frequency electroacupuncture may enhance hippocampal synaptic transmission and potentially improve memory disorders in Alzheimer's disease rats. PMID:27335565

  8. Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission

    Accardi, Michael V.; Daniels, Bryan A.; Brown, Patricia M. G. E.; Fritschy, Jean-Marc; Tyagarajan, Shiva K.; Bowie, Derek

    2014-01-01

    Neuronal communication imposes a heavy metabolic burden in maintaining ionic gradients essential for action potential firing and synaptic signalling. Although cellular metabolism is known to regulate excitatory neurotransmission, it is still unclear whether the brain’s energy supply affects inhibitory signalling. Here we show that mitochondrial-derived reactive oxygen species (mROS) regulate the strength of postsynaptic GABAA receptors at inhibitory synapses of cerebellar stellate cells. Inhibition is strengthened through a mechanism that selectively recruits α3-containing GABAA receptors into synapses with no discernible effect on resident α1-containing receptors. Since mROS promotes the emergence of postsynaptic events with unique kinetic properties, we conclude that newly recruited α3-containing GABAA receptors are activated by neurotransmitter released onto discrete postsynaptic sites. Although traditionally associated with oxidative stress in neurodegenerative disease, our data identify mROS as a putative homeostatic signalling molecule coupling cellular metabolism to the strength of inhibitory transmission.

  9. Salvia miltiorrhiza Bunge Blocks Ethanol-Induced Synaptic Dysfunction through Regulation of NMDA Receptor-Dependent Synaptic Transmission

    Park, Hye Jin; Lee, Seungheon; Jung, Ji Wook; Lee, Young Choon; Choi, Seong-Min; Kim, Dong hyun

    2016-01-01

    Consumption of high doses of ethanol can lead to amnesia, which often manifests as a blackout. These blackouts experienced by ethanol consumers may be a major cause of the social problems associated with excess ethanol consumption. However, there is currently no established treatment for preventing these ethanol-induced blackouts. In this study, we tested the ethanol extract of the roots of Salvia miltiorrhiza (SM) for its ability to mitigate ethanol-induced behavioral and synaptic deficits. ...

  10. DAMGO depresses inhibitory synaptic transmission via different downstream pathways of μ opioid receptors in ventral tegmental area and periaqueductal gray.

    Zhang, W; Yang, H L; Song, J J; Chen, M; Dong, Y; Lai, B; Yu, Y G; Ma, L; Zheng, P

    2015-08-20

    Opioid-induced rewarding and motorstimulant effects are mediated by an increased activity of the ventral tegmental area (VTA) dopamine (DA) neurons. The excitatory mechanism of opioids on VTA-DA neurons has been proposed to be due to the depression of GABAergic synaptic transmission in VTA-DA neurons. However, how opioids depress GABAergic synaptic transmission in VTA-DA neurons remain to be studied. In the present study, we explored the mechanism of the inhibitory effect of [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) on GABAergic synaptic transmission in VTA-DA neurons using multiple approaches and techniques. Our results showed that (1) DAMGO inhibits GABAergic inputs in VTA-DA neurons at presynaptic sites; (2) effect of DAMGO on GABAergic inputs in VTA-DA neurons is inhibited by potassium channel blocker 4-aminopyridine (4-AP) and Gi protein inhibitor N-ethylmaleimide (NEM); (3) phospholipase A2 (PLA2) does not mediate the effect of DAMGO on GABAergic inputs in VTA-DA neurons, but mediates it in the periaqueductal gray (PAG); (4) multiple downstream signaling molecules of μ receptors do not mediate the effect of DAMGO on GABAergic inputs in VTA-DA neurons. These results suggest that DAMGO depresses inhibitory synaptic transmission via μ receptor-Gi protein-Kv channel pathway in VTA-DA neurons, but via μ receptor-PLA2 pathway in PAG neurons. PMID:26047721

  11. Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome.

    Kashima, Risa; Roy, Sougata; Ascano, Manuel; Martinez-Cerdeno, Veronica; Ariza-Torres, Jeanelle; Kim, Sunghwan; Louie, Justin; Lu, Yao; Leyton, Patricio; Bloch, Kenneth D; Kornberg, Thomas B; Hagerman, Paul J; Hagerman, Randi; Lagna, Giorgio; Hata, Akiko

    2016-01-01

    Epigenetic silencing of fragile X mental retardation 1 (FMR1) causes fragile X syndrome (FXS), a common inherited form of intellectual disability and autism. FXS correlates with abnormal synapse and dendritic spine development, but the molecular link between the absence of the FMR1 product FMRP, an RNA binding protein, and the neuropathology is unclear. We found that the messenger RNA encoding bone morphogenetic protein type II receptor (BMPR2) is a target of FMRP. Depletion of FMRP increased BMPR2 abundance, especially that of the full-length isoform that bound and activated LIM domain kinase 1 (LIMK1), a component of the noncanonical BMP signal transduction pathway that stimulates actin reorganization to promote neurite outgrowth and synapse formation. Heterozygosity for BMPR2 rescued the morphological abnormalities in neurons both in Drosophila and in mouse models of FXS, as did the postnatal pharmacological inhibition of LIMK1 activity. Compared with postmortem prefrontal cortex tissue from healthy subjects, the amount of full-length BMPR2 and of a marker of LIMK1 activity was increased in this brain region from FXS patients. These findings suggest that increased BMPR2 signal transduction is linked to FXS and that the BMPR2-LIMK1 pathway is a putative therapeutic target in patients with FXS and possibly other forms of autism. PMID:27273096

  12. Syncrip/hnRNP Q influences synaptic transmission and regulates BMP signaling at the Drosophila neuromuscular synapse

    James M. Halstead

    2014-08-01

    Full Text Available Synaptic plasticity involves the modulation of synaptic connections in response to neuronal activity via multiple pathways. One mechanism modulates synaptic transmission by retrograde signals from the post-synapse that influence the probability of vesicle release in the pre-synapse. Despite its importance, very few factors required for the expression of retrograde signals, and proper synaptic transmission, have been identified. Here, we identify the conserved RNA binding protein Syncrip as a new factor that modulates the efficiency of vesicle release from the motoneuron and is required for correct synapse structure. We show that syncrip is required genetically and its protein product is detected only in the muscle and not in the motoneuron itself. This unexpected non-autonomy is at least partly explained by the fact that Syncrip modulates retrograde BMP signals from the muscle back to the motoneuron. We show that Syncrip influences the levels of the Bone Morphogenic Protein ligand Glass Bottom Boat from the post-synapse and regulates the pre-synapse. Our results highlight the RNA-binding protein Syncrip as a novel regulator of synaptic output. Given its known role in regulating translation, we propose that Syncrip is important for maintaining a balance between the strength of presynaptic vesicle release and postsynaptic translation.

  13. Stochastic resonance in the synaptic transmission between hair cells and vestibular primary afferents in development.

    Flores, A; Manilla, S; Huidobro, N; De la Torre-Valdovinos, B; Kristeva, R; Mendez-Balbuena, I; Galindo, F; Treviño, M; Manjarrez, E

    2016-05-13

    The stochastic resonance (SR) is a phenomenon of nonlinear systems in which the addition of an intermediate level of noise improves the response of such system. Although SR has been studied in isolated hair cells and in the bullfrog sacculus, the occurrence of this phenomenon in the vestibular system in development is unknown. The purpose of the present study was to explore for the existence of SR via natural mechanical-stimulation in the hair cell-vestibular primary afferent transmission. In vitro experiments were performed on the posterior semicircular canal of the chicken inner ear during development. Our experiments showed that the signal-to-noise ratio of the afferent multiunit activity from E15 to P5 stages of development exhibited the SR phenomenon, which was characterized by an inverted U-like response as a function of the input noise level. The inverted U-like graphs of SR acquired their higher amplitude after the post-hatching stage of development. Blockage of the synaptic transmission with selective antagonists of the NMDA and AMPA/Kainate receptors abolished the SR of the afferent multiunit activity. Furthermore, computer simulations on a model of the hair cell - primary afferent synapse qualitatively reproduced this SR behavior and provided a possible explanation of how and where the SR could occur. These results demonstrate that a particular level of mechanical noise on the semicircular canals can improve the performance of the vestibular system in their peripheral sensory processing even during embryonic stages of development. PMID:26926966

  14. Potentiation of synaptic transmission in Rat anterior cingulate cortex by chronic itch.

    Zhang, Ting-Ting; Shen, Feng-Yan; Ma, Li-Qing; Wen, Wen; Wang, Bin; Peng, Yuan-Zhi; Wang, Zhi-Ru; Zhao, Xuan

    2016-01-01

    Itch and pain share similar mechanisms. It has been well documented that the anterior cingulate cortex (ACC) is important for pain-related perception. ACC has also been approved to be a potential pruritus-associated brain region. However, the mechanism of sensitization in pruriceptive neurons in the ACC is not clear. In current study, a chronic itch model was established by diphenylcyclopropenone (DCP) application. We found that both the frequency and amplitude of miniature excitatory postsynaptic currents in the ACC were enhanced after the formation of chronic itch. The paired-pulse ratio in ACC neurons recorded from the DCP group were smaller than those recorded in control group at the 50-ms interval. We also observe a significant increase in the AMPA/NMDA ratio in the DCP group. Moreover, an increased inward rectification of AMPARs in ACC pyramidal neurons was observed in the DCP group. Interestingly, the calculated ratio of silent synapses was significantly reduced in the DCP group compared with controls. Taken together, we conclude that a potentiation of synaptic transmission in the ACC can be induced by chronic itch, and unsilencing silent synapses, which probably involved recruitment of AMPARS, contributed to the potentiation of postsynaptic transmission. PMID:27472923

  15. Synaptic transmission changes in fear memory circuits underlie key features of an animal model of schizophrenia.

    Pollard, Marie; Varin, Christophe; Hrupka, Brian; Pemberton, Darrel J; Steckler, Thomas; Shaban, Hamdy

    2012-02-01

    Non-competitive antagonists of the N-methyl-d-aspartate receptor (NMDA) such as phencyclidine (PCP) elicit schizophrenia-like symptoms in healthy individuals. Similarly, PCP dosing in rats produces typical behavioral phenotypes that mimic human schizophrenia symptoms. Although schizophrenic behavioral phenotypes of the PCP model have been extensively studied, the underlying alterations of intrinsic neuronal properties and synaptic transmission in relevant limbic brain microcircuits remain elusive. Acute brain slice electrophysiology and immunostaining of inhibitory neurons were used to identify neuronal circuit alterations of the amygdala and hippocampus associated with changes in extinction of fear learning in rats following PCP treatment. Subchronic PCP application led to impaired long-term potentiation (LTP) and marked increases in the ratio of NMDA to 2-amino-3(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor-mediated currents at lateral amygdala (LA) principal neurons without alterations in parvalbumin (PV) as well as non-PV, glutamic acid decarboxylase 67 (GAD 67) immunopositive neurons. In addition, LTP was impaired at the Schaffer collateral to CA1 hippocampal pathway coincident with a reduction in colocalized PV and GAD67 immunopositive neurons in the CA3 hippocampal area. These effects occurred without changes in spontaneous events or intrinsic membrane properties of principal cells in the LA. The impairment of LTP at both amygdalar and hippocampal microcircuits, which play a key role in processing relevant survival information such as fear and extinction memory concurred with a disruption of extinction learning of fear conditioned responses. Our results show that subchronic PCP administration in rats impairs synaptic functioning in the amygdala and hippocampus as well as processing of fear-related memories. PMID:22085880

  16. Effect of electroacupuncture on synaptic transmission in dentate gyrus of the hippocampus in cerebral ischemic injured rats

    Haibo Yu; Zhuoxin Yang; Ling Wang; Min Pi; Jiawei Zhang

    2006-01-01

    BACKGROUND: Some studies suggest that the long-term potentiation (LTP) of synaptic transmission may be the basis for the neural synaptic plasticity of hippocampus, but can be evoked by various factors including electroacupuncture.OBJECTIVE: To observe the effect of electroacupuncture on the activities of basic synaptic transmission in dentate gyrus of hippocampus and the changes of high frequency stimulation (HFS) induced activity of synaptic transmission in cerebral ischemic injured rats.DESIGN: A randomized control trial.SETTING: Shenzhen Hospital of Traditional Chinese Medicine affiliated to Guangzhou University of Traditional Chinese Medicine.MATERIALS: Sixty healthy male Wistar rats, weighing 150-250 g, were provided by the Experimental Animal Center of Guangzhou University of Traditional Chinese Medicine. The experiment began after adaptation of environment for 1 week under standard experimental environment. The main experimental instruments included the programming electrical acupuncture apparatus (PCEA, product of the Institute of Acupuncture and Meridians, Anhui College of Traditional Chinese Medicine) and multichannel physiologic recorder (RM-86, Nihon Konden).METHODS: The experiment was carried out in Guangzhou University of Traditional Chinese Medicine between July 2003 and July 2004. ① Embedding of brain electrodes: In reference of the Pellegrino's rat brain atlas, the bipolar electrode stimulator was embedded into the perforant path (PP) anterior to the entorhinal area with location coordinates of AP 7.5 mm, L 4.2 mm and H 3.0 mm, that is, 7.5 mm posterior to the anterior fontanelle, 4.2 mm laterally on the right side and 3.0 mm under the subcortex. The subcortex recorder electrode coordinates are AP 3.8 mm, L 2.5 mm and H 3.5 mm, located in the granular cell layer of the unilateral dentate gyrus (DG) of hippocampus, at the site of which an opening with the diameter of 1.5 mm was drilled for the purpose of embedding of the stimulating and recording

  17. Alteration of AMPA Receptor-Mediated Synaptic Transmission by Alexa Fluor 488 and 594 in Cerebellar Stellate Cells.

    Maroteaux, Matthieu; Liu, Siqiong June

    2016-01-01

    The fluorescent dyes, Alexa Fluor 488 and 594 are commonly used to visualize dendritic structures and the localization of synapses, both of which are critical for the spatial and temporal integration of synaptic inputs. However, the effect of the dyes on synaptic transmission is not known. Here we investigated whether Alexa Fluor dyes alter the properties of synaptic currents mediated by two subtypes of AMPA receptors (AMPARs) at cerebellar stellate cell synapses. In naive mice, GluA2-lacking AMPAR-mediated synaptic currents displayed an inwardly rectifying current-voltage (I-V) relationship due to blockade by cytoplasmic spermine at depolarized potentials. We found that the inclusion of 100 µm Alexa Fluor dye, but not 10 µm, in the pipette solution led to a gradual increase in the amplitude of EPSCs at +40 mV and a change in the I-V relationship from inwardly rectifying to more linear. In mice exposed to an acute stress, AMPARs switched to GluA2-containing receptors, and 100 µm Alexa Fluor 594 did not alter the I-V relationship of synaptic currents. Therefore, a high concentration of Alexa Fluor dye changed the I-V relationship of EPSCs at GluA2-lacking AMPAR synapses. PMID:27280156

  18. Alteration of AMPA Receptor-Mediated Synaptic Transmission by Alexa Fluor 488 and 594 in Cerebellar Stellate Cells1 2 3

    Maroteaux, Matthieu; Liu, Siqiong June

    2016-01-01

    Abstract The fluorescent dyes, Alexa Fluor 488 and 594 are commonly used to visualize dendritic structures and the localization of synapses, both of which are critical for the spatial and temporal integration of synaptic inputs. However, the effect of the dyes on synaptic transmission is not known. Here we investigated whether Alexa Fluor dyes alter the properties of synaptic currents mediated by two subtypes of AMPA receptors (AMPARs) at cerebellar stellate cell synapses. In naive mice, GluA...

  19. Structural elements that underlie Doc2β function during asynchronous synaptic transmission.

    Xue, Renhao; Gaffaney, Jon D; Chapman, Edwin R

    2015-08-01

    Double C2-like domain-containing proteins alpha and beta (Doc2α and Doc2β) are tandem C2-domain proteins proposed to function as Ca(2+) sensors for asynchronous neurotransmitter release. Here, we systematically analyze each of the negatively charged residues that mediate binding of Ca(2+) to the β isoform. The Ca(2+) ligands in the C2A domain were dispensable for Ca(2+)-dependent translocation to the plasma membrane, with one exception: neutralization of D220 resulted in constitutive translocation. In contrast, three of the five Ca(2+) ligands in the C2B domain are required for translocation. Importantly, translocation was correlated with the ability of the mutants to enhance asynchronous release when overexpressed in neurons. Finally, replacement of specific Ca(2+)/lipid-binding loops of synaptotagmin 1, a Ca(2+) sensor for synchronous release, with corresponding loops from Doc2β, resulted in chimeras that yielded slower kinetics in vitro and slower excitatory postsynaptic current decays in neurons. Together, these data reveal the key determinants of Doc2β that underlie its function during the slow phase of synaptic transmission. PMID:26195798

  20. Xyloside primed glycosaminoglycans alter hair bundle micromechanical coupling and synaptic transmission: Pharmacokinetics

    Holman, Holly A.; Tran, Vy M.; Nguyen, Lynn Y.; Arungundram, Sailaja; Kalita, Mausam; Kuberan, Balagurunathan; Rabbitt, Richard D.

    2015-12-01

    Glycosaminoglycans (GAGs) are ubiquitous in the inner ear, and disorders altering their structure or production often result in debilitating hearing and balance deficits. The specific mechanisms responsible for loss of hair-cell function are not well understood. We recently reported that introduction of a novel BODIPY conjugated xyloside (BX) into the endolymph primes fluorescent GAGs in vivo [6, 15]. Confocal and two-photon fluorescence imaging revealed rapid turnover and assembly of a glycocalyx enveloping the kinocilia and extending into the cupula, a structure that presumably serves as a mechanical link between the hair bundle and the cupula. Extracellular fluorescence was also observed around the basolateral surface of hair cells and surrounding afferent nerve projections into the crista. Single unit afferent recordings during mechanical hair bundle stimulation revealed temporary interruption of synaptic transmission following BX administration followed by recovery, demonstrating an essential role for GAGs in function of the hair cell synapse. In the present work we present a pharmacokinetic model to quantify the time course of BX primed GAG production and turnover in the ear.

  1. Xyloside primed glycosaminoglycans alter hair bundle micromechanical coupling and synaptic transmission: Pharmacokinetics

    Holman, Holly A.; Nguyen, Lynn Y. [Bioengineering, University of Utah, Salt Lake City, Utah (United States); Tran, Vy M.; Arungundram, Sailaja; Kalita, Mausam [Medicinal Chemistry, University of Utah, Salt Lake City, Utah (United States); Kuberan, Balagurunathan [Medicinal Chemistry, University of Utah, Salt Lake City, Utah (United States); Neuroscience Program, University of Utah, Salt Lake City, Utah (United States); Rabbitt, Richard D. [Bioengineering, University of Utah, Salt Lake City, Utah (United States); Neuroscience Program, University of Utah, Salt Lake City, Utah (United States); Otolaryngology, University of Utah, Salt Lake City, Utah (United States); Marine Biological Laboratory, Woods Hole, Massachusetts (United States)

    2015-12-31

    Glycosaminoglycans (GAGs) are ubiquitous in the inner ear, and disorders altering their structure or production often result in debilitating hearing and balance deficits. The specific mechanisms responsible for loss of hair-cell function are not well understood. We recently reported that introduction of a novel BODIPY conjugated xyloside (BX) into the endolymph primes fluorescent GAGs in vivo [6, 15]. Confocal and two-photon fluorescence imaging revealed rapid turnover and assembly of a glycocalyx enveloping the kinocilia and extending into the cupula, a structure that presumably serves as a mechanical link between the hair bundle and the cupula. Extracellular fluorescence was also observed around the basolateral surface of hair cells and surrounding afferent nerve projections into the crista. Single unit afferent recordings during mechanical hair bundle stimulation revealed temporary interruption of synaptic transmission following BX administration followed by recovery, demonstrating an essential role for GAGs in function of the hair cell synapse. In the present work we present a pharmacokinetic model to quantify the time course of BX primed GAG production and turnover in the ear.

  2. Forskolin Enhances Synaptic Transmission in Rat Dorsal Striatum through NMDA Receptors and PKA in Different Phases.

    Cho, Hyeong Seok; Lee, Hyun Ho; Choi, Se Joon; Kim, Ki Jung; Jeun, Seung Hyun; Li, Qing-Zhong; Sung, Ki-Wug

    2008-12-01

    The effect of forskolin on corticostriatal synaptic transmission was examined by recording excitatory postsynaptic currents (EPSCs) in rat brain slices using the whole-cell voltage-clamp technique. Forskolin produced a dose-dependent increase of corticostriatal EPSCs (1, 3, 10, and 30 microM) immediately after its treatment, and the increase at 10 and 30 microM was maintained even after its washout. When the brain slices were pre-treated with (DL)-2-amino-5-phosphonovaleric acid (AP-V, 100 microM), an NMDA receptor antagonist, the acute effect of forskolin (10 microM) was blocked. However, after washout of forskolin, an increase of corticostriatal EPSCs was still observed even in the presence of AP-V. When KT 5720 (5 microM), a protein kinase A (PKA) inhibitor, was applied through the patch pipette, forskolin (10 microM) increased corticostriatal EPSCs, but this increase was not maintained. When forskolin was applied together with AP-V and KT 5720, both the increase and maintenance of the corticostriatal EPSCs were blocked. These results suggest that forskolin activates both NMDA receptors and PKA, however, in a different manner. PMID:19967070

  3. Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission

    Frigerio, Francesca; Karaca, Melis; De Roo, Mathias;

    2012-01-01

    was questioned here by generation of CNS-specific GDH-null mice (CnsGlud1(-/-)); which were viable, fertile and without apparent behavioral problems. GDH immunoreactivity as well as enzymatic activity were absent in Cns-Glud1(-/-) brains. Immunohistochemical analyses on brain sections revealed that...... the pyramidal cells of control animals were positive for GDH, whereas the labeling was absent in hippocampal sections of Cns-Glud1(-/-) mice. Electrophysiological recordings showed that deletion of GDH within the CNS did not alter synaptic transmission in standard conditions. Cns-Glud1(-/-) mice...... glutamine transporters and of glutamine synthetase. Present data show that the lack of GDH in the CNS modifies the metabolic handling of glutamate without altering synaptic transmission....

  4. Pre-synaptic histamine H₃ receptors modulate glutamatergic transmission in rat globus pallidus.

    Osorio-Espinoza, A; Alatorre, A; Ramos-Jiménez, J; Garduño-Torres, B; García-Ramírez, M; Querejeta, E; Arias-Montaño, J-A

    2011-03-10

    The globus pallidus, a neuronal nucleus involved in the control of motor behavior, expresses high levels of histamine H(3) receptors (H(3)Rs) most likely located on the synaptic afferents to the nucleus. In this work we studied the effect of the activation of rat pallidal H(3)Rs on depolarization-evoked neurotransmitter release from slices, neuronal firing rate in vivo and turning behavior. Perfusion of globus pallidus slices with the selective H(3)R agonist immepip had no effect on the release of [(3)H]-GABA ([(3)H]-γ-aminobutyric acid) or [(3)H]-dopamine evoked by depolarization with high (20 mM) K(+), but significantly reduced [(3)H]-d-aspartate release (-44.8 ± 2.6% and -63.7 ± 6.2% at 30 and 100 nM, respectively). The effect of 30 nM immepip was blocked by 10 μM of the selective H(3)R antagonist A-331440 (4'-[3-[(3(R)-dimethylamino-1-pyrrolidinyl]propoxy]-[1,1-biphenyl]-4'-carbonitrile). Intra-pallidal injection of immepip (0.1 μl, 100 μM) decreased spontaneous neuronal firing rate in anaesthetized rats (peak inhibition 68.8±10.3%), and this effect was reversed in a partial and transitory manner by A-331440 (0.1 μl, 1 mM). In free-moving rats the infusion of immepip (0.5 μl; 10, 50 and 100 μM) into the globus pallidus induced dose-related ipsilateral turning following systemic apomorphine (0.5 mg/kg, s.c.). Turning behavior induced by immepip (0.5 μl, 50 μM) and apomorphine was partially prevented by the local injection of A-331440 (0.5 μl, 1 mM) and was not additive to the turning evoked by the intra-pallidal injection of antagonists at ionotropic glutamate receptors (0.5 μl, 1 mM each of AP-5, dl-2-amino-5-phosphonovaleric acid, and CNQX, 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione). These results indicate that pre-synaptic H(3)Rs modulate glutamatergic transmission in rat globus pallidus and thus participate in the control of movement by basal ganglia. PMID:21195747

  5. Mitochondria-Targeted Antioxidant SS31 Prevents Amyloid Beta-Induced Mitochondrial Abnormalities and Synaptic Degeneration in Alzheimer’s Disease

    Calkins, Marcus J.; P. Hemachandra Reddy; Maria Manczak

    2012-01-01

    In neuronal systems, the health and activity of mitochondria and synapses are tightly coupled. For this reason, it has been postulated that mitochondrial abnormalities may, at least in part, drive neurodegeneration in conditions such as Alzheimer’s disease (AD). Mounting evidence from multiple Alzheimer’s disease cell and mouse models and postmortem brains suggest that loss of mitochondrial integrity may be a key factor that mediates synaptic loss. Therefore, the preventio...

  6. The Role of cGMP on Adenosine A1 Receptor-mediated Inhibition of Synaptic Transmission at the Hippocampus

    Pinto, Isa; Serpa, André; Sebastião, Ana M.; Cascalheira, José F.

    2016-01-01

    Both adenosine A1 receptor and cGMP inhibit synaptic transmission at the hippocampus and recently it was found that A1 receptor increased cGMP levels in hippocampus, but the role of cGMP on A1 receptor-mediated inhibition of synaptic transmission remains to be established. In the present work we investigated if blocking the NOS/sGC/cGMP/PKG pathway using nitric oxide synthase (NOS), protein kinase G (PKG), and soluble guanylyl cyclase (sGC) inhibitors modify the A1 receptor effect on synaptic transmission. Neurotransmission was evaluated by measuring the slope of field excitatory postsynaptic potentials (fEPSPs) evoked by electrical stimulation at hippocampal slices. N6-cyclopentyladenosine (CPA, 15 nM), a selective A1 receptor agonist, reversibly decreased the fEPSPs by 54 ± 5%. Incubation of the slices with an inhibitor of NOS (L-NAME, 200 μM) decreased the CPA effect on fEPSPs by 57 ± 9% in female rats. In males, ODQ (10 μM), an sGC inhibitor, decreased the CPA inhibitory effect on fEPSPs by 23 ± 6%, but only when adenosine deaminase (ADA,1 U/ml) was present; similar results were found in females, where ODQ decreased CPA-induced inhibition of fEPSP slope by 23 ± 7%. In male rats, the presence of the PKG inhibitor (KT5823, 1 nM) decreased the CPA effect by 45.0 ± 9%; similar results were obtained in females, where KT5823 caused a 32 ± 9% decrease on the CPA effect. In conclusion, the results suggest that the inhibitory action of adenosine A1 receptors on synaptic transmission at hippocampus is, in part, mediated by the NOS/sGC/cGMP/PKG pathway.

  7. The neurotoxin 1-methyl-4-phenylpyridinium (MPP+ alters hippocampal excitatory synaptic transmission by modulation of the GABAergic system

    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

  8. Plasticity of GABA transporters: an unconventional route to shape inhibitory synaptic transmission

    Annalisa eScimemi

    2014-01-01

    The brain relies on GABAergic neurons to control the ongoing activity of neuronal networks. GABAergic neurons control the firing pattern of excitatory cells, the temporal structure of membrane potential oscillations and the time window for integration of synaptic inputs. These actions require a fine control of the timing of GABA receptor activation which, in turn, depends on the precise timing of GABA release from pre-synaptic terminals and GABA clearance from the extracellular space. Extrace...

  9. Acetyl-l-carnitine restores synaptic transmission and enhances the inducibility of stable LTP after oxygen-glucose deprivation.

    Kocsis, Kitti; Frank, Rita; Szabó, József; Knapp, Levente; Kis, Zsolt; Farkas, Tamás; Vécsei, László; Toldi, József

    2016-09-22

    Hypoxic circumstances result in functional and structural impairments of the brain. Oxygen-glucose deprivation (OGD) on hippocampal slices is a technique widely used to investigate the consequences of ischemic stroke and the potential neuroprotective effects of different drugs. Acetyl-l-carnitine (ALC) is a naturally occurring substance in the body, and it can therefore be administered safely even in relatively high doses. In previous experiments, ALC pretreatment proved to be effective against global hypoperfusion. In the present study, we investigated whether ALC can be protective in an OGD model. We are not aware of any earlier study in which the long-term potentiation (LTP) function on hippocampal slices was measured after OGD. Therefore, we set out to determine whether an effective ALC concentration has an effect on synaptic plasticity after OGD in the hippocampal CA1 subfield of rats. A further aim was to investigate the mechanism underlying the protective effect of this compound. The experiments revealed that ALC is neuroprotective against OGD in a dose-dependent manner, which is manifested not only in the regeneration of the impaired synaptic transmission after the OGD, but also in the inducibility and stability of the LTP. In the case of the most effective concentration of ALC (500μM), use of a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) revealed that the PI3K/Akt signaling pathway has a key role in the restoration of the synaptic transmission and plasticity reached by ALC treatment. PMID:27378558

  10. [The role of synaptic transmission in memory and neurodegeneration processes and effects of neurotropic preparations].

    Voronina, T A

    2003-01-01

    Academician Zakusov, in his book Pharmacology of Central Synapses (Moscow, 1973), emphasized the central role of synaptic processes in regulation of various forms of behavior, memory, and psychotropic drug action. The paper considers most promising directions in the search for substances possessing nootropic and neuroprotector properties, many of which were developed at the Institute of Pharmacology based on the notion about synaptic processes. These investigations led to the creation of well-known drugs such as mexidole, noopept, nooglutyl, beglimin, etc. Special attention is devoted to the implementation and modern development of the ideas of Academician Zakusov. Recent data are presented on the role of neuropeptides, neurotrophins, and intracellular signaling mechanisms in synaptic plasticity, memory processes, and development of neurodegenerative states. PMID:12962041

  11. Endocannabinoids blunt the augmentation of synaptic transmission by serotonin 2A receptors in the nucleus tractus solitarii (nTS)

    Austgen, James R.; Kline, David D.

    2013-01-01

    Serotonin (5-Hydroxytryptamine, 5-HT) and the 5-HT2 receptor modulate cardiovascular and autonomic function in part through actions in the nTS, the primary termination and integration point for cardiorespiratory afferents in the brainstem. In other brain regions, 5-HT2 receptors (5-HT2R) modify synaptic transmission directly, as well as through 5-HT2AR-induced endocannabinoid release. This study examined the role of 5-HT2AR as well as their interaction with endocannabinoids on neurotransmissi...

  12. From Synaptic Transmission to Cognition: An Intermediary Role for Dendritic Spines

    Gonzalez-Burgos, Ignacio

    2012-01-01

    Dendritic spines are cytoplasmic protrusions that develop directly or indirectly from the filopodia of neurons. Dendritic spines mediate excitatory neurotransmission and they can isolate the electrical activity generated by synaptic impulses, enabling them to translate excitatory afferent information via several types of plastic changes, including…

  13. Electrical coupling and excitatory synaptic transmission between rhythmogenic respiratory neurons in the preBötzinger complex

    Rekling, J C; Shao, X M; Feldman, J L

    2000-01-01

    Breathing pattern is postulated to be generated by brainstem neurons. However, determination of the underlying cellular mechanisms, and in particular the synaptic interactions between respiratory neurons, has been difficult. Here we used dual recordings from two distinct populations of brainstem...... respiratory neurons, hypoglossal (XII) motoneurons, and rhythmogenic (type-1) neurons in the preBötzinger complex (preBötC), the hypothesized site for respiratory rhythm generation, to determine whether electrical and chemical transmission is present. Using an in vitro brainstem slice preparation from newborn...... recordings also demonstrated unidirectional excitatory chemical transmission (EPSPs of approximately 3 mV) between type-1 neurons. These data indicate that respiratory motor output from the brainstem involves gap junction-mediated current transfer between motoneurons. Furthermore, bidirectional electrical...

  14. Selective optical control of synaptic transmission in the subcortical visual pathway by activation of viral vector-expressed halorhodopsin.

    Katsuyuki Kaneda

    Full Text Available The superficial layer of the superior colliculus (sSC receives visual inputs via two different pathways: from the retina and the primary visual cortex. However, the functional significance of each input for the operation of the sSC circuit remains to be identified. As a first step toward understanding the functional role of each of these inputs, we developed an optogenetic method to specifically suppress the synaptic transmission in the retino-tectal pathway. We introduced enhanced halorhodopsin (eNpHR, a yellow light-sensitive, membrane-targeting chloride pump, into mouse retinal ganglion cells (RGCs by intravitreously injecting an adeno-associated virus serotype-2 vector carrying the CMV-eNpHR-EYFP construct. Several weeks after the injection, whole-cell recordings made from sSC neurons in slice preparations revealed that yellow laser illumination of the eNpHR-expressing retino-tectal axons, putatively synapsing onto the recorded cells, effectively inhibited EPSCs evoked by electrical stimulation of the optic nerve layer. We also showed that sSC spike activities elicited by visual stimulation were significantly reduced by laser illumination of the sSC in anesthetized mice. These results indicate that photo-activation of eNpHR expressed in RGC axons enables selective blockade of retino-tectal synaptic transmission. The method established here can most likely be applied to a variety of brain regions for studying the function of individual inputs to these regions.

  15. The F-box protein MEC-15 (FBXW9 promotes synaptic transmission in GABAergic motor neurons in C. elegans.

    Yu Sun

    Full Text Available Ubiquitination controls the activity of many proteins and has been implicated in almost every aspect of neuronal cell biology. Characterizing the precise function of ubiquitin ligases, the enzymes that catalyze ubiquitination of target proteins, is key to understanding distinct functions of ubiquitination. F-box proteins are the variable subunits of the large family of SCF ubiquitin ligases and are responsible for binding and recognizing specific ubiquitination targets. Here, we investigated the function of the F-box protein MEC-15 (FBXW9, one of a small number of F-box proteins evolutionarily conserved from C. elegans to mammals. mec-15 is widely expressed in the nervous system including GABAergic and cholinergic motor neurons. Electrophysiological and behavioral analyses indicate that GABAergic synaptic transmission is reduced in mec-15 mutants while cholinergic transmission appears normal. In the absence of MEC-15, the abundance of the synaptic vesicle protein SNB-1 (synaptobrevin is reduced at synapses and increased in cell bodies of GABAergic motor neurons, suggesting that MEC-15 affects the trafficking of SNB-1 between cell bodies and synapses and may promote GABA release by regulating the abundance of SNB-1 at synapses.

  16. Potentiation of Inhibitory Synaptic Transmission by Extracellular ATP in Rat Suprachiasmatic Nuclei

    Bhattacharya, Anirban; Vávra, Vojtěch; Svobodová, Irena; Bendová, Z.; Vereb, G.; Zemková, Hana

    2013-01-01

    Roč. 33, č. 18 (2013), s. 8035-8044. ISSN 0270-6474 R&D Projects: GA AV ČR(CZ) IAA500110910; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) EE2.3.30.0025 Institutional support: RVO:67985823 Keywords : suprachiasmatic nucleus * P2X receptors * P2Y receptors * ATP * GABA * spontaneous inhibitory synaptic currents Subject RIV: ED - Physiology Impact factor: 6.747, year: 2013

  17. Src, a Molecular Switch Governing Gain Control of Synaptic Transmission Mediated by N-methyl-D-Aspartate Receptors

    Yu, Xian-Min; Salter, Michael W.

    1999-07-01

    The N-methyl-D-aspartate (NMDA) receptor is a principal subtype of glutamate receptor mediating fast excitatory transmission at synapses in the dorsal horn of the spinal cord and other regions of the central nervous system. NMDA receptors are crucial for the lasting enhancement of synaptic transmission that occurs both physiologically and in pathological conditions such as chronic pain. Over the past several years, evidence has accumulated indicating that the activity of NMDA receptors is regulated by the protein tyrosine kinase, Src. Recently it has been discovered that, by means of up-regulating NMDA receptor function, activation of Src mediates the induction of the lasting enhancement of excitatory transmission known as long-term potentiation in the CA1 region of the hippocampus. Also, Src has been found to amplify the up-regulation of NMDA receptor function that is produced by raising the intracellular concentration of sodium. Sodium concentration increases in neuronal dendrites during high levels of firing activity, which is precisely when Src becomes activated. Therefore, we propose that the boost in NMDA receptor function produced by the coincidence of activating Src and raising intracellular sodium may be important in physiological and pathophysiological enhancement of excitatory transmission in the dorsal horn of the spinal cord and elsewhere in the central nervous system.

  18. Layer- and area-specific actions of norepinephrine on cortical synaptic transmission.

    Salgado, Humberto; Treviño, Mario; Atzori, Marco

    2016-06-15

    The cerebral cortex is a critical target of the central noradrenergic system. The importance of norepinephrine (NE) in the regulation of cortical activity is underscored by clinical findings that involve this catecholamine and its receptor subtypes in the regulation of a large number of emotional and cognitive functions and illnesses. In this review, we highlight diverse effects of the LC/NE system in the mammalian cortex. Indeed, electrophysiological, pharmacological, and behavioral studies in the last few decades reveal that NE elicits a mixed repertoire of excitatory, inhibitory, and biphasic effects on the firing activity and transmitter release of cortical neurons. At the intrinsic cellular level, NE can produce a series of effects similar to those elicited by other monoamines or acetylcholine, associated with systemic arousal. At the synaptic level, NE induces numerous acute changes in synaptic function, and ׳gates' the induction of long-term plasticity of glutamatergic synapses, consisting in an enhancement of engaged and relevant cortical synapses and/or depression of unengaged synapses. Equally important in shaping cortical function, in many cortical areas NE promotes a characteristic, most often reversible, increase in the gain of local inhibitory synapses, whose extent and temporal properties vary between different areas and sometimes even between cortical layers of the same area. While we are still a long way from a comprehensive theory of the function of the LC/NE system, its cellular, synaptic, and plastic effects are consistent with the hypothesis that noradrenergic modulation is critical in coordinating the activity of cortical and subcortical circuits for the integration of sensory activity and working memory. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26820639

  19. EPO induces changes in synaptic transmission and plasticity in the dentate gyrus of rats.

    Almaguer-Melian, William; Mercerón-Martínez, Daymara; Delgado-Ocaña, Susana; Pavón-Fuentes, Nancy; Ledón, Nuris; Bergado, Jorge A

    2016-06-01

    Erythropoietin has shown wide physiological effects on the central nervous system in animal models of disease, and in healthy animals. We have recently shown that systemic EPO administration 15 min, but not 5 h, after daily training in a water maze is able to induce the recovery of spatial memory in fimbria-fornix chronic-lesioned animals, suggesting that acute EPO triggers mechanisms which can modulate the active neural plasticity mechanism involved in spatial memory acquisition in lesioned animals. Additionally, this EPO effect is accompanied by the up-regulation of plasticity-related early genes. More remarkably, this time-dependent effects on learning recovery could signify that EPO in nerve system modulate specific living-cellular processes. In the present article, we focus on the question if EPO could modulate the induction of long-term synaptic plasticity like LTP and LTD, which presumably could support our previous published data. Our results show that acute EPO peripheral administration 15 min before the induction of synaptic plasticity is able to increase the magnitude of the LTP (more prominent in PSA than fEPSP-Slope) to facilitate the induction of LTD, and to protect LTP from depotentiation. These findings showing that EPO modulates in vivo synaptic plasticity sustain the assumption that EPO can act not only as a neuroprotective substance, but is also able to modulate transient neural plasticity mechanisms and therefore to promote the recovery of nerve function after an established chronic brain lesion. According to these results, EPO could be use as a molecular tool for neurorestaurative treatments. Synapse 70:240-252, 2016. © 2016 Wiley Periodicals, Inc. PMID:26860222

  20. A role for Mints in transmitter release: Mint 1 knockout mice exhibit impaired GABAergic synaptic transmission

    Ho, Angela; Morishita, Wade; Hammer, Robert E.; Malenka, Robert C.; Südhof, Thomas C.

    2003-01-01

    Mints (also called X11-like proteins) are adaptor proteins composed of divergent N-terminal sequences that bind to synaptic proteins such as CASK (Mint 1 only) and Munc18-1 (Mints 1 and 2) and conserved C-terminal PTB- and PDZ-domains that bind to widely distributed proteins such as APP, presenilins, and Ca2+ channels (all Mints). We find that Mints 1 and 2 are similarly expressed in most neurons except for inhibitory interneurons that contain selectively high levels of Mint 1. Using knockout...

  1. DISC1 Protein Regulates γ-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons.

    Wei, Jing; Graziane, Nicholas M; Gu, Zhenglin; Yan, Zhen

    2015-11-13

    Association studies have suggested that Disrupted-in-Schizophrenia 1 (DISC1) confers a genetic risk at the level of endophenotypes that underlies many major mental disorders. Despite the progress in understanding the significance of DISC1 at neural development, the mechanisms underlying DISC1 regulation of synaptic functions remain elusive. Because alterations in the cortical GABA system have been strongly linked to the pathophysiology of schizophrenia, one potential target of DISC1 that is critically involved in the regulation of cognition and emotion is the GABAA receptor (GABAAR). We found that cellular knockdown of DISC1 significantly reduced GABAAR-mediated synaptic and whole-cell current, whereas overexpression of wild-type DISC1, but not the C-terminal-truncated DISC1 (a schizophrenia-related mutant), significantly increased GABAAR currents in pyramidal neurons of the prefrontal cortex. These effects were accompanied by DISC1-induced changes in surface GABAAR expression. Moreover, the regulation of GABAARs by DISC1 knockdown or overexpression depends on the microtubule motor protein kinesin 1 (KIF5). Our results suggest that DISC1 exerts an important effect on GABAergic inhibitory transmission by regulating KIF5/microtubule-based GABAAR trafficking in the cortex. The knowledge gained from this study would shed light on how DISC1 and the GABA system are linked mechanistically and how their interactions are critical for maintaining a normal mental state. PMID:26424793

  2. Similar oxysterols may lead to opposite effects on synaptic transmission: Olesoxime versus 5α-cholestan-3-one at the frog neuromuscular junction.

    Kasimov, M R; Zakyrjanova, G F; Giniatullin, A R; Zefirov, A L; Petrov, A M

    2016-07-01

    Cholesterol oxidation products frequently have a high biological activity. In the present study, we have used microelectrode recording of end plate currents and FM-based optical detection of synaptic vesicle exo-endocytosis to investigate the effects of two structurally similar oxysterols, olesoxime (cholest-4-en-3-one, oxime) and 5ɑ-cholestan-3-one (5ɑCh3), on neurotransmission at the frog neuromuscular junction. Olesoxime is an exogenous, potentially neuroprotective, substance and 5ɑCh3 is an intermediate product in cholesterol metabolism, which is elevated in the case of cerebrotendinous xanthomatosis. We found that olesoxime slightly increased evoked neurotransmitter release in response to a single stimulus and significantly reduced synaptic depression during high frequency activity. The last effect was due to an increase in both the number of synaptic vesicles involved in exo-endocytosis and the rate of synaptic vesicle recycling. In contrast, 5ɑCh3 reduced evoked neurotransmitter release during the low- and high frequency synaptic activities. The depressant action of 5ɑCh3 was associated with a reduction in the number of synaptic vesicles participating in exo- and endocytosis during high frequency stimulation, without a change in rate of the synaptic vesicle recycling. Of note, olesoxime increased the staining of synaptic membranes with the B-subunit of cholera toxin and the formation of fluorescent ganglioside GM1 clusters, and decreased the fluorescence of 22-NBD-cholesterol, while 5ɑCh3 had the opposite effects, suggesting that the two oxysterols have different effects on lipid raft stability. Taken together, these data show that these two structurally similar oxysterols induce marked different changes in neuromuscular transmission which are related with the alteration in synaptic vesicle cycle. PMID:27102612

  3. Neuronal glutamate transporters regulate synaptic transmission in single synapses on CA1 hippocampal neurons.

    Kondratskaya, Elena; Shin, Min-Chul; Akaike, Norio

    2010-01-15

    Glutamate is the major excitatory transmitter in CNS although it causes severe brain damage by pathologic excitotoxicity. Efficient neurotransmission is controlled by powerful protection and support afforded by specific high-affinity glutamate transporters in neurons and glia, clearing synaptic glutamate. While the role of glial cells in glutamate uptake is well defined, the role of neuronal transporters remains poorly understood. The evaluation of impact of neuronal transporters on spontaneous and evoked EPSC in hippocampal CA1 neurons within a model 'single bouton preparation' by pre- and postsynaptic uptake was addressed. In whole-cell patch clamp experiments the influence of blocking, pre- or both pre- and postsynaptic glutamate transporters (GluT) on spontaneous and evoked postsynaptic currents (sEPSC and eEPSC), was examined by manipulating the content of intracellular solution. Suppressing GluT by non-transportable inhibitor TBOA (10 microM) led to remarkable alteration of glutamate uptake process and was reflected in measurable changes of general properties of synaptic currents. Elimination of intracellular K(+) concentration required for glutamate transporter operation by using Cs(+)-based internal solution (postsynaptic GluTs are non-functional apriori), causes the deficient of presynaptic glutamate transporters. Applied in such conditions glutamate transporter inhibitor TBOA (10 microM) affected the occurrence of synaptic event and thus unregulated the transmitter release. eEPSCs were generally suppressed both in amplitude (to 48.73+/-7.03% vs. control) and in success rate (R(suc)) by TBOA (from 91.1+/-7.5% in control to 79.57+/-13.2%). In contrast, with K(+)-based solution in patch pipette (pre- and postsynaptic GluT are intact), amplitude of eEPSC was substantially potentiated by pre-treatment with TBOA (152.1+/-11%), whereas (R(suc)) was reduced to 79.8+/-8.3% in average. The identical reduction of event success rate as well as increased pair

  4. Synaptic determinants of Rett syndrome

    Elena M B Boggio

    2010-08-01

    Full Text Available There is mounting evidence showing that the structural and molecular organization of synaptic connections are affected both in human patients and in animal models of neurological and psychiatric diseases. As a consequence of these experimental observations, it has been introduced the concept of synapsopathies, a notion describing brain disorders of synaptic function and plasticity. A close correlation between neurological diseases and synaptic abnormalities is especially relevant for those syndromes including also mental retardation in their symptomatology, such as Rett Syndrome (RS. RS (MIM312750 is an X-linked dominant neurological disorder that is caused, in the majority of cases by mutations in methyl-CpG-binding protein 2 (MeCP2. This review will focus on the current knowledge of the synaptic alterations produced by mutations of the gene MeCP2 in mouse models of RS and will highlight prospects experimental therapies currently in use. Different experimental approaches have revealed that RS could be the consequence of an impairment in the homeostasis of synaptic transmission in specific brain regions. Indeed, several forms of experience-induced neuronal plasticity are impaired in the absence of MeCP2. Based on the results presented in this review, it is reasonable to propose that understanding how the brain is affected by diseases such as RS is at reach. This effort will bring us closer to identify the neurobiological bases of human cognition.

  5. Transmission of clonal chromosomal abnormalities in human hematopoietic stem and progenitor cells surviving radiation exposure

    Highlights: • Radiation induced formation and transmission of chromosomal aberrations were assessed. • Cytogenetic analysis was performed in human CD34+ HSPC by mFISH. • We report transmission of stable aberrations in irradiated, clonally expanded HSPC. • Unstable aberrations in clonally expanded HSPC occur independently of irradiation. • Carbon ions and X-rays bear a similar risk for propagation of cytogenetic changes. - Abstract: In radiation-induced acute myeloid leukemia (rAML), clonal chromosomal abnormalities are often observed in bone marrow cells of patients, suggesting that their formation is crucial in the development of the disease. Since rAML is considered to originate from hematopoietic stem and progenitor cells (HSPC), we investigated the frequency and spectrum of radiation-induced chromosomal abnormalities in human CD34+ cells. We then measured stable chromosomal abnormalities, a possible biomarker of leukemia risk, in clonally expanded cell populations which were grown for 14 days in a 3D-matrix (CFU-assay). We compared two radiation qualities used in radiotherapy, sparsely ionizing X-rays and densely ionizing carbon ions (29 and 60–85 keV/μm, doses between 0.5 and 4 Gy). Only a negligible number of de novo arising, unstable aberrations (≤0.05 aberrations/cell, 97% breaks) were measured in the descendants of irradiated HSPC. However, stable aberrations were detected in colonies formed by irradiated HSPC. All cells of the affected colonies exhibited one or more identical aberrations, indicating their clonal origin. The majority of the clonal rearrangements (92%) were simple exchanges such as translocations (77%) and pericentric inversions (15%), which are known to contribute to the development of rAML. Carbon ions were more efficient in inducing cell killing (maximum of ∼30–35% apoptotic cells for 2 Gy carbon ions compared to ∼25% for X-rays) and chromosomal aberrations in the first cell-cycle after exposure (∼70% and ∼40

  6. Transmission of clonal chromosomal abnormalities in human hematopoietic stem and progenitor cells surviving radiation exposure

    Kraft, Daniela, E-mail: d.kraft@gsi.de [GSI Helmholtz Center for Heavy Ion Research, Department of Biophysics, Planckstr. 1, 64291 Darmstadt (Germany); Institute for Transfusion Medicine und Immunohematology, DRK-Blutspendedienst Baden-Wuerttemberg—Hessen, Johann Wolfgang Goethe-University Hospital, Sandhofstrasse 1, 60528 Frankfurt (Germany); Ritter, Sylvia, E-mail: s.ritter@gsi.de [GSI Helmholtz Center for Heavy Ion Research, Department of Biophysics, Planckstr. 1, 64291 Darmstadt (Germany); Durante, Marco, E-mail: m.durante@gsi.de [GSI Helmholtz Center for Heavy Ion Research, Department of Biophysics, Planckstr. 1, 64291 Darmstadt (Germany); Institute for Condensed Matter Physics, Physics Department, Technical University Darmstadt, Hochschulstraße 6-8, 64289 Darmstadt (Germany); Seifried, Erhard, E-mail: e.seifried@blutspende.de [Institute for Transfusion Medicine und Immunohematology, DRK-Blutspendedienst Baden-Wuerttemberg—Hessen, Johann Wolfgang Goethe-University Hospital, Sandhofstrasse 1, 60528 Frankfurt (Germany); Fournier, Claudia, E-mail: c.fournier@gsi.de [GSI Helmholtz Center for Heavy Ion Research, Department of Biophysics, Planckstr. 1, 64291 Darmstadt (Germany); Tonn, Torsten, E-mail: t.tonn@blutspende.de [Institute for Transfusion Medicine und Immunohematology, DRK-Blutspendedienst Baden-Wuerttemberg—Hessen, Johann Wolfgang Goethe-University Hospital, Sandhofstrasse 1, 60528 Frankfurt (Germany); Technische Universität Dresden, Med. Fakultät Carl Gustav Carus, Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North-East, Blasewitzer Straße 68/70, 01307 Dresden (Germany)

    2015-07-15

    Highlights: • Radiation induced formation and transmission of chromosomal aberrations were assessed. • Cytogenetic analysis was performed in human CD34+ HSPC by mFISH. • We report transmission of stable aberrations in irradiated, clonally expanded HSPC. • Unstable aberrations in clonally expanded HSPC occur independently of irradiation. • Carbon ions and X-rays bear a similar risk for propagation of cytogenetic changes. - Abstract: In radiation-induced acute myeloid leukemia (rAML), clonal chromosomal abnormalities are often observed in bone marrow cells of patients, suggesting that their formation is crucial in the development of the disease. Since rAML is considered to originate from hematopoietic stem and progenitor cells (HSPC), we investigated the frequency and spectrum of radiation-induced chromosomal abnormalities in human CD34{sup +} cells. We then measured stable chromosomal abnormalities, a possible biomarker of leukemia risk, in clonally expanded cell populations which were grown for 14 days in a 3D-matrix (CFU-assay). We compared two radiation qualities used in radiotherapy, sparsely ionizing X-rays and densely ionizing carbon ions (29 and 60–85 keV/μm, doses between 0.5 and 4 Gy). Only a negligible number of de novo arising, unstable aberrations (≤0.05 aberrations/cell, 97% breaks) were measured in the descendants of irradiated HSPC. However, stable aberrations were detected in colonies formed by irradiated HSPC. All cells of the affected colonies exhibited one or more identical aberrations, indicating their clonal origin. The majority of the clonal rearrangements (92%) were simple exchanges such as translocations (77%) and pericentric inversions (15%), which are known to contribute to the development of rAML. Carbon ions were more efficient in inducing cell killing (maximum of ∼30–35% apoptotic cells for 2 Gy carbon ions compared to ∼25% for X-rays) and chromosomal aberrations in the first cell-cycle after exposure (∼70% and

  7. Liprin-α2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission

    S.A. Spangler (Samantha); S.K. Schmitz (Sabine); J.T. Kevenaar (Josta); E. de Graaff (Esther); M. De Wit (Meike); J.A.A. Demmers (Jeroen); P.W. Toonen (Pim ); C.C. Hoogenraad (Casper)

    2013-01-01

    textabstractThe presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-α2 as a key organizer in this process. We show that liprin-α2 levels were r

  8. Astragaloside Ⅳ inhibits spontaneous synaptic transmission and synchronized Ca2+ oscillations on hippocampal neurons

    Shao-qing ZHU; Lei QI; Yan-fang RUI; Ru-xin LI; Xiang-ping HE; Zuo-ping XIE

    2008-01-01

    Aim: To investigate the changes in the spontaneous neuronal excitability in-duced by astragaloside Ⅳ (AGS-Ⅳ) in the cultured hippocampal network. Methods: Hippocampal neurons in culture for 9-11 d were used for this study. The sponta-neous synaptic activities of these hippocampal neurons were examined by Ca2+ imaging and whole-cell patch-clamp techniques. In total, 40 mg/L AGS-Ⅳ dis-solved in DMSO and 2 mL/L DMSO were applied to the neurons under a micro-scope while the experiments were taking place. Results: AGS-Ⅳ inhibited the frequencies of synchronized spontaneous Ca2+ oscillations to 59.39%+3.25% (mean+SEM), the spontaneous postsynaptic currents to 43.78%±7.72% (mean±SEM), and the spontaneous excitatory postsynaptic currents to 49.25%±7.06% (mean±SEM) of those of the control periods, respectively, at 16 min after the AGS-Ⅳ applications. AGS-Ⅳ also decreased the peak values of the voltage-gated K+ and Na+ channel currents at that time point. Conclusion: These results indicate that AGS-Ⅳ suppresses the spontaneous neuronal excitabilities effectively. Such a modulation of neuronal activity could represent new evidence for AGS-Ⅳ as a neuroprotector.

  9. Inhibitory synaptic transmission from the substantia nigra pars reticulata to the ventral medial thalamus in mice.

    Kase, Daisuke; Uta, Daisuke; Ishihara, Hiromi; Imoto, Keiji

    2015-08-01

    The cortico-basal ganglia-thalamic loop circuit is involved in variety of motor, association and limbic functions. The basal ganglia receive neural information from various areas of the cerebral cortex and transfer them back to the frontal and motor cortex via the ventral medial (VM), and the anterior-ventral lateral thalamic complex. The projection from the basal ganglia to the thalamus is GABAergic, and, therefore, the output from the basal ganglia cannot directly evoke excitation in the thalamic nuclei. The mechanism underlying the information transfer via the inhibitory projection remains unclear. To address this issue, we recorded electrophysiological properties of nigro-thalamic synapses from the VM neuron. We developed a nigro-thalamic slice preparation, in which the projection from the substantia nigra pars reticulata (SNr) to VM nucleus is stored, to enable the selective activation of the projection from the SNr. We characterized synaptic properties and membrane properties of the VM neuron, and developed a VM neuron model to simulate the impacts of SNr inputs on VM neuron activity. Neural simulation suggested that the inhibitory projection from SNr can control neural activity in two ways: a disinhibition from the spontaneous nigral inhibition and a β-band synchronization evoked by combination of excitation and inhibition of SNr activity. PMID:25887794

  10. GABAergic synaptic transmission regulates calcium influx during spike-timing dependent plasticity

    Trevor Balena

    2010-06-01

    Full Text Available Coincident pre- and postsynaptic activity of hippocampal neurons alters the strength of gamma-aminobutyric acid (GABAA-mediated inhibition through a Ca2+-dependent regulation of cation-chloride cotransporters. This long-term synaptic modulation is termed GABAergic spike-timing dependent plasticity (STDP. In the present study, we examined whether the properties of the GABAergic synapses themselves modulate the required postsynaptic Ca2+ influx during GABAergic STDP induction. To do this we first identified GABAergic synapses between cultured hippocampal neurons based on their relatively long decay time constants and their reversal potentials which lay close to the resting membrane potential. GABAergic STDP was then induced by coincidentally (± 1 ms firing the pre- and postsynaptic neurons at 5 Hz for 30 seconds, while postsynaptic Ca2+ was imaged with the Ca2+-sensitive fluorescent dye Fluo4-AM. In all cases, the induction of GABAergic STDP increased postsynaptic Ca2+ above resting levels. We further found that the magnitude of this increase correlated with the amplitude and polarity of the GABAergic postsynaptic current (GPSC; hyperpolarizing GPSCs reduced the Ca2+ influx in comparison to both depolarizing GPSCs, and postsynaptic neurons spiked alone. This relationship was influenced by both the driving force for Cl- and GABAA conductance (which had positive correlations with the Ca2+ influx. The spike-timing order during STDP induction did not influence the correlation between GPSC amplitude and Ca2+ influx, which is likely accounted for by the symmetrical GABAergic STDP window.

  11. Dissociation of μ- and δ-opioid inhibition of glutamatergic synaptic transmission in superficial dorsal horn

    Vaughan Christopher W

    2010-10-01

    Full Text Available Abstract Background There is anatomical and behavioural evidence that μ- and δ-opioid receptors modulate distinct nociceptive modalities within the superficial dorsal horn. The aim of the present study was to examine whether μ- and δ-opioid receptor activation differentially modulates TRP sensitive inputs to neurons within the superficial dorsal horn. To do this, whole cell patch clamp recordings were made from lamina I - II neurons in rat spinal cord slices in vitro to examine the effect of opioids on TRP agonist-enhanced glutamatergic spontaneous miniature excitatory postsynaptic currents (EPSCs. Results Under basal conditions the μ-opioid agonist DAMGO (3 μM reduced the rate of miniature EPSCs in 68% of neurons, while the δ- and κ-opioid agonists deltorphin-II (300 nM and U69593 (300 nM did so in 13 - 17% of neurons tested. The TRP agonists menthol (400 μM and icilin (100 μM both produced a Ca2+-dependent increase in miniature EPSC rate which was unaffected by the voltage dependent calcium channel (VDCC blocker Cd2+. The proportion of neurons in which deltorphin-II reduced the miniature EPSC rate was enhanced in the presence of icilin (83%, but not menthol (0%. By contrast, the proportion of DAMGO and U69593 responders was unaltered in the presence of menthol (57%, 0%, or icilin (57%, 17%. Conclusions These findings demonstrate that δ-opioid receptor activation selectively inhibits inputs activated by icilin, whereas μ-opioid receptor activation has a more widespread effect on synaptic inputs to neurons in the superficial dorsal horn. These findings suggest that δ-opioids may provide a novel analgesic approach for specific, TRPA1-like mediated pain modalities.

  12. Alterations in striatal synaptic transmission are consistent across genetic mouse models of Huntington's disease

    Damian M Cummings

    2010-06-01

    Full Text Available Since the identification of the gene responsible for HD (Huntington's disease, many genetic mouse models have been generated. Each employs a unique approach for delivery of the mutated gene and has a different CAG repeat length and background strain. The resultant diversity in the genetic context and phenotypes of these models has led to extensive debate regarding the relevance of each model to the human disorder. Here, we compare and contrast the striatal synaptic phenotypes of two models of HD, namely the YAC128 mouse, which carries the full-length huntingtin gene on a yeast artificial chromosome, and the CAG140 KI (knock-in mouse, which carries a human/mouse chimaeric gene that is expressed in the context of the mouse genome, with our previously published data obtained from the R6/2 mouse, which is transgenic for exon 1 mutant huntingtin. We show that striatal MSNs (medium-sized spiny neurons in YAC128 and CAG140 KI mice have similar electrophysiological phenotypes to that of the R6/2 mouse. These include a progressive increase in membrane input resistance, a reduction in membrane capacitance, a lower frequency of spontaneous excitatory postsynaptic currents and a greater frequency of spontaneous inhibitory postsynaptic currents in a subpopulation of striatal neurons. Thus, despite differences in the context of the inserted gene between these three models of HD, the primary electrophysiological changes observed in striatal MSNs are consistent. The outcomes suggest that the changes are due to the expression of mutant huntingtin and such alterations can be extended to the human condition.

  13. Melamine Alters Glutamatergic Synaptic Transmission of CA3-CA1 Synapses Presynaptically Through Autophagy Activation in the Rat Hippocampus.

    Zhang, Hui; Wang, Hui; Xiao, Xi; Zhang, Tao

    2016-01-01

    Melamine is an industrial chemical that can cause central nervous system disorders including excitotoxicity and cognitive impairment. Its illegal use in powdered baby formula was the focus of a milk scandal in China in 2008. One of our previous studies showed that melamine impaired glutamatergic transmission in rat hippocampal CA1 pyramidal cells. However, the underlying mechanism of action of melamine is unclear, and it is unknown if the CA3-CA1 pathway is directly involved. In the present study, a whole-cell patch-clamp technique was employed to investigate the effect of melamine on the hippocampal CA3-CA1 pathway in vitro. Both the evoked excitatory postsynaptic current (eEPSC) and the paired-pulse ratio (PPR) were recorded. Furthermore, we examined whether autophagy was involved in glutamatergic transmission alterations induced by melamine. Our data showed that melamine significantly increased the amplitude of eEPSCs in a dose-dependent manner. Inhibition of the N-methyl-D-aspartic acid receptor did not prevent the increase in eEPSC amplitude. In addition, the PPR was remarkably decreased by a melamine concentration of 5 × 10(-5) g/mL. It was found that autophagy could be activated by melamine and an autophagy inhibitor, 3-MA, prevented the melamine-induced increase in eEPSC amplitude. Overall, our results show that melamine presynaptically alters glutamatergic synaptic transmission of hippocampal CA3-CA1 synapses in vitro and this is likely associated with autophagy alteration. PMID:26530910

  14. Conditioned taste aversion prevents the long-lasting BDNF-induced enhancement of synaptic transmission in the insular cortex: A metaplastic effect.

    Rivera-Olvera, Alejandro; Rodríguez-Durán, Luis F; Escobar, Martha L

    2016-04-01

    Homeostatic plasticity mechanisms dynamically adjust synaptic strengths to promote stability that is crucial for memory storage. Metaplasticity is an example of these forms of plasticity that modify the capacity of synapses to experience subsequent Hebbian modifications. In particular, training in several behavioral tasks modifies the ability to induce long-term potentiation (LTP). Recently, we have reported that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP generated by high frequency stimulation in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC). One of the key molecular players that underlie long-term synaptic plasticity is brain-derived neurotrophic factor (BDNF). Previous studies from our group reported that acute microinfusion of BDNF in the IC induces a lasting potentiation of synaptic efficacy at the Bla-IC projection. Thus, the aim of the present study was to analyze whether CTA training modifies the ability to induce subsequent BDNF-induced potentiation of synaptic transmission in the Bla-IC projection in vivo. Accordingly, CTA trained rats received intracortical microinfusion of BDNF in order to induce lasting potentiation 48h after the aversion test. Our results show that CTA training prevents the induction of in vivo BDNF-LTP in the Bla-IC projection. The present results provide evidence that CTA modulates BDNF-dependent changes in IC synaptic strength. PMID:26854904

  15. Reduction of the cholesterol sensor SCAP in the brains of mice causes impaired synaptic transmission and altered cognitive function.

    Ryo Suzuki

    Full Text Available The sterol sensor SCAP is a key regulator of SREBP-2, the major transcription factor controlling cholesterol synthesis. Recently, we showed that there is a global down-regulation of cholesterol synthetic genes, as well as SREBP-2, in the brains of diabetic mice, leading to a reduction of cholesterol synthesis. We now show that in mouse models of type 1 and type 2 diabetes, this is, in part, the result of a decrease of SCAP. Homozygous disruption of the Scap gene in the brains of mice causes perinatal lethality associated with microcephaly and gliosis. Mice with haploinsufficiency of Scap in the brain show a 60% reduction of SCAP protein and ~30% reduction in brain cholesterol synthesis, similar to what is observed in diabetic mice. This results in impaired synaptic transmission, as measured by decreased paired pulse facilitation and long-term potentiation, and is associated with behavioral and cognitive changes. Thus, reduction of SCAP and the consequent suppression of cholesterol synthesis in the brain may play an important role in the increased rates of cognitive decline and Alzheimer disease observed in diabetic states.

  16. Indian red scorpion venom depresses spinal synaptic transmission without involving NMDA receptors.

    Maurya, Amar N; Deshpande, Shripad B

    2010-05-14

    Stings of Indian red scorpion (Mesobuthus tamulus, MBT) produce neurological abnormalities such as convulsions and paralysis. These parameters indicate the activity at alpha-motoneuron. The present study was therefore, undertaken to evaluate the effect of MBT-venom on spinal reflexes and the involvement of N-methyl-d-aspartate (NMDA) receptors. The experiments were performed on isolated hemisected spinal cords from 4 to 6 days old rats. Stimulation of a dorsal root with supramaximal strength at 0.1Hz evoked monosynaptic (MSR) and polysynaptic reflex (PSR) potentials in the corresponding segmental ventral root. Superfusion of MBT-venom depressed the spinal reflexes in a time- and a concentration-dependent (0.1-1microg/ml) manner. MBT-venom at 0.1, 0.3 and 1.0microg/ml produced maximal depression of 55, 75 and 90% at 30, 10 and 7min, respectively. The time required to produce 50% depression (T-50) of MSR was 19.0, 8.0, and 3.6min and for PSR was 15.0, 5.6, and 2.9min at 0.1, 0.3 and 1microg/ml of venom, respectively. Pre-treatment with DL-alpha-2-amino-5-phosphonovaleric acid (APV) decreased MSR by 26% and abolished PSR. In the presence of APV, the MBT-venom-induced depression of MSR was not different from the venom only group. The results indicate that venom-induced depression of spinal reflexes did not involve NMDA receptors. PMID:20347939

  17. In vivo synaptic transmission in the zebra finch high vocal center and robust nucleus of the arcopallium after different stimulus patterns

    Suqun Liao; Wenxiao Liu; Peng Xiao; Dongfeng Li

    2008-01-01

    BACKGROUND: Electrophysiological studies using brain slices have revealed that the developmental regulation of synaptic plasticity in vocal learning pathway is essential for song learning in zebra finches. Publications reporting in vivo electrophysiological investigation are scarce. Many aspects of neural mechanisms underlying song learning and production still remain uncertain.OBJECTIVE: To observe the efficacy of paired pulses and the effect on synaptic transmission induced by low-frequency stimulations, high-frequency stimulations, and theta-burst stimulations.DESIGN, TIME AND SETTING: A comparative observation. The experiment was conducted from October 2006 to October 2007 in the Neurophysiology Laboratory of South-China Normal University.MATERIALS: Twenty-four adult male zebra finches were supplied by the Department of Animal Experiment of College of Life Sciences, South China Normal University. A SEN-7203 stimulator (NIHON KOHDEN), as well as a DSJ-731WF microelectrode amplifier and DSJ-F amplifier (provided by South-China Normal University), were used to stimulate and record, respectively.METHODS: Animals were randomly divided into low-frequency, high-frequency, and theta-burst frequency stimulation groups. After recording evoked potentials, an input-output curve was evaluated. Subsequently, the efficacy of paired pulses with different stimulus intensity (1/3, 1/2, 2/3, or 3/4 of the value that induced the largest synaptic response), as well as interpulse intervals (50, 75, and 100ms), was measured in each group. The test stimulus intensity was set to a level that evoked 1/2 or 1/3 amplitude of the maximum response.MAIN OUTCOME MEASURES: Changes in amplitude, slope, and area of evoked potentials elicited by different stimulus patterns.RESULTS: (1) Efficacy of paired pulses: there was significant paired-pulse facilitation in the high vocal center and robust nucleus of the arcopallium (HVC-RA) synapse. Efficacy decreased when paired-pulse intervals or stimulus

  18. Peptide and lipid modulation of glutamatergic afferent synaptic transmission in the solitary tract nucleus

    Michael C. Andresen

    2013-01-01

    Full Text Available The brainstem nucleus of the solitary tract (NTS holds the first central neurons in major homeostatic reflex pathways. These homeostatic reflexes regulate and coordinate multiple organ systems from gastrointestinal to cardiopulmonary functions. The core of many of these pathways arise from cranial visceral afferent neurons that enter the brain as the solitary tract (ST with more than two-thirds arising from the gastrointestinal system. About one quarter of ST afferents have myelinated axons but the majority are classed as unmyelinated C-fibers. All ST afferents release the fast neurotransmitter glutamate with remarkably similar, high-probability release characteristics. Second order NTS neurons receive surprisingly limited primary afferent information with one or two individual inputs converging on single second order NTS neurons. A- and C-fiber afferents never mix at NTS second order neurons. Many transmitters modify the basic glutamatergic excitatory postsynaptic current (EPSC often by reducing glutamate release or interrupting terminal depolarization. Thus, a distinguishing feature of ST transmission is presynaptic expression of G-protein coupled receptors for peptides common to peripheral or forebrain (e.g. hypothalamus neuron sources. Presynaptic receptors for angiotensin (AT1, vasopressin (V1a, oxytocin (OT, opioid (MOR, ghrelin (GHSR1 and cholecystokinin (CCK differentially control glutamate release on particular subsets of neurons with most other ST afferents unaffected. Lastly, lipid-like signals are transduced by two key ST presynaptic receptors, the transient receptor potential vanilloid type 1 (TRPV1 and the cannabinoid receptor (CB1 that oppositely control glutamate release. Increasing evidence suggests that peripheral nervous signaling mechanisms are repurposed at central terminals to control excitation and are major sites of signal integration of peripheral and central inputs particularly from the hypothalamus.

  19. Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.

    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.

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

    Ying-Biao Chen; Fen-Sheng Huang; Yun-Qing Li

    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....

  1. σ2-Adaptin Facilitates Basal Synaptic Transmission and Is Required for Regenerating Endo-Exo Cycling Pool Under High-Frequency Nerve Stimulation in Drosophila.

    Choudhury, Saumitra Dey; Mushtaq, Zeeshan; Reddy-Alla, Suneel; Balakrishnan, Sruthi S; Thakur, Rajan S; Krishnan, Kozhalmannom S; Raghu, Padinjat; Ramaswami, Mani; Kumar, Vimlesh

    2016-05-01

    The functional requirement of adapter protein 2 (AP2) complex in synaptic membrane retrieval by clathrin-mediated endocytosis is not fully understood. Here we isolated and functionally characterized a mutation that dramatically altered synaptic development. Based on the aberrant neuromuscular junction (NMJ) synapse, we named this mutation angur (a Hindi word meaning "grapes"). Loss-of-function alleles of angur show more than twofold overgrowth in bouton numbers and a dramatic decrease in bouton size. We mapped the angur mutation to σ2-adaptin, the smallest subunit of the AP2 complex. Reducing the neuronal level of any of the subunits of the AP2 complex or disrupting AP2 complex assembly in neurons phenocopied the σ2-adaptin mutation. Genetic perturbation of σ2-adaptin in neurons leads to a reversible temperature-sensitive paralysis at 38°. Electrophysiological analysis of the mutants revealed reduced evoked junction potentials and quantal content. Interestingly, high-frequency nerve stimulation caused prolonged synaptic fatigue at the NMJs. The synaptic levels of subunits of the AP2 complex and clathrin, but not other endocytic proteins, were reduced in the mutants. Moreover, bone morphogenetic protein (BMP)/transforming growth factor β (TGFβ) signaling was altered in these mutants and was restored by normalizing σ2-adaptin in neurons. Thus, our data suggest that (1) while σ2-adaptin facilitates synaptic vesicle (SV) recycling for basal synaptic transmission, its activity is also required for regenerating SVs during high-frequency nerve stimulation, and (2) σ2-adaptin regulates NMJ morphology by attenuating TGFβ signaling. PMID:26920756

  2. GSK-3β inhibitors reverse cocaine-induced synaptic transmission dysfunction in the nucleus accumbens.

    Zhao, Rui; Chen, Jiaojiao; Ren, Zhaoxiang; Shen, Hui; Zhen, Xuechu

    2016-11-01

    Nucleus accumbens receives glutamatergic projection from the prefrontal cortex (PFC) and dopaminergic input from the Ventral tegmental area (VTA). Recent studies have suggested a critical role for serine/threonine kinase glycogen synthase kinase 3β (GSK3β) in cocaine-induced hyperactivity; however, the effect of GSK3β on the modulation of glutamatergic and dopaminergic afferents is unclear. In this study, we found that the GSK3 inhibitors, LiCl (100 mg/kg, i.p.) or SB216763 (2.5 mg/kg, i.p.), blocked the cocaine-induced hyperlocomotor activity in rats. By employing single-unit recordings in vivo, we found that pretreatment with either SB216763 or LiCl for 15 min reversed the cocaine-inhibited firing frequency of medium spiny neuron (MSN) in the nucleus accumbens (NAc). Preperfusion of SB216763 (5 μM) ameliorated the inhibitory effect of cocaine on both the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (up to 99 ± 6.8% inhibition) and N-methyl-D-aspartic acid receptor (NMDAR)-mediate EPSC (up to 73 ± 9.7% inhibition) in the NAc in brain slices. The effect of cocaine on AMPA and NMDA receptor-mediate excitatory postsynaptic current (EPSC) were mimicked by the D1 -like receptor agonist SKF 38393 and blocked by the D1 -like receptor antagonist SCH 23390, whereas D2 -like receptor agonist or antagonist failed to mimic or to block the action of cocaine. Preperfusion of SB216763 for 5 min also ameliorated the inhibitory effect of SKF38393 on both AMPA and NMDA receptor-mediated components of EPSC, indicate the effect of SB216763 on cocaine was via the D1 -like receptor. Moreover, cocaine inhibited the presynaptic release of glutamate in the NAc, and SB216763 reversed this effect. In conclusion, D1 receptor-GSK3β pathway, which mediates glutamatergic transmission in the NAc core through a presynaptic mechanism, plays an important role in acute cocaine-induced hyperlocomotion. PMID:27377051

  3. Transmission electron microscopic observations of acrosome and head abnormalities in impala (Aepyceros melampus sperm from the Kruger National Park

    D.J. Ackerman

    1997-01-01

    Full Text Available Sperm morphological features play an important role in semen evaluation. Exposure to a variety of chemical compounds, especially environmental endocrine disrupters, elicit abnormalities in sperm of certain species. Baseline data on ultrastructure of normal sperm as well as abnormalities observed concomitantly, are required before causal links between such substances and abnormalities can be established. Live spermatozoa were collected from the cauda epididymis of 64 impala rams in the Kruger National Park and studied by transmission electron microscopy to document normal sperm features and abnormalities. The following abnormalities of the acrosome and sperm head were documented from micrographs: Loose acrosome in various stages of disintegration, lip forming of the acrosome; bizarre head, crater defect, poor condensation of the nucleus and the Dag defect. The observed abnormalities were very similar to those reported for other members of the Bovidae. Different forms of a hollow sphere, formed by the nucleus and covered by an abnormal acrosome have not previously been described for other species.

  4. NMDA and non-NMDA receptors contribute to synaptic transmission between the medial geniculate body and the lateral nucleus of the amygdala.

    Li, X F; Phillips, R; LeDoux, J E

    1995-01-01

    We examined whether the NMDA class of excitatory amino acid receptors contribute to synaptic transmission in the pathway connecting the medial geniculate body (MGB) with the lateral nucleus of the amygdala (LA) using extracellular single unit recordings and microiontophoresis. Cells were identified in LA on the basis of responsivity to electrical stimulation of the MGB. For each cell, a level of current was found for the iontophoretic ejection of the NMDA antagonist AP5 that blocked responses elicited by iontophoresis of NMDA, but had no effect on responses elicited by AMPA. Iontophoresis of AP5 with this level of current blocked the excitatory response elicited by MGB stimulation in most cells tested. Microinfusion of AP5 (25, 50, or 100 microM) also blocked the responses. Additional studies tested individual cells with both AP5 and the AMPA antagonist CNQX and showed that blockade of either NMDA or AMPA receptors interferes with synaptic transmission. Finally, iontophoretic ejection of either AP5 or CNQX blocked short-latency (< 25 ms) responses elicited in LA by peripheral auditory stimulation. Together, these results suggest that the synaptic evocation of action potentials in the thalamo-amygdala pathway depends on both NMDA and non-NMDA receptors. We hypothesize that non-NMDA receptors are most likely required to depolarize the cell sufficiently to remove the blockade of NMDA channels by magnesium and NMDA receptors are required to further depolarize the membrane to the level required for action potential generation. PMID:7589322

  5. Astrocytes optimize synaptic fidelity

    Nadkarni, Suhita; Jung, Peter; Levine, Herbert

    2007-03-01

    Most neuronal synapses in the central nervous system are enwrapped by an astrocytic process. This relation allows the astrocyte to listen to and feed back to the synapse and to regulate synaptic transmission. We combine a tested mathematical model for the Ca^2+ response of the synaptic astrocyte and presynaptic feedback with a detailed model for vesicle release of neurotransmitter at active zones. The predicted Ca^2+ dependence of the presynaptic synaptic vesicle release compares favorably for several types of synapses, including the Calyx of Held. We hypothesize that the feedback regulation of the astrocyte onto the presynaptic terminal optimizes the fidelity of the synapse in terms of information transmission.

  6. [Functional changes in the chromatophilic substance and RNA content of the cytoplasm of sympathetic neurons in the presence of synaptic transmission disorders].

    Gorelikov, P L

    1981-07-01

    At a disturbed synaptic transmission in the rabbit cranial sympathetic cervical ganglion in histological sections stained with gallocyanin chrome alum, distribution of the chromatophilic substance was studied, and in the same sections RNA content was determined cytophotometrically. In ganglia of intact animals three groups of neurons with various structure of the chromatophilic substance were defined and their quantitative relation was stated. After administration of various doses of the ganglio-blockader, there was an essential difference in the changes of the chromatophilic substance, but they were unitypical in mono- and double-nuclear neurons. In the same cells, the synaptic blockade produced a rather great increase in the content of the cytoplasmic RNA. Comparing the quantitative data with the visual observation results, a conclusion was made that it is not reliable to use any changes in the chromatophilic substance as a criterium on quantitative shifts in the neuronal RNA and for the morphological test of the neuronal functional activity. PMID:6170279

  7. Botulinum and Tetanus Neurotoxin-Induced Blockade of Synaptic Transmission in Networked Cultures of Human and Rodent Neurons.

    Beske, Phillip H; Bradford, Aaron B; Grynovicki, Justin O; Glotfelty, Elliot J; Hoffman, Katie M; Hubbard, Kyle S; Tuznik, Kaylie M; McNutt, Patrick M

    2016-02-01

    Clinical manifestations of tetanus and botulism result from an intricate series of interactions between clostridial neurotoxins (CNTs) and nerve terminal proteins that ultimately cause proteolytic cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and functional blockade of neurotransmitter release. Although detection of cleaved SNARE proteins is routinely used as a molecular readout of CNT intoxication in cultured cells, impaired synaptic function is the pathophysiological basis of clinical disease. Work in our laboratory has suggested that the blockade of synaptic neurotransmission in networked neuron cultures offers a phenotypic readout of CNT intoxication that more closely replicates the functional endpoint of clinical disease. Here, we explore the value of measuring spontaneous neurotransmission frequencies as novel and functionally relevant readouts of CNT intoxication. The generalizability of this approach was confirmed in primary neuron cultures as well as human and mouse stem cell-derived neurons exposed to botulinum neurotoxin serotypes A-G and tetanus neurotoxin. The sensitivity and specificity of synaptic activity as a reporter of intoxication was evaluated in assays representing the principal clinical and research purposes of in vivo studies. Our findings confirm that synaptic activity offers a novel and functionally relevant readout for the in vitro characterizations of CNTs. They further suggest that the analysis of synaptic activity in neuronal cell cultures can serve as a surrogate for neuromuscular paralysis in the mouse lethal assay, and therefore is expected to significantly reduce the need for terminal animal use in toxin studies and facilitate identification of candidate therapeutics in cell-based screening assays. PMID:26615023

  8. Defective synaptic transmission and structure in the dentate gyrus and selective fear memory impairment in the Rsk2 mutant mouse model of Coffin-Lowry syndrome.

    Morice, Elise; Farley, Séverine; Poirier, Roseline; Dallerac, Glenn; Chagneau, Carine; Pannetier, Solange; Hanauer, André; Davis, Sabrina; Vaillend, Cyrille; Laroche, Serge

    2013-10-01

    The Coffin-Lowry syndrome (CLS) is a syndromic form of intellectual disability caused by loss-of-function of the RSK2 serine/threonine kinase encoded by the rsk2 gene. Rsk2 knockout mice, a murine model of CLS, exhibit spatial learning and memory impairments, yet the underlying neural mechanisms are unknown. In the current study, we examined the performance of Rsk2 knockout mice in cued, trace and contextual fear memory paradigms and identified selective deficits in the consolidation and reconsolidation of hippocampal-dependent fear memories as task difficulty and hippocampal demand increase. Electrophysiological, biochemical and electron microscopy analyses were carried out in the dentate gyrus of the hippocampus to explore potential alterations in neuronal functions and structure. In vivo and in vitro electrophysiology revealed impaired synaptic transmission, decreased network excitability and reduced AMPA and NMDA conductance in Rsk2 knockout mice. In the absence of RSK2, standard measures of short-term and long-term potentiation (LTP) were normal, however LTP-induced CREB phosphorylation and expression of the transcription factors EGR1/ZIF268 were reduced and that of the scaffolding protein SHANK3 was blocked, indicating impaired activity-dependent gene regulation. At the structural level, the density of perforated and non-perforated synapses and of multiple spine boutons was not altered, however, a clear enlargement of spine neck width and post-synaptic densities indicates altered synapse ultrastructure. These findings show that RSK2 loss-of-function is associated in the dentate gyrus with multi-level alterations that encompass modifications of glutamate receptor channel properties, synaptic transmission, plasticity-associated gene expression and spine morphology, providing novel insights into the mechanisms contributing to cognitive impairments in CLS. PMID:23742761

  9. Adenosine (ADO) released during orthodromic stimulation of the frog sympathetic ganglion inhibits phosphatidylinositol turnover (PI) associated with synaptic transmission

    The authors have previously demonstrated that 3H-purine release was enhanced during synaptic activation of the prelabelled frog sympathetic ganglion. In addition, during orthodromic stimulation, there is an increased 3H-inositol release (an index of PI) that occurs during the poststimulation period and not during the period of stimulation. They hypothesized that endogenous ADO inhibits PI turnover during orthodromic stimulation. To test this hypothesis (1) they performed experiments to directly measure ADO release in the extracellular fluid by placing the ganglion in a 5 μl drop of Ringer's and let it come to equilibrium with the interstitial fluid, (2) they destroyed endogenous ADO by suffusing adenosine deaminase (ADA) during the stimulation period. Their results show (1) orthodromic stimulation increases release of ADO into the bathing medium, (2) ADA induced an increase of PI during the stimulation period in contrast to an increase seen only during the poststimulation period when ADA was omitted. They conclude that there is dual control of PI during synaptic activity, a stimulatory effect (cause unknown) and a short lived inhibitory effect that is probably caused by adenosine

  10. Amplification of neuromuscular transmission by methylprednisolone involves activation of presynaptic facilitatory adenosine A2A receptors and redistribution of synaptic vesicles.

    Oliveira, L; Costa, A C; Noronha-Matos, J B; Silva, I; Cavalcante, W L G; Timóteo, M A; Corrado, A P; Dal Belo, C A; Ambiel, C R; Alves-do-Prado, W; Correia-de-Sá, P

    2015-02-01

    The mechanisms underlying improvement of neuromuscular transmission deficits by glucocorticoids are still a matter of debate despite these compounds have been used for decades in the treatment of autoimmune myasthenic syndromes. Besides their immunosuppressive action, corticosteroids may directly facilitate transmitter release during high-frequency motor nerve activity. This effect coincides with the predominant adenosine A2A receptor tonus, which coordinates the interplay with other receptors (e.g. muscarinic) on motor nerve endings to sustain acetylcholine (ACh) release that is required to overcome tetanic neuromuscular depression in myasthenics. Using myographic recordings, measurements of evoked [(3)H]ACh release and real-time video microscopy with the FM4-64 fluorescent dye, results show that tonic activation of facilitatory A2A receptors by endogenous adenosine accumulated during 50 Hz bursts delivered to the rat phrenic nerve is essential for methylprednisolone (0.3 mM)-induced transmitter release facilitation, because its effect was prevented by the A2A receptor antagonist, ZM 241385 (10 nM). Concurrent activation of the positive feedback loop operated by pirenzepine-sensitive muscarinic M1 autoreceptors may also play a role, whereas the corticosteroid action is restrained by the activation of co-expressed inhibitory M2 and A1 receptors blocked by methoctramine (0.1 μM) and DPCPX (2.5 nM), respectively. Inhibition of FM4-64 loading (endocytosis) by methylprednisolone following a brief tetanic stimulus (50 Hz for 5 s) suggests that it may negatively modulate synaptic vesicle turnover, thus increasing the release probability of newly recycled vesicles. Interestingly, bulk endocytosis was rehabilitated when methylprednisolone was co-applied with ZM241385. Data suggest that amplification of neuromuscular transmission by methylprednisolone may involve activation of presynaptic facilitatory adenosine A2A receptors by endogenous adenosine leading to synaptic

  11. DEEP BRAIN STIMULATION IN MIDLINE THALAMIC REGION FACILITATES SYNAPTIC TRANSMISSION AND SHORTTERM MEMORY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE.

    Arrieta-Cruz, Isabel; Pavlides, Constantine; Pasinetti, Giulio Maria

    2010-09-01

    Based on evidence suggesting that deep brain stimulation (DBS) may promote certain cognitive processes, we have been interested in developing DBS as a means of mitigating memory and learning impairments in Alzheimer's disease (AD). In this study we used an animal model of AD (TgCRND8 mice) to determine the effects of high-frequency stimulation (HFS) on non-amyloidogenic α-secretase activity and DBS in short-term memory. We tested our hypothesis using hippocampal slices (in vitro studies) from TgCRND8 mice to evaluate whether HFS increases α-secretase activity (non-amyloidogenic pathway) in the CA1 region. In a second set of experiments, we performed in vivo studies to evaluate whether DBS in midline thalamic region re-establishes hippocampal dependent short-term memory in TgCRND8 mice. The results showed that application of HFS to isolated hippocampal slices significantly increased synaptic plasticity in the CA1 region and promoted a 2-fold increase of non-amyloidogenic α-secretase activity, in comparison to low frequency stimulated controls from TgCRND8 mice. In the in vivo studies, DBS treatment facilitated acquisition of object recognition memory in TgCRND8 mice, in comparison to their own baseline before treatment. These results provide evidence that DBS could enhance short-term memory in the CA1 region of hippocampus in a mouse model of AD. PMID:23227306

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

    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 explain

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

    Ying-Biao Chen

    2015-05-01

    Full Text Available 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 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 using a whole-cell patch-clamp approach. PPNs were identified by retrograde labeling with the fluorescent tracer 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 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 explain the mechanism of action of morphine treatment and morphine-induced bladder dysfunction in the

  14. Regulation of synaptic transmission in the mossy fibre-granule cell pathway of rat cerebellum by metabotropic glutamate receptors.

    Vetter, P; Garthwaite, J; Batchelor, A M

    1999-06-01

    The role of metabotropic glutamate receptors (mGluRs) in the mossy fibre-granule cell pathway in rat cerebellum was studied using slice preparations and electrophysiological techniques. Application of the group I selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) evoked, in a concentration-dependent manner (EC50 = 33 microM), a depolarising/hyperpolarising complex response from granule cells which was preferentially inhibited by the group I selective antagonist (S)-4-carboxyphenylglycine (4CPG). The group III selective agonist L-amino-4-phosphonobutyrate (AP4) evoked a hyperpolarising response (EC50 = 10 microM) which was inhibited by the group II/III selective antagonist (S)-alpha-methyl-4-phosphonophenylglycine (MPPG). The group II agonist (2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)glycine (DCG-IV) elicited no measurable voltage change. The amplitude of the synaptically-mediated mossy fibre response in granule cells was unaffected during application of AP4, was reduced by DHPG and was enhanced by DCG-IV (EC50 = 80 nM). These effects were inhibited by the group selective antagonists 4CPG and (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-4), respectively. Further investigation using patch-clamp recording revealed that DCG-IV potently inhibited spontaneous GABAergic currents. We conclude that group I and III (but not group II) mGluRs are functionally expressed by granule cells, whereas unexpectedly group II or III mGluRs do not appear to be present presynaptically on mossy fibre terminals. Group II mGluRs are located on Golgi cell terminals; when activated these receptors cause disinhibition, a function which may be important for gating information transfer from the mossy fibres to the granule cells. PMID:10465684

  15. Modulatory effects of serotonin on glutamatergic synaptic transmission and long-term depression in the deep cerebellar nuclei.

    Murano, M; Saitow, F; Suzuki, H

    2011-01-13

    The deep cerebellar nuclei (DCN) are the terminal components of the cerebellar circuitry and constitute its primary output structure. Their activity is important for certain forms of motor learning as well as generation and control of movement. DCN neurons receive glutamatergic excitatory inputs from the pontine nuclei via mossy fibres (MFs) and concomitantly receive inputs from 5-HT-containing neurons of the raphe nuclei. We aimed to explore the roles of 5-HT at MF-DCN synapses by using cerebellar slices from 11 to 15-day-old rats. Bath application of 5-HT reversibly decreased the amplitude of stimulation-evoked excitatory postsynaptic currents (eEPSCs) via the activation of 5-HT1B receptors at the presynaptic terminals of the MFs. Burst stimulation of the MFs elicited long-term depression (LTD) at the MF-DCN synapses that require activation of the group I metabotropic glutamate receptor (mGluR). In the presence of 5-HT, the extent of burst-induced LTD of MF EPSCs was significantly reduced. Application of 5-HT also decreased the amplitude of mGluR-dependent slow EPSCs evoked by similar burst stimulation. Furthermore, (S)-3,5-dihydroxyphenylglycine (DHPG), a group I mGluR agonist, induced chemical LTD of MF EPSCs, and 5-HT had no significant effect on this LTD. Taken together, the results suggest that 5-HT not only has transitory inhibitory effects on MF EPSCs but also plays a role in regulating the long-term synaptic efficacy. PMID:20969929

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

    Bonansco, Christian; Fuenzalida, Marco

    2016-01-01

    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. PMID:27006834

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

    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.

  18. Familial hemiplegic migraine type-1 mutated cav2.1 calcium channels alter inhibitory and excitatory synaptic transmission in the lateral superior olive of mice.

    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. Action of (D-Pro4)-β-casomorphin/sub 1-5/ on processes of synaptic transmission

    The peptide (D-Pro4)-β-casomorphin/sub 1-5/ is a potent and long acting analgesic. Furthermore it is able to antagonize apomorphine-induced behavioral patterns, which are preferentially used as screening methods to detect dopaminolytic or neuroleptic properties. Because all of these tests do not exclude interaction of drugs with transmission systems other than the dopaminergic, biochemical studies were undertaken to estimate possible influences of the opioid peptide on processes of dopaminergic, serotonergic, and cholinergic transmission systems. In lower concentrations (D-Pro4)-β-casomorphin/sub 1-5/ enhances the potassium-stimulated release of acetylcholine from hippocampal slices and the basal overflow of dopamine from striatal slices. In high concentrations an augmentation of the potassium evoked release of dopamine and a reduction of the binding of [3h]spiperone on dopaminergic and serotonergic striatal receptors could be observed. These biochemical findings are discussed with regard to the behavioral patterns induced by this opioid peptide. (author)

  20. Astroglial networks scale synaptic activity and plasticity

    Pannasch, Ulrike; Vargová, Lydia; Reingruber, Jürgen; Ezan, Pascal; Holcman, David; Giaume, Christian; Syková, Eva; Rouach, Nathalie

    2011-01-01

    Astrocytes dynamically interact with neurons to regulate synaptic transmission. Although the gap junction proteins connexin 30 (Cx30) and connexin 43 (Cx43) mediate the extensive network organization of astrocytes, their role in synaptic physiology is unknown. Here we show, by inactivating Cx30 and Cx43 genes, that astroglial networks tone down hippocampal synaptic transmission in CA1 pyramidal neurons. Gap junctional networking facilitates extracellular glutamate and potassium removal during...

  1. Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis.

    Robert Nisticò

    Full Text Available Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS and its mouse model, experimental autoimmune encephalomyelitis (EAE. In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP induction was favored over long-term depression (LTD in EAE, as shown by a significant rightward shift in the frequency-synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS.

  2. Monoallelic deletion of the microRNA biogenesis gene Dgcr8 produces deficits in the development of excitatory synaptic transmission in the prefrontal cortex

    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.

  3. Blockade of presynaptic 4-aminopyridine-sensitive potassium channels increases initial neurotransmitter release probability, reinstates synaptic transmission altered by GABAB receptor activation in rat midbrain periaqueductal gray.

    Li, Guangying; Liu, Zhi-Liang; Zhang, Wei-Ning; Yang, Kun

    2016-01-01

    The activation of γ-aminobutyric acid receptor subtype B (GABAB) receptors in the midbrain ventrolateral periaqueductal gray (vlPAG) induces both postsynaptic and presynaptic inhibition. Whereas the postsynaptic inhibition is mediated by G protein-coupled inwardly rectifying K channels, the presynaptic inhibition of neurotransmitter release is primarily mediated by voltage-gated calcium channels. Using whole-cell recordings from acute rat PAG slices, we report here that the bath application of 4-aminopyridine, a voltage-gated K channel blocker, increases the initial GABA and glutamate release probability (P) and reinstates P depressed by presynaptic GABAB receptor activation at inhibitory and excitatory synapses, respectively. However, Ba, which blocks G protein-coupled inwardly rectifying K channels, does not produce similar effects. Our data suggest that the blockade of presynaptic 4-aminopyridine-sensitive K channels in vlPAG facilitates neurotransmitter release and reinstates synaptic transmission that has been altered by presynaptic GABAB receptor activation. Because vlPAG is involved in the descending pain control system, the present results may have potential therapeutic applications. PMID:26575285

  4. Estradiol attenuates ischemia-induced death of hippocampal neurons and enhances synaptic transmission in aged, long-term hormone-deprived female rats.

    Tomoko Inagaki

    Full Text Available BACKGROUND: Transient global forebrain ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons, and the ovarian hormone 17β-estradiol (E2 reduces neuronal loss in young and middle-aged females. The neuroprotective efficacy of E2 after a prolonged period of hormone deprivation is controversial, and few studies examine this issue in aged animals given E2 treatment after induction of ischemia. METHODOLOGY/PRINCIPAL FINDINGS: The present study investigated the neuroprotective effects of E2 administered immediately after global ischemia in aged female rats (15-18 months after 6 months of hormone deprivation. We also used electrophysiological methods to assess whether CA1 synapses in the aging hippocampus remain responsive to E2 after prolonged hormone withdrawal. Animals were ovariohysterectomized and underwent 10 min global ischemia 6 months later. A single dose of E2 (2.25 µg infused intraventricularly after reperfusion significantly increased cell survival, with 45% of CA1 neurons surviving vs 15% in controls. Ischemia also induced moderate loss of CA3/CA4 pyramidal cells. Bath application of 1 nM E2 onto brain slices derived from non-ischemic aged females after 6 months of hormone withdrawal significantly enhanced excitatory transmission at CA1 synapses evoked by Schaffer collateral stimulation, and normal long-term potentiation (LTP was induced. The magnitude of LTP and of E2 enhancement of field excitatory postsynaptic potentials was indistinguishable from that recorded in slices from young rats. CONCLUSIONS/SIGNIFICANCE: The data demonstrate that 1 acute post-ischemic infusion of E2 into the brain ventricles is neuroprotective in aged rats after 6 months of hormone deprivation; and 2 E2 enhances synaptic transmission in CA1 pyramidal neurons of aged long-term hormone deprived females. These findings provide evidence that the aging hippocampus remains responsive to E2 administered either in vivo or in vitro even after

  5. Autism-Associated Mutations in ProSAP2/Shank3 Impair Synaptic Transmission and Neurexin–Neuroligin-Mediated Transsynaptic Signaling

    Arons, Magali H.; Thynne, Charlotte J.; Grabrucker, Andreas M; Li, Dong; Schoen, Michael; Cheyne, Juliette E.; Boeckers, Tobias M.; Montgomery, Johanna M; Garner, Craig C.

    2012-01-01

    Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders (ASDs), including Neuroligins, Neurexins, and members of the ProSAP/Shank family, thereby suggesting that these genetic forms of autism may share common synaptic mechanisms. Initial studies of ASD-associated mutations in ProSAP2/Shank3 support a role for this protein in glutamate receptor function and spine morphology, but these synaptic phenotypes are...

  6. Blocking effects of human tau on squid giant synapse transmission and its prevention by T-817 MA

    Herman Moreno

    2011-05-01

    Full Text Available Filamentous tau inclusions are hallmarks of Alzheimer’s disease (AD and related neurodegenerative tauopathies, but the molecular mechanisms involved in tau mediated changes in neuronal function and their possible effects on synaptic transmission are unknown. We have evaluated the effects of human tau protein injected directly into the presynaptic terminal axon of the squid giant synapse, which affords functional, structural, and biochemical analysis of its action on the synaptic release process. Indeed, we have found that at physiological concentrations recombinant human tau isoforms (h-tau 42 become phosphorylated, produce a rapid synaptic transmission block, and induce the formation of clusters of aggregated synaptic vesicles in the vicinity of the active zone. Presynaptic voltage clamp recordings demonstrate that h-tau does not modify the presynaptic calcium current amplitude or kinetics. Analysis of synaptic noise at the post-synaptic axon following pre-synaptic h-tau42 microinjection revealed an initial phase of increase spontaneous transmitter release followed by a marked reduction in noise. Finally, systemic administration of T-817MA, a proposed neuro-protective agent, rescued tau-induced synaptic abnormalities. Our results show novel mechanisms of h-tau42 mediated synaptic transmission failure and more importantly identify a potential therapeutic agent to treat/prevent tau-related neurotoxicity.

  7. EDITORIAL: Synaptic electronics Synaptic electronics

    Demming, Anna; Gimzewski, James K.; Vuillaume, Dominique

    2013-09-01

    Conventional computers excel in logic and accurate scientific calculations but make hard work of open ended problems that human brains handle easily. Even von Neumann—the mathematician and polymath who first developed the programming architecture that forms the basis of today's computers—was already looking to the brain for future developments before his death in 1957 [1]. Neuromorphic computing uses approaches that better mimic the working of the human brain. Recent developments in nanotechnology are now providing structures with very accommodating properties for neuromorphic approaches. This special issue, with guest editors James K Gimzewski and Dominique Vuillaume, is devoted to research at the serendipitous interface between the two disciplines. 'Synaptic electronics', looks at artificial devices with connections that demonstrate behaviour similar to synapses in the nervous system allowing a new and more powerful approach to computing. Synapses and connecting neurons respond differently to incident signals depending on the history of signals previously experienced, ultimately leading to short term and long term memory behaviour. The basic characteristics of a synapse can be replicated with around ten simple transistors. However with the human brain having around 1011 neurons and 1015 synapses, artificial neurons and synapses from basic transistors are unlikely to accommodate the scalability required. The discovery of nanoscale elements that function as 'memristors' has provided a key tool for the implementation of synaptic connections [2]. Leon Chua first developed the concept of the 'The memristor—the missing circuit element' in 1971 [3]. In this special issue he presents a tutorial describing how memristor research has fed into our understanding of synaptic behaviour and how they can be applied in information processing [4]. He also describes, 'The new principle of local activity, which uncovers a minuscule life-enabling "Goldilocks zone", dubbed the

  8. EDITORIAL: Synaptic electronics Synaptic electronics

    Demming, Anna; Gimzewski, James K.; Vuillaume, Dominique

    2013-09-01

    Conventional computers excel in logic and accurate scientific calculations but make hard work of open ended problems that human brains handle easily. Even von Neumann—the mathematician and polymath who first developed the programming architecture that forms the basis of today's computers—was already looking to the brain for future developments before his death in 1957 [1]. Neuromorphic computing uses approaches that better mimic the working of the human brain. Recent developments in nanotechnology are now providing structures with very accommodating properties for neuromorphic approaches. This special issue, with guest editors James K Gimzewski and Dominique Vuillaume, is devoted to research at the serendipitous interface between the two disciplines. 'Synaptic electronics', looks at artificial devices with connections that demonstrate behaviour similar to synapses in the nervous system allowing a new and more powerful approach to computing. Synapses and connecting neurons respond differently to incident signals depending on the history of signals previously experienced, ultimately leading to short term and long term memory behaviour. The basic characteristics of a synapse can be replicated with around ten simple transistors. However with the human brain having around 1011 neurons and 1015 synapses, artificial neurons and synapses from basic transistors are unlikely to accommodate the scalability required. The discovery of nanoscale elements that function as 'memristors' has provided a key tool for the implementation of synaptic connections [2]. Leon Chua first developed the concept of the 'The memristor—the missing circuit element' in 1971 [3]. In this special issue he presents a tutorial describing how memristor research has fed into our understanding of synaptic behaviour and how they can be applied in information processing [4]. He also describes, 'The new principle of local activity, which uncovers a minuscule life-enabling "Goldilocks zone", dubbed the

  9. Effect of insulin on excitatory synaptic transmission onto dopamine neurons of the ventral tegmental area in a mouse model of hyperinsulinemia

    Liu, S; Labouèbe, G; S. Karunakaran; Clee, S.M.; Borgland, S L

    2013-01-01

    Obesity has drastically increased over the last few decades. Obesity is associated with elevated insulin levels, which can gain access to the brain, including into dopamine neurons of the ventral tegmental area (VTA), a brain region critical for mediating reward-seeking behavior. Synaptic plasticity of VTA dopamine neurons is associated with altered motivation to obtain reinforcing substances such as food and drugs of abuse. Under physiological circumstances, insulin in the VTA can suppress e...

  10. Fluoxetine (prozac) and serotonin act on excitatory synaptic transmission to suppress single layer 2/3 pyramidal neuron-triggered cell assemblies in the human prefrontal cortex.

    Komlosi, G.; Molnar, G.; Rozsa, M.; Olah, S.; Barzo, P.; Tamas, G.

    2012-01-01

    Selective serotonin reuptake inhibitors are the most widely prescribed drugs targeting the CNS with acute and chronic effects in cognitive, emotional and behavioral processes. This suggests that microcircuits of the human cerebral cortex are powerfully modulated by selective serotonin reuptake inhibitors, however, direct measurements of serotonergic regulation on human synaptic interactions are missing. Using multiple whole-cell patch-clamp recordings from neurons in acute cortical slices der...

  11. Syntaxin 1B, but not syntaxin 1A, is necessary for the regulation of synaptic vesicle exocytosis and of the readily releasable pool at central synapses.

    Tatsuya Mishima

    Full Text Available Two syntaxin 1 (STX1 isoforms, HPC-1/STX1A and STX1B, are coexpressed in neurons and function as neuronal target membrane (t-SNAREs. However, little is known about their functional differences in synaptic transmission. STX1A null mutant mice develop normally and do not show abnormalities in fast synaptic transmission, but monoaminergic transmissions are impaired. In the present study, we found that STX1B null mutant mice died within 2 weeks of birth. To examine functional differences between STX1A and 1B, we analyzed the presynaptic properties of glutamatergic and GABAergic synapses in STX1B null mutant and STX1A/1B double null mutant mice. We found that the frequency of spontaneous quantal release was lower and the paired-pulse ratio of evoked postsynaptic currents was significantly greater in glutamatergic and GABAergic synapses of STX1B null neurons. Deletion of STX1B also accelerated synaptic vesicle turnover in glutamatergic synapses and decreased the size of the readily releasable pool in glutamatergic and GABAergic synapses. Moreover, STX1A/1B double null neurons showed reduced and asynchronous evoked synaptic vesicle release in glutamatergic and GABAergic synapses. Our results suggest that although STX1A and 1B share a basic function as neuronal t-SNAREs, STX1B but not STX1A is necessary for the regulation of spontaneous and evoked synaptic vesicle exocytosis in fast transmission.

  12. Roles of Synaptic MAGUK Proteins in Analgesia and Anesthesia

    TAO Yuan-xiang

    2004-01-01

    @@ In the central nervous system, synapses, highly specialized sites of contact between neurons, are organized to facilitate the transmission of signals from the pre-synaptic terminal to the postsynaptic membrane and to activate subsequent signal transduction cascades that result in appropriate cellular events. Efficient and precise organization of synaptic proteins such as receptors, ion channels, and signaling molecules at both pre-synaptic and postsynaptic membranes is critical for proper signal transmission.

  13. Synaptic plasticity and phosphorylation

    Lee, Hey-Kyoung

    2006-01-01

    A number of neuronal functions, including synaptic plasticity, depend on proper regulation of synaptic proteins, many of which can be rapidly regulated by phosphorylation. Neuronal activity controls the function of these synaptic proteins by exquisitely regulating the balance of various protein kinase and protein phosphatase activity. Recent understanding of synaptic plasticity mechanisms underscores important roles that these synaptic phosphoproteins play in regulating both pre- and post-syn...

  14. Synaptic Vesicle Proteins and Active Zone Plasticity

    Kittel, Robert J.; Heckmann, Manfred

    2016-01-01

    Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the AZ. The protein-rich cytomatrix at the active zone (CAZ) provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and AZ states, which has heretofore received little attention.

  15. Normal photoresponses and altered b-wave responses to APB in the mdxCv3 mouse isolated retina ERG supports role for dystrophin in synaptic transmission

    GREEN, DANIEL G.; Guo, Hao; PILLERS, DE-ANN M.

    2004-01-01

    The mdxCv3 mouse is a model for Duchenne muscular dystrophy (DMD). DMD is an X-linked disorder with defective expression of the protein dystrophin, and which is associated with a reduced b-wave and has other electroretinogram (ERG) abnormalities. To assess potential causes for the abnormalities, we recorded ERGs from pieces of isolated C57BL/6J and mdxCv3 mouse retinas, including measurements of transretinal and intraretinal potentials. The ERGs from the isolated mdxCv3 retina differ from tho...

  16. Inflammation reduces the contribution of N-type calcium channels to primary afferent synaptic transmission onto NK1 receptor-positive lamina I neurons in the rat dorsal horn.

    Rycroft, Beth K; Vikman, Kristina S; Christie, MacDonald J

    2007-05-01

    N-type calcium channels contribute to the release of glutamate from primary afferent terminals synapsing onto nocisponsive neurons in the dorsal horn of the spinal cord, but little is known of functional adaptations to these channels in persistent pain states. Subtype-selective conotoxins and other drugs were used to determine the role of different calcium channel types in a rat model of inflammatory pain. Electrically evoked primary afferent synapses onto lumber dorsal horn neurons were examined three days after induction of inflammation with intraplantar complete Freund's adjuvant. The maximal inhibitory effect of the N-type calcium channel blockers, omega-conotoxins CVID and MVIIA, were attenuated in NK1 receptor-positive lamina I neurons after inflammation, but the potency of CVID was unchanged. This was associated with reduced inhibition of the frequency of asynchronous-evoked synaptic events by CVID studied in the presence of extracellular strontium, suggesting reduced N-type channel contribution to primary afferent synapses after inflammation. After application of CVID, the relative contributions of P/Q and L channels to primary afferent transmission and the residual current were unchanged by inflammation, suggesting the adaptation was specific to N-type channels. Blocking T-type channels did not affect synaptic amplitude under control or inflamed conditions. Reduction of N-type channel contribution to primary afferent transmission was selective for NK1 receptor-positive neurons identified by post hoc immunohistochemistry and did not occur at synapses in laminae II(o) or II(i), or inhibitory synapses. These results suggest that inflammation selectively downregulates N-type channels in the terminals of primary afferents synapsing onto (presumed) nociceptive lamina I NK1 receptor-positive neurons. PMID:17303639

  17. Deep mRNA sequencing of the Tritonia diomedea brain transcriptome provides access to gene homologues for neuronal excitability, synaptic transmission and peptidergic signalling.

    Adriano Senatore

    Full Text Available The sea slug Tritonia diomedea (Mollusca, Gastropoda, Nudibranchia, has a simple and highly accessible nervous system, making it useful for studying neuronal and synaptic mechanisms underlying behavior. Although many important contributions have been made using Tritonia, until now, a lack of genetic information has impeded exploration at the molecular level.We performed Illumina sequencing of central nervous system mRNAs from Tritonia, generating 133.1 million 100 base pair, paired-end reads. De novo reconstruction of the RNA-Seq data yielded a total of 185,546 contigs, which partitioned into 123,154 non-redundant gene clusters (unigenes. BLAST comparison with RefSeq and Swiss-Prot protein databases, as well as mRNA data from other invertebrates (gastropod molluscs: Aplysia californica, Lymnaea stagnalis and Biomphalaria glabrata; cnidarian: Nematostella vectensis revealed that up to 76,292 unigenes in the Tritonia transcriptome have putative homologues in other databases, 18,246 of which are below a more stringent E-value cut-off of 1x10-6. In silico prediction of secreted proteins from the Tritonia transcriptome shotgun assembly (TSA produced a database of 579 unique sequences of secreted proteins, which also exhibited markedly higher expression levels compared to other genes in the TSA.Our efforts greatly expand the availability of gene sequences available for Tritonia diomedea. We were able to extract full length protein sequences for most queried genes, including those involved in electrical excitability, synaptic vesicle release and neurotransmission, thus confirming that the transcriptome will serve as a useful tool for probing the molecular correlates of behavior in this species. We also generated a neurosecretome database that will serve as a useful tool for probing peptidergic signalling systems in the Tritonia brain.

  18. Activation of group II metabotropic glutamate receptors induces long-term depression of excitatory synaptic transmission in the substantia nigra pars reticulata

    Johnson, Kari A.; Niswender, Colleen M.; Conn, P. Jeffrey; Xiang, Zixiu

    2011-01-01

    Activation of group II metabotropic glutamate receptors (mGlu2 and mGlu3) has been implicated as a potential therapeutic strategy for treating both motor symptoms and progressive neurodegeneration in Parkinson's disease (PD). Modulation of excitatory transmission in the basal ganglia represents a possible mechanism by which group II mGlu agonists could exert antiparkinsonian effects. Previous studies have identified reversible effects of mGlu2/3 activation on excitatory transmission at variou...

  19. Early developmental bisphenol-A exposure sex-independently impairs spatial memory by remodeling hippocampal dendritic architecture and synaptic transmission in rats.

    Liu, Zhi-Hua; Ding, Jin-Jun; Yang, Qian-Qian; Song, Hua-Zeng; Chen, Xiang-Tao; Xu, Yi; Xiao, Gui-Ran; Wang, Hui-Li

    2016-01-01

    Bisphenol-A (BPA, 4, 4'-isopropylidene-2-diphenol), a synthetic xenoestrogen that widely used in the production of polycarbonate plastics, has been reported to impair hippocampal development and function. Our previous study has shown that BPA exposure impairs Sprague-Dawley (SD) male hippocampal dendritic spine outgrowth. In this study, the sex-effect of chronic BPA exposure on spatial memory in SD male and female rats and the related synaptic mechanism were further investigated. We found that chronic BPA exposure impaired spatial memory in both SD male and female rats, suggesting a dysfunction of hippocampus without gender-specific effect. Further investigation indicated that BPA exposure causes significant impairment of dendrite and spine structure, manifested as decreased dendritic complexity, dendritic spine density and percentage of mushroom shaped spines in hippocampal CA1 and dentate gyrus (DG) neurons. Furthermore, a significant reduction in Arc expression was detected upon BPA exposure. Strikingly, BPA exposure significantly increased the mIPSC amplitude without altering the mEPSC amplitude or frequency, accompanied by increased GABAARβ2/3 on postsynaptic membrane in cultured CA1 neurons. In summary, our study indicated that Arc, together with the increased surface GABAARβ2/3, contributed to BPA induced spatial memory deficits, providing a novel molecular basis for BPA achieved brain impairment. PMID:27578147

  20. Methamphetamine blunts Ca(2+) currents and excitatory synaptic transmission through D1/5 receptor-mediated mechanisms in the mouse medial prefrontal cortex.

    González, Betina; Rivero-Echeto, Celeste; Muñiz, Javier A; Cadet, Jean Lud; García-Rill, Edgar; Urbano, Francisco J; Bisagno, Verónica

    2016-05-01

    Psychostimulant addiction is associated with dysfunctions in frontal cortex. Previous data demonstrated that repeated exposure to methamphetamine (METH) can alter prefrontal cortex (PFC)-dependent functions. Here, we show that withdrawal from repetitive non-contingent METH administration (7 days, 1 mg/kg) depressed voltage-dependent calcium currents (ICa ) and increased hyperpolarization-activated cation current (IH ) amplitude and the paired-pulse ratio of evoked excitatory postsynaptic currents (EPSCs) in deep-layer pyramidal mPFC neurons. Most of these effects were blocked by systemic co-administration of the D1/D5 receptor antagonist SCH23390 (0.5 and 0.05 mg/kg). In vitro METH (i.e. bath-applied to slices from naïve-treated animals) was able to emulate its systemic effects on ICa and evoked EPSCs paired-pulse ratio. We also provide evidence of altered mRNA expression of (1) voltage-gated calcium channels P/Q-type Cacna1a (Cav 2.1), N-type Cacna1b (Cav 2.2), T-type Cav 3.1 Cacna1g, Cav 3.2 Cacna1h, Cav 3.3 Cacna1i and the auxiliary subunit Cacna2d1 (α2δ1); (2) hyperpolarization-activated cyclic nucleotide-gated channels Hcn1 and Hcn2; and (3) glutamate receptors subunits AMPA-type Gria1, NMDA-type Grin1 and metabotropic Grm1 in the mouse mPFC after repeated METH treatment. Moreover, we show that some of these changes in mRNA expression were sensitive D1/5 receptor blockade. Altogether, these altered mechanisms affecting synaptic physiology and transcriptional regulation may underlie PFC functional alterations that could lead to PFC impairments observed in METH-addicted individuals. PMID:25871318

  1. Synapsin IIa controls the reserve pool of glutamatergic synaptic vesicles

    Gitler, Daniel; Cheng, Qing; Greengard, Paul; Augustine, George J.

    2008-01-01

    Synapsins regulate synaptic transmission by controlling the reserve pool of synaptic vesicles. Each of the three mammalian synapsin genes is subject to alternative splicing, yielding several isoforms whose roles are unknown. To investigate the function of these isoforms, we examined the synaptic effects of introducing each isoform into glutamatergic cultured hippocampal neurons from synapsin triple knock-out mice. Remarkably, we found that synapsin IIa was the only isoform that could rescue t...

  2. Concurrent Imaging of Synaptic Vesicle Recycling and Calcium Dynamics

    Li, Haiyan; Foss, Sarah M.; Dobryy, Yuriy L.; Park, C. Kevin; Hires, Samuel Andrew; Shaner, Nathan C.; Tsien, Roger Y.; Osborne, Leslie C.; Voglmaier, Susan M.

    2011-01-01

    Synaptic transmission involves the calcium dependent release of neurotransmitter from synaptic vesicles. Genetically encoded optical probes emitting different wavelengths of fluorescent light in response to neuronal activity offer a powerful approach to understand the spatial and temporal relationship of calcium dynamics to the release of neurotransmitter in defined neuronal populations. To simultaneously image synaptic vesicle recycling and changes in cytosolic calcium, we developed a red-sh...

  3. Concurrent imaging of synaptic vesicle recycling and calcium dynamics.

    Haiyan eLi; Foss, Sarah M.; Yuriy eDobryy; C. Kevin ePark; Samuel Andrew Hires; Shaner, Nathan C.; Tsien, Roger Y.; Osborne, Leslie C.; Voglmaier, Susan M.

    2011-01-01

    Synaptic transmission involves the calcium-dependent release of neurotransmitter from synaptic vesicles. Genetically encoded optical probes emitting different wavelengths of fluorescent light in response to neuronal activity offer a powerful approach to understand the spatial and temporal relationship of calcium dynamics to the release of neurotransmitter in defined neuronal populations. To simultaneously image synaptic vesicle recycling and changes in cytosolic calcium, we developed a red-...

  4. Cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans.

    Dania eVecchia

    2015-02-01

    Full Text Available Familial hemiplegic migraine type 1 (FHM1 is caused by gain-of-function mutations in CaV2.1 (P/Q-type Ca2+ channels. Knockin (KI mice carrying the FHM1 R192Q missense mutation show enhanced cortical excitatory synaptic transmission at pyramidal cell synapses but unaltered cortical inhibitory neurotransmission at fast-spiking interneuron synapses. Enhanced cortical glutamate release was shown to cause the facilitation of cortical spreading depression (CSD in R192Q KI mice. It, however, remains unknown how other FHM1 mutations affect cortical synaptic transmission. Here, we studied neurotransmission in cortical neurons in microculture from KI mice carrying the S218L mutation, which causes a severe FHM syndrome in humans and an allele-dosage dependent facilitation of experimental CSD in KI mice, which is larger than that caused by the R192Q mutation. We show gain-of-function of excitatory neurotransmission, due to increased action-potential evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at multipolar interneuron synapses in S218L KI mice. In contrast with the larger gain-of-function of neuronal CaV2.1 current in homozygous than heterozygous S218L KI mice, the gain-of-function of evoked glutamate release, the paired-pulse ratio and the Ca2+ dependence of the EPSC were all similar in homozygous and heterozygous S218L KI mice, suggesting compensatory changes in the homozygous mice. Furthermore, we reveal a unique feature of S218L KI cortical synapses which is the presence of a fraction of mutant CaV2.1 channels being open at resting potential. Our data suggest that, while the gain-of-function of evoked glutamate release may explain the facilitation of CSD in heterozygous S218L KI mice, the further facilitation of CSD in homozygous S218L KI mice is due to other CaV2.1-dependent mechanisms, that likely include Ca2+ influx at voltages sub-threshold for action

  5. Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology.

    Polydoro, Manuela; Acker, Christopher M; Duff, Karen; Castillo, Pablo E; Davies, Peter

    2009-08-26

    A hallmark feature of Alzheimer's disease pathology is the presence of neurofibrillary tangles (NFTs), which are intracellular aggregates of conformationally abnormal and hyperphosphorylated tau. The presence of NFTs in the forebrain is associated with impairments of cognitive function, supporting a central role for tau in dementia. The significance of the accumulation of NFTs for neuronal and cognitive function is still obscure. It is possible that NFTs disrupt synaptic transmission and plasticity, leading to memory deficits and cognitive malfunction. To elucidate the relationship between the development of tau pathology and synaptic and cognitive functions, we performed behavioral tests and electrophysiological experiments in the htau mouse. Here we report age-dependent cognitive and physiological impairments in htau mice that preceded neurodegeneration. Twelve-month-old htau mice with moderate tau pathology, but not 4-month-old mice with early-stage tau pathology, presented cognitive deficits in an object recognition memory task in which the visual recognition memory of a novel object was disrupted. Moreover, only 12-month-old htau mice exhibit spatial memory deficits, as indicated by the impaired performance in the Morris water maze. In addition, we report that basal synaptic transmission and induction of long-term potentiation with high-frequency stimulation, but not theta burst stimulation, is perturbed in hippocampal CA1 region of old but not young htau mice. Our results suggest that tau pathology may underlie an age-dependent learning impairment through disruption of synaptic function. PMID:19710325

  6. Abnormal cubic-tetragonal phase transition of barium strontium titanate nanoparticles studied by in situ Raman spectroscopy and transmission electron microscopy heating experiments

    Zhang, Yin; Chen, Chen; Gao, Ran; Xia, Feng; Li, YueSheng; Che, Renchao, E-mail: rcche@fudan.edu.cn [Laboratory of Advanced Materials, Department of Materials Science, Collaborative Innovation Center of Chemistry for Energy Materials, Fudan University, Shanghai 200438 (China)

    2015-11-02

    Phase stability of the ferroelectric materials at high temperature is extremely important to their device performance. Ba{sub x}Sr{sub 1−x}TiO{sub 3} (BST) nanoparticles with different Sr contents (x = 1, 0.91, 0.65, 0.4, and 0) are prepared by a facile hydrothermal method. Using Raman spectroscopy and transmission electron microscopy (TEM) analyses under in situ heating conditions (up to 300 °C), the phase transitions of BST nanoparticles between 25 °C and 280 °C are comprehensively investigated. The original Curie temperature of BST nanoparticles decreases abruptly with the increase in Sr content, which is more obvious than in the bulk or film material. Besides, an abnormal phase transition from cubic to tetragonal structure is observed from BST nanoparticles and the transition temperature rises along with the increase in Sr content. Direct TEM evidences including a slight lattice distortion have been provided. Differently, BaTiO{sub 3} nanoparticles remained in the tetragonal phase during the above temperature ranges.

  7. Abnormal cubic-tetragonal phase transition of barium strontium titanate nanoparticles studied by in situ Raman spectroscopy and transmission electron microscopy heating experiments

    Phase stability of the ferroelectric materials at high temperature is extremely important to their device performance. BaxSr1−xTiO3 (BST) nanoparticles with different Sr contents (x = 1, 0.91, 0.65, 0.4, and 0) are prepared by a facile hydrothermal method. Using Raman spectroscopy and transmission electron microscopy (TEM) analyses under in situ heating conditions (up to 300 °C), the phase transitions of BST nanoparticles between 25 °C and 280 °C are comprehensively investigated. The original Curie temperature of BST nanoparticles decreases abruptly with the increase in Sr content, which is more obvious than in the bulk or film material. Besides, an abnormal phase transition from cubic to tetragonal structure is observed from BST nanoparticles and the transition temperature rises along with the increase in Sr content. Direct TEM evidences including a slight lattice distortion have been provided. Differently, BaTiO3 nanoparticles remained in the tetragonal phase during the above temperature ranges

  8. Action of (D-ProU)-US -casomorphin/sub 1-5/ on processes of synaptic transmission. [Use of TH-spiperone for binding studies

    Kammerer, E.; Koch, S.; Roque, D.M.L.

    1985-01-01

    The peptide (D-ProU)-US -casomorphin/sub 1-5/ is a potent and long acting analgesic. Furthermore it is able to antagonize apomorphine-induced behavioral patterns, which are preferentially used as screening methods to detect dopaminolytic or neuroleptic properties. Because all of these tests do not exclude interaction of drugs with transmission systems other than the dopaminergic, biochemical studies were undertaken to estimate possible influences of the opioid peptide on processes of dopaminergic, serotonergic, and cholinergic transmission systems. In lower concentrations (D-ProU)-US -casomorphin/sub 1-5/ enhances the potassium-stimulated release of acetylcholine from hippocampal slices and the basal overflow of dopamine from striatal slices. In high concentrations an augmentation of the potassium evoked release of dopamine and a reduction of the binding of (TH)spiperone on dopaminergic and serotonergic striatal receptors could be observed. These biochemical findings are discussed with regard to the behavioral patterns induced by this opioid peptide. (author).

  9. 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

    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

  10. Co-Application of Corticosterone and Growth Hormone Upregulates NR2B Protein and Increases the NR2B:NR2A Ratio and Synaptic Transmission in the Hippocampus

    Ghada S. Mahmoud

    2014-10-01

    Full Text Available Objectives: This in vitro study aimed to investigate the possible mechanism underlying the protective effect of growth hormone (GH on hippocampal function during periods of heightened glucocorticoid exposure. Methods: This study was conducted between January and June 2005 at the Joan C. Edwards School of Medicine, Marshall University, in Huntington, West Virginia, USA. The effects of the co-application of GH and corticosterone (CORT were tested at different concentrations on the field excitatory postsynaptic potentials (fEPSPs of the hippocampal slices of rats in two different age groups. Changes in the protein expression of N-methyl-D-aspartate receptor (NMDAR subunits NR1, NR2B and NR2A were measured in hippocampal brain slices treated with either artificial cerebrospinal fluid (ACSF, low doses of CORT alone or both CORT and GH for three hours. Results: The co-application of CORT and GH was found to have an additive effect on hippocampal synaptic transmission compared to either drug alone. Furthermore, the combined use of low concentrations of GH and CORT was found to have significantly higher effects on the enhancement of fEPSPs in older rats compared to young ones. Both GH and CORT enhanced the protein expression of the NR2A subunit. Simultaneous exposure to low concentrations of GH and CORT significantly enhanced NR2B expression and increased the NR2B:NR2A ratio. In contrast, perfusion with CORT alone caused significant suppression in the NR1 and NR2B protein expression and a decrease in the NR2B:NR2A ratio. Conclusion: These results suggest that NMDARs provide a potential target for mediating the GH potential protective effect against stress and age-related memory and cognitive impairment.

  11. Synaptic Plasticity and Nociception

    ChenJianguo

    2004-01-01

    Synaptic plasticity is one of the fields that progresses rapidly and has a lot of success in neuroscience. The two major types of synaptie plasticity: long-term potentiation ( LTP and long-term depression (LTD are thought to be the cellular mochanisms of learning and memory. Recently, accumulating evidence suggests that, besides serving as a cellular model for learning and memory, the synaptic plasticity involves in other physiological or pathophysiological processes, such as the perception of pain and the regulation of cardiovascular system. This minireview will focus on the relationship between synaptic plasticity and nociception.

  12. Astrocytes: Orchestrating synaptic plasticity?

    De Pittà, M; Brunel, N; Volterra, A

    2016-05-26

    Synaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neural activity. Because synaptic plasticity is the major candidate mechanism for learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. In particular, a prominent aspect that remains debated is how the plasticity mechanisms, that encompass a broad spectrum of temporal and spatial scales, come to play together in a concerted fashion. Here we review and discuss evidence that pinpoints to a possible non-neuronal, glial candidate for such orchestration: the regulation of synaptic plasticity by astrocytes. PMID:25862587

  13. The Spacing Principle for Unlearning Abnormal Neuronal Synchrony

    Popovych, Oleksandr V.; Markos N Xenakis; Peter A. Tass

    2015-01-01

    Desynchronizing stimulation techniques were developed to specifically counteract abnormal neuronal synchronization relevant to several neurological and psychiatric disorders. The goal of our approach is to achieve an anti-kindling, where the affected neural networks unlearn abnormal synaptic connectivity and, hence, abnormal neuronal synchrony, by means of desynchronizing stimulation, in particular, Coordinated Reset (CR) stimulation. As known from neuroscience, psychology and education, lear...

  14. Synaptic plasticity, AMPA-R trafficking, and Ras-MAPK signaling

    Yun GU; Ruth L STORNETTA

    2007-01-01

    Synaptic modification of transmission is a general phenomenon expressed at al-most every excitatory synapse in the mammalian brain. Over the last three decades,much has been discovered about the cellular, synaptic, molecular, and signalingmechanisms responsible for controlling synaptic transmission and plasticity. Here,we present a brief review of these mechanisms with emphasis on the currentunderstanding of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid recep-tor (AMPA-R) trafficking and Ras-mitogen-activated protein kinase (MAPK)signaling events involved in controlling synaptic transmission.

  15. NMDA receptor subunit composition determines the polarity of leptin-induced synaptic plasticity

    Moult, Peter R; Harvey, Jenni

    2011-01-01

    Leptin is a hormone that crosses the blood-brain barrier and regulates numerous CNS functions. The hippocampus in particular is an important site for leptin action. Indeed, leptin markedly influences excitatory synaptic transmission and synaptic plasticity in this brain region. Recent studies indicate that leptin modulation of hippocampal excitatory synaptic transmission is age-dependent however the cellular basis for this is unclear. Here we show that early in development leptin evokes a tra...

  16. Synapse geometry and receptor dynamics modulate synaptic strength.

    Dominik Freche

    Full Text Available Synaptic transmission relies on several processes, such as the location of a released vesicle, the number and type of receptors, trafficking between the postsynaptic density (PSD and extrasynaptic compartment, as well as the synapse organization. To study the impact of these parameters on excitatory synaptic transmission, we present a computational model for the fast AMPA-receptor mediated synaptic current. We show that in addition to the vesicular release probability, due to variations in their release locations and the AMPAR distribution, the postsynaptic current amplitude has a large variance, making a synapse an intrinsic unreliable device. We use our model to examine our experimental data recorded from CA1 mice hippocampal slices to study the differences between mEPSC and evoked EPSC variance. The synaptic current but not the coefficient of variation is maximal when the active zone where vesicles are released is apposed to the PSD. Moreover, we find that for certain type of synapses, receptor trafficking can affect the magnitude of synaptic depression. Finally, we demonstrate that perisynaptic microdomains located outside the PSD impacts synaptic transmission by regulating the number of desensitized receptors and their trafficking to the PSD. We conclude that geometrical modifications, reorganization of the PSD or perisynaptic microdomains modulate synaptic strength, as the mechanisms underlying long-term plasticity.

  17. What Is Transmitted in "Synaptic Transmission"?

    Montagna, Erik; de Azevedo, Adriana M. S.; Romano, Camilla; Ranvaud, Ronald

    2010-01-01

    Even students that obtain a high grade in neurophysiology often carry away a serious misconception concerning the final result of the complex set of events that follows the arrival of an action potential at the presynaptic terminal. The misconception consists in considering that "at a synapse, information is passed on from one neuron to the next"…

  18. Synaptic Vesicle Exocytosis

    Südhof, Thomas C; Rizo, Josep

    2011-01-01

    Presynaptic nerve terminals release neurotransmitters by synaptic vesicle exocytosis. Membrane fusion mediating synaptic exocytosis and other intracellular membrane traffic is affected by a universal machinery that includes SNARE (for “soluble NSF-attachment protein receptor”) and SM (for “Sec1/Munc18-like”) proteins. During fusion, vesicular and target SNARE proteins assemble into an α-helical trans-SNARE complex that forces the two membranes tightly together, and SM proteins likely wrap aro...

  19. Synaptic remodeling of neuronal circuits in early retinal degeneration

    Florentina eSoto

    2015-10-01

    Full Text Available Photoreceptor degenerations are a major cause of blindness and among the most common forms of neurodegeneration in humans. Studies of mouse models revealed that synaptic dysfunction often precedes photoreceptor degeneration, and that abnormal synaptic input from photoreceptors to bipolar cells causes circuits in the inner retina to become hyperactive. Here, we provide a brief overview of frequently used mouse models of photoreceptor degenerations. We then discuss insights into circuit remodeling triggered by early synaptic dysfunction in the outer and hyperactivity in the inner retina. We discuss these insights in the context of other experimental manipulations of synaptic function and activity. Knowledge of the plasticity and early remodeling of retinal circuits will be critical for the design of successful vision rescue strategies.

  20. Synaptic remodeling of neuronal circuits in early retinal degeneration

    Soto, Florentina; Kerschensteiner, Daniel

    2015-01-01

    Photoreceptor degenerations are a major cause of blindness and among the most common forms of neurodegeneration in humans. Studies of mouse models revealed that synaptic dysfunction often precedes photoreceptor degeneration, and that abnormal synaptic input from photoreceptors to bipolar cells causes circuits in the inner retina to become hyperactive. Here, we provide a brief overview of frequently used mouse models of photoreceptor degenerations. We then discuss insights into circuit remodeling triggered by early synaptic dysfunction in the outer and hyperactivity in the inner retina. We discuss these insights in the context of other experimental manipulations of synaptic function and activity. Knowledge of the plasticity and early remodeling of retinal circuits will be critical for the design of successful vision rescue strategies. PMID:26500497

  1. Inhibitory glycinergic neurotransmission in the mammalian auditory brainstem upon prolonged stimulation: short-term plasticity and synaptic reliability

    Jürgen Franke

    2014-03-01

    Full Text Available Short-term plasticity plays a key role in synaptic transmission and has been extensively investigated for excitatory synapses. Much less is known about inhibitory synapses. Here we analyze the performance of glycinergic connections between the medial nucleus of the trapezoid body (MNTB and the lateral superior olive (LSO in the auditory brainstem, where high spike rates as well as fast and precise neurotransmission are hallmarks. Analysis was performed in acute mouse slices shortly after hearing onset (postnatal day (P11 and eight days later (P19. Stimulation was done at 37°C with 1–400 Hz for 40 s. Moreover, in a novel approach named marathon experiments, a very prolonged stimulation protocol was employed, comprising 10 trials of 1-min challenge and 1-min recovery periods at 50 Hz and 1 Hz, respectively, thus lasting up to 20 min and amounting to > 30,000 stimulus pulses. IPSC peak amplitudes displayed short-term depression (STD and synaptic attenuation in a frequency-dependent manner. No facilitation was observed. STD in the MNTB-LSO connections was less pronounced than reported in the upstream calyx of Held-MNTB connections. At P11, the STD level and the failure rate were slightly lower within the ms-to-s range than at P19. During prolonged stimulation periods lasting 40 s, P19 connections sustained virtually failure-free transmission up to frequencies of 100 Hz, whereas P11 connections did so only up to 50 Hz. In marathon experiments, P11 synapses recuperated reproducibly from synaptic attenuation during all recovery periods, demonstrating a robust synaptic machinery at hearing onset. At 26°C, transmission was severely impaired and comprised abnormally high amplitudes after minutes of silence, indicative of imprecisely regulated vesicle pools. Our study takes a fresh look at synaptic plasticity and stability by extending conventional stimulus periods in the ms-to-s range to minutes. It also provides a framework for future analyses of

  2. 环境因素对海-气界面低频异常声透射的影响研究∗%Influences of environmental factors on low frequency abnormal sound transmission through sea-air interface

    郭业才; 连晨方; 张秀再; 赵益波

    2015-01-01

    针对海中声源在海-气界面低频异常声透射问题,根据两层媒质声传输模型,分析了大气声速和密度与气压、气温、湿度及海水中声速和密度与海温、盐度间的关系,研究了低频声透射和传输受温度、气压、盐度、湿度等因素的影响,分析了各因素对声透射和传输的影响程度。结果表明:1)声透射到大气中的声功率与气温、湿度负相关,与海温、盐度、气压正相关;2)单极子与水平偶极子声源辐射到海中的声功率与海温、盐度负相关,而垂直偶极子声源辐射到海中的声功率与海温、盐度正相关;3)声透射指向性与海温正相关,与气温负相关;4)低频声透射受温度影响最大,其次是盐度,受气压和湿度影响较小,垂直偶极子声源的声透射受温度影响大于水平偶极子和单极子声源。%In view of low frequency abnormal sound transmission of sound source in the sea at the sea-air interface, according to the two-layer medium sound transmission model, we analyze the relationships of the sound speed and the density of the atmosphere with the atmospheric pressure, the air temperature, the humidity;we also analyze the relationships of the sound velocity and the density of seawater with the sea surface temperature (SST) and salinity;we investigate the low-frequency abnormal sound transmissions influenced by temperature, pressure, salinity, humidity and other environmental factors;we analyze the influences of various factors on the sound transmission. The obtained results are as follows. 1) the sound power in the air, obtained by the sound transmission of sound source in the shallow sea, is negatively correlated with atmospheric temperature and humidity, and positively correlated with the SST, salinity, and atmospheric pressure. 2) The sound power that is radiated into the sea by the monopole and horizontal dipole source at the sea, is negatively correlated with SST and

  3. Mutual and intermittent enhancements of synchronization transitions by autaptic and synaptic delay in scale-free neuron networks

    Wang, Qi; Gong, Yubing; Xie, Huijuan

    2016-05-01

    In neural networks, there exist both synaptic delays among different neurons and autaptic self-feedback delays in a neuron itself. In this paper, we study synchronization transitions induced by synaptic and autaptic delays in scale-free neuron networks, mainly exploring how these two time delays affect synchronization transitions induced by each other. It is found that the synchronization transitions induced by synaptic (autaptic) delay are intermittently enhanced when autaptic (synaptic) delay is varied. There are optimal autaptic strength and synaptic coupling strength by which the synchronization transitions induced by autaptic and synaptic delays become strongest. The underlying mechanisms are briefly discussed in terms of the relationships of autaptic delay, synaptic delay, and inter-burst interval. These results show that synaptic and autaptic delays could contribute to each other and enhance synchronization transitions in the neuronal networks. This implies that autaptic and synaptic delays could play a vital role for the information transmission in neural systems.

  4. Lavandula angustifolia extract improves deteriorated synaptic plasticity in an animal model of Alzheimer’s disease

    Masoud Soheili; Mostafa Rezaei Tavirany; Mahmoud Salami

    2015-01-01

    Objective(s): Neurodegenerative Alzheimer’s disease (AD) is associated with profound deficits in synaptic transmission and synaptic plasticity. Long-term potentiation (LTP), an experimental form of synaptic plasticity, is intensively examined in hippocampus. In this study we evaluated the effect of aqueous extract of lavender (Lavandula angustifolia) on induction of LTP in the CA1 area of hippocampus. In response to stimulation of the Schaffer collaterals the baseline or tetanized field extra...

  5. THE TRANSMISSION PATH OF THE 500 hPa TEMPERATURE RESPONSE TO THE SOUTH CHINA SEA SST MONTHLY ABNORMALITY IN WINTER

    2000-01-01

    In view of the SSTA study mostly confined to summer, this work tries to take another look from the point of winter. Using a two-layer general circulation model (IAP-GCM Ⅱ) developed at the Institute of Atmospheric Physics of the Chinese Academy of Sciences, numerical experiments are conducted to study the transmission paths of the 500-hPa response field of temperature in association with monthly winter anomalies of SST for the South China Sea. The result shows that the response field splits into two branches in transmission when the anomaly is positive -- one travels counterclockwise to the north arriving in the Qinghai-Xizang (Tibetan) Plateau via southeastern China after leaving the sea and the other goes southwards; the transmission becomes clockwise when anomaly turns negative so that it starts from the sea and passes the Bay of Thailand before, as in the case of positive anomaly, reaching the plateau. Our work has shown that the South China Sea SST is essential for the prediction of short-term climate in southeast China.

  6. Pregnenolone sulfate induces NMDA receptor dependent release of dopamIne from synaptIc termInals in the striatum

    Whittaker, Matthew T.; Gibbs, Terrell T.; Farb, David H.

    2008-01-01

    Neuromodulators that alter the balance between lower-frequency glutamate-mediated excitatory and higher-frequency GABA-mediated inhibitory synaptic transmission are likely to participate in core mechanisms for CNS function and may contribute to the pathophysiology of neurological disorders such as schizophrenia and Alzheimer's disease. Pregnenolone sulfate (PS) modulates both ionotropic glutamate and GABAA receptor mediated synaptic transmission. The enzymes necessary for PS synthesis and deg...

  7. Congenital Abnormalities

    ... blood flow to the fetus impair fetal growth. Alcohol consumption and certain drugs during pregnancy significantly increase the risk that a baby will be born with abnormalities (e.g. fetal alcohol spectrum disorders ). Eating raw or uncooked foods during pregnancy can also be dangerous to health of the ...

  8. mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis

    Veronica Costa

    2016-04-01

    Full Text Available Hyperfunction of the mTORC1 pathway has been associated with idiopathic and syndromic forms of autism spectrum disorder (ASD, including tuberous sclerosis, caused by loss of either TSC1 or TSC2. It remains largely unknown how developmental processes and biochemical signaling affected by mTORC1 dysregulation contribute to human neuronal dysfunction. Here, we have characterized multiple stages of neurogenesis and synapse formation in human neurons derived from TSC2-deleted pluripotent stem cells. Homozygous TSC2 deletion causes severe developmental abnormalities that recapitulate pathological hallmarks of cortical malformations in patients. Both TSC2+/− and TSC2−/− neurons display altered synaptic transmission paralleled by molecular changes in pathways associated with autism, suggesting the convergence of pathological mechanisms in ASD. Pharmacological inhibition of mTORC1 corrects developmental abnormalities and synaptic dysfunction during independent developmental stages. Our results uncouple stage-specific roles of mTORC1 in human neuronal development and contribute to a better understanding of the onset of neuronal pathophysiology in tuberous sclerosis.

  9. mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis.

    Costa, Veronica; Aigner, Stefan; Vukcevic, Mirko; Sauter, Evelyn; Behr, Katharina; Ebeling, Martin; Dunkley, Tom; Friedlein, Arno; Zoffmann, Sannah; Meyer, Claas A; Knoflach, Frédéric; Lugert, Sebastian; Patsch, Christoph; Fjeldskaar, Fatiha; Chicha-Gaudimier, Laurie; Kiialainen, Anna; Piraino, Paolo; Bedoucha, Marc; Graf, Martin; Jessberger, Sebastian; Ghosh, Anirvan; Bischofberger, Josef; Jagasia, Ravi

    2016-04-01

    Hyperfunction of the mTORC1 pathway has been associated with idiopathic and syndromic forms of autism spectrum disorder (ASD), including tuberous sclerosis, caused by loss of either TSC1 or TSC2. It remains largely unknown how developmental processes and biochemical signaling affected by mTORC1 dysregulation contribute to human neuronal dysfunction. Here, we have characterized multiple stages of neurogenesis and synapse formation in human neurons derived from TSC2-deleted pluripotent stem cells. Homozygous TSC2 deletion causes severe developmental abnormalities that recapitulate pathological hallmarks of cortical malformations in patients. Both TSC2(+/-) and TSC2(-/-) neurons display altered synaptic transmission paralleled by molecular changes in pathways associated with autism, suggesting the convergence of pathological mechanisms in ASD. Pharmacological inhibition of mTORC1 corrects developmental abnormalities and synaptic dysfunction during independent developmental stages. Our results uncouple stage-specific roles of mTORC1 in human neuronal development and contribute to a better understanding of the onset of neuronal pathophysiology in tuberous sclerosis. PMID:27052171

  10. Impaired synaptic clustering of postsynaptic density proteins and altered signal transmission in hippocampal neurons, and disrupted learning behavior in PDZ1 and PDZ2 ligand binding-deficient PSD-95 knockin mice

    Nagura Hitoshi; Ishikawa Yasuyuki; Kobayashi Katsunori; Takao Keizo; Tanaka Tomo; Nishikawa Kouki; Tamura Hideki; Shiosaka Sadao; Suzuki Hidenori; Miyakawa Tsuyoshi; Fujiyoshi Yoshinori; Doi Tomoko

    2012-01-01

    Abstract Background Postsynaptic density (PSD)-95-like membrane-associated guanylate kinases (PSD-MAGUKs) are scaffold proteins in PSDs that cluster signaling molecules near NMDA receptors. PSD-MAGUKs share a common domain structure, including three PDZ (PDZ1/2/3) domains in their N-terminus. While multiple domains enable the PSD-MAGUKs to bind various ligands, the contribution of each PDZ domain to synaptic organization and function is not fully understood. Here, we focused on the PDZ1/2 dom...

  11. [Peptidergic modulation of the hippocampus synaptic activity].

    Skrebitskiĭ, V G; Kondratenko, R V; Povarov, I S; Dereviagin, V I

    2011-11-01

    Effects of two newly synthesized nootropic and anxiolytic dipeptides: Noopept and Selank on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) or Selank (2 microM) significantly increased the frequency of spike-dependent spontaneous m1PSCs, whereas spike-independent mlPSCs remained unchanged. It was suggested that both peptides mediated their effect sue to activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion, at least for Noonent. PMID:22390072

  12. The origin of glutamatergic synaptic inputs controls synaptic plasticity and its modulation by alcohol in mice nucleus accumbens.

    Ji, Xincai; Saha, Sucharita; Martin, Gilles E

    2015-01-01

    It is widely accepted that long-lasting changes of synaptic strength in the nucleus accumbens (NAc), a brain region involved in drug reward, mediate acute and chronic effects of alcohol. However, our understanding of the mechanisms underlying the effects of alcohol on synaptic plasticity is limited by the fact that the NAc receives glutamatergic inputs from distinct brain regions (e.g., the prefrontal cortex (PFCx), the amygdala and the hippocampus), each region providing different information (e.g., spatial, emotional and cognitive). Combining whole-cell patch-clamp recordings and the optogenetic technique, we examined synaptic plasticity, and its regulation by alcohol, at cortical, hippocampal and amygdala inputs in fresh slices of mouse tissue. We showed that the origin of synaptic inputs determines the basic properties of glutamatergic synaptic transmission, the expression of spike-timing dependent long-term depression (tLTD) and long-term potentiation (LTP) and long-term potentiation (tLTP) and their regulation by alcohol. While we observed both tLTP and tLTD at amygadala and hippocampal synapses, we showed that cortical inputs only undergo tLTD. Functionally, we provide evidence that acute Ethyl Alcohol (EtOH) has little effects on higher order information coming from the PFCx, while severely impacting the ability of emotional and contextual information to induce long-lasting changes of synaptic strength. PMID:26257641

  13. Synaptic electronics: materials, devices and applications

    In this paper, the recent progress of synaptic electronics is reviewed. The basics of biological synaptic plasticity and learning are described. The material properties and electrical switching characteristics of a variety of synaptic devices are discussed, with a focus on the use of synaptic devices for neuromorphic or brain-inspired computing. Performance metrics desirable for large-scale implementations of synaptic devices are illustrated. A review of recent work on targeted computing applications with synaptic devices is presented. (topical review)

  14. Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine

    Martella, Giuseppina; Tassone, Annalisa; Sciamanna, Giuseppe; Platania, Paola; Cuomo, Dario; Viscomi, Maria Teresa; Bonsi, Paola; Cacci, Emanuele; Biagioni, Stefano; Usiello, Alessandro; Bernardi, Giorgio; Sharma, Nutan

    2009-01-01

    DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M1 receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M2/M4 receptor knockout mice, in which an increased striatal acetylcholine level has been

  15. A Model of Synaptic Reconsolidation

    Kastner, David B.; Schwalger, Tilo; Ziegler, Lorric; Gerstner, Wulfram

    2016-01-01

    Reconsolidation of memories has mostly been studied at the behavioral and molecular level. Here, we put forward a simple extension of existing computational models of synaptic consolidation to capture hippocampal slice experiments that have been interpreted as reconsolidation at the synaptic level. The model implements reconsolidation through stabilization of consolidated synapses by stabilizing entities combined with an activity-dependent reservoir of stabilizing entities that are immune to protein synthesis inhibition (PSI). We derive a reduced version of our model to explore the conditions under which synaptic reconsolidation does or does not occur, often referred to as the boundary conditions of reconsolidation. We find that our computational model of synaptic reconsolidation displays complex boundary conditions. Our results suggest that a limited resource of hypothetical stabilizing molecules or complexes, which may be implemented by protein phosphorylation or different receptor subtypes, can underlie the phenomenon of synaptic reconsolidation. PMID:27242410

  16. mGluR-dependent synaptic plasticity in drug-seeking.

    ManuelMameli

    2012-08-01

    Full Text Available A primary feature of drug addiction is the compulsive use despite negative consequences. A general consensus is emerging on the capacity of addictive substances to co-opt synaptic transmission and synaptic plasticity in brain circuits which are involved in reinforcement and reward processing. A current hypothesis is that drug-driven neuroadaptations during learning and memory processes divert the functions of these brain circuits, eventually leading to addictive behaviors. Metabotropic glutamate receptors (mGluRs not only lead to long-term modulation of synaptic transmission but they have been implicated in drug-evoked synaptic plasticity and drug-seeking behaviors in two important ways. mGluR-dependent modulation of synaptic transmission is impaired by drug experience but interestingly their activation has been indicated as a strategy to restore baseline transmission after drug-evoked synaptic plasticity. Here we focus on the cellular mechanisms underlying mGluR-dependent long-term changes of excitatory synapses, and review results implicating these receptors in drug-evoked synaptic plasticity.

  17. Spontaneous Activity Drives Local Synaptic Plasticity In Vivo.

    Winnubst, Johan; Cheyne, Juliette E; Niculescu, Dragos; Lohmann, Christian

    2015-07-15

    Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in the mouse visual cortex in vivo. Analyzing activity changes across large populations of synapses revealed a simple and efficient local plasticity rule: synapses that exhibit low synchronicity with nearby neighbors (depressed in their transmission frequency. Asynchronous electrical stimulation of individual synapses in hippocampal slices showed that this is due to a decrease in synaptic transmission efficiency. Accordingly, experimentally increasing local synchronicity, by stimulating synapses in response to spontaneous activity at neighboring synapses, stabilized synaptic transmission. Finally, blockade of the high-affinity proBDNF receptor p75(NTR) prevented the depression of asynchronously stimulated synapses. Thus, spontaneous activity drives local synaptic plasticity at individual synapses in an "out-of-sync, lose-your-link" fashion through proBDNF/p75(NTR) signaling to refine neuronal connectivity. VIDEO ABSTRACT. PMID:26182421

  18. Spike-timing dependent plasticity beyond synapse - pre- and post-synaptic plasticity of intrinsic neuronal excitability

    Dominique Debanne

    2010-06-01

    Full Text Available Long-lasting plasticity of synaptic transmission is classically thought to be the cellular substrate for information storage in the brain. Recent data indicate however that it is not the whole story. Persistent changes in the intrinsic neuronal excitability have been shown to occur in parallel to the induction of long-term synaptic modifications. This form of plasticity depends on the regulation of voltage-gated ion channels. Here we review the experimental evidence for plasticity of neuronal excitability induced at pre- or post-synaptic sites when long-term plasticity of synaptic transmission is induced with Spike-Timing-Dependent Plasticity (STDP protocols. We describe the induction and expression mechanisms of the induced changes in excitability. Finally, the functional synergy between synaptic and non-synaptic plasticity and their spatial extent are discussed.

  19. Late onset deficits in synaptic plasticity in the valproic acid rat model of autism

    Henry Giles Stratten Martin

    2014-01-01

    Full Text Available Valproic acid (VPA is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP due to an up-regulation of NMDA receptor (NMDAR expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDA receptors during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general.

  20. 大鼠初级传入纤维与脊髓背角神经元间的动作电序列的突触传递%SYNAPTIC TRANSMISSION OF VARIOUS SPIKE TRAINS BETWEEN PRIMARY AFFERENT FIBER AND SPINAL DORSAL HORN NEURON IN THE RAT

    万业宏; 菅忠; 文治洪; 王玉英; 胡三觉

    2004-01-01

    Peripheral sensory neurons encode continuous, time-varying signals into spike trains, which are finally relayed to the brain through synaptic transmission. But how various types of spike trains are transmitted across chemical synapses between neurons is still an open question. Here the synaptic transmission of various spike trains between primary Aδ afferent fiber and spinal dorsal horn neuron was investigated. Regular, periodic and stochastic stimulus trains were composed of either brief bursts or single pulses. "Events" were defined as the longest sequences of spikes with all interspike intervals less than or equal to a certain threshold and the interevent intervals (IEIs) were extracted from spike trains. The IEI analysis by time-IEI graphs and return maps showed that the main temporal structure of presynaptic input trains could be detected in postsynaptic output trains, especially under brief-burst stimulation. By calculating the mutual information between input and output trains, it was found that brief bursts could more reliably transmit the information carried by input trains across synapses.These results suggested that the main temporal characters of peripheral input trains can be transmitted across synapses, and that brief-burst firing is more effective during synapse transmission of neural information. The present research takes a step forward to exploring the mystery of neural coding from the aspect of synaptic transmission.%外周感觉神经元通过动作电位序列对信号进行编码,这些动作电位序列经过突触传递最终到达脑部.但是各种脉冲序列如何通过神经元之间的化学突触进行传递依然是一个悬而未决的问题.研究了初级传入Aδ纤维与背角神经元之间各种动作电位序列的突触传递过程.用于刺激的规则、周期、随机脉冲序列由短簇脉冲或单个脉冲构成.定义"事件"(event)为峰峰间期(interspike interval)小于或等于规定阈值的最长动作电位

  1. Concurrent imaging of synaptic vesicle recycling and calcium dynamics.

    Haiyan eLi

    2011-11-01

    Full Text Available Synaptic transmission involves the calcium-dependent release of neurotransmitter from synaptic vesicles. Genetically encoded optical probes emitting different wavelengths of fluorescent light in response to neuronal activity offer a powerful approach to understand the spatial and temporal relationship of calcium dynamics to the release of neurotransmitter in defined neuronal populations. To simultaneously image synaptic vesicle recycling and changes in cytosolic calcium, we developed a red-shifted reporter of vesicle recycling based on a vesicular glutamate transporter, VGLUT1-mOrange2 (VGLUT1-mOr2, and a presynaptically-localized green calcium indicator, synaptophysin-GCaMP3 (SyGCaMP3 with a large dynamic range. The fluorescence of VGLUT1-mOr2 is quenched by the low pH of synaptic vesicles. Exocytosis upon electrical stimulation exposes the luminal mOr2 to the neutral extracellular pH and relieves fluorescence quenching. Re-acidification of the vesicle upon endocytosis again reduces fluorescence intensity. Changes in fluorescence intensity thus monitor synaptic vesicle exo- and endocytosis, as demonstrated previously for the green VGLUT1-pHluorin. To monitor changes in calcium, we fused the synaptic vesicle protein synaptophysin to the recently improved calcium indicator GCaMP3. SyGCaMP3 is targeted to presynaptic varicosities, and exhibits changes in fluorescence in response to electrical stimulation consistent with changes in calcium concentration. Using real-time imaging of both reporters expressed in the same synapses, we determine the time course of changes in VGLUT1 recycling in relation to changes in presynaptic calcium concentration. Inhibition of P/Q- and N-type calcium channels reduces calcium levels, as well as the rate of synaptic vesicle exocytosis and the fraction of vesicles released.

  2. Concurrent Imaging of Synaptic Vesicle Recycling and Calcium Dynamics

    Li, Haiyan; Foss, Sarah M.; Dobryy, Yuriy L.; Park, C. Kevin; Hires, Samuel Andrew; Shaner, Nathan C.; Tsien, Roger Y.; Osborne, Leslie C.; Voglmaier, Susan M.

    2011-01-01

    Synaptic transmission involves the calcium dependent release of neurotransmitter from synaptic vesicles. Genetically encoded optical probes emitting different wavelengths of fluorescent light in response to neuronal activity offer a powerful approach to understand the spatial and temporal relationship of calcium dynamics to the release of neurotransmitter in defined neuronal populations. To simultaneously image synaptic vesicle recycling and changes in cytosolic calcium, we developed a red-shifted reporter of vesicle recycling based on a vesicular glutamate transporter, VGLUT1-mOrange2 (VGLUT1-mOr2), and a presynaptically localized green calcium indicator, synaptophysin-GCaMP3 (SyGCaMP3) with a large dynamic range. The fluorescence of VGLUT1-mOr2 is quenched by the low pH of synaptic vesicles. Exocytosis upon electrical stimulation exposes the luminal mOr2 to the neutral extracellular pH and relieves fluorescence quenching. Reacidification of the vesicle upon endocytosis again reduces fluorescence intensity. Changes in fluorescence intensity thus monitor synaptic vesicle exo- and endocytosis, as demonstrated previously for the green VGLUT1-pHluorin. To monitor changes in calcium, we fused the synaptic vesicle protein synaptophysin to the recently improved calcium indicator GCaMP3. SyGCaMP3 is targeted to presynaptic varicosities, and exhibits changes in fluorescence in response to electrical stimulation consistent with changes in calcium concentration. Using real time imaging of both reporters expressed in the same synapses, we determine the time course of changes in VGLUT1 recycling in relation to changes in presynaptic calcium concentration. Inhibition of P/Q- and N-type calcium channels reduces calcium levels, as well as the rate of synaptic vesicle exocytosis and the fraction of vesicles released. PMID:22065946

  3. Synaptic dynamics in analog VLSI.

    Bartolozzi, Chiara; Indiveri, Giacomo

    2007-10-01

    Synapses are crucial elements for computation and information transfer in both real and artificial neural systems. Recent experimental findings and theoretical models of pulse-based neural networks suggest that synaptic dynamics can play a crucial role for learning neural codes and encoding spatiotemporal spike patterns. Within the context of hardware implementations of pulse-based neural networks, several analog VLSI circuits modeling synaptic functionality have been proposed. We present an overview of previously proposed circuits and describe a novel analog VLSI synaptic circuit suitable for integration in large VLSI spike-based neural systems. The circuit proposed is based on a computational model that fits the real postsynaptic currents with exponentials. We present experimental data showing how the circuit exhibits realistic dynamics and show how it can be connected to additional modules for implementing a wide range of synaptic properties. PMID:17716003

  4. Synaptic contacts impaired by styrene-7,8-oxide toxicity

    Styrene-7,8-oxide (SO), a chemical compound widely used in industrial applications, is a potential hazard for humans, particularly in occupational settings. Neurobehavioral changes are consistently observed in occupationally exposed individuals and alterations of neurotransmitters associated with neuronal loss have been reported in animal models. Although the toxic effects of styrene have been extensively documented, the molecular mechanisms responsible for SO-induced neurotoxicity are still unclear. A possible dopamine-mediated effect of styrene neurotoxicity has been previously demonstrated, since styrene oxide alters dopamine neurotransmission in the brain. Thus, the present study hypothesizes that styrene neurotoxicity may involve synaptic contacts. Primary striatal neurons were exposed to styrene oxide at different concentrations (0.1-1 mM) for different time periods (8, 16, and 24 h) to evaluate the dose able to induce synaptic impairments. The expression of proteins crucial for synaptic transmission such as Synapsin, Synaptophysin, and RAC-1 were considered. The levels of Synaptophysin and RAC-1 decreased in a dose-dependent manner. Accordingly, morphological alterations, observed at the ultrastructural level, primarily involved the pre-synaptic compartment. In SO-exposed cultures, the biochemical cascade of caspases was activated affecting the cytoskeleton components as their target. Thus the impairments in synaptic contacts observed in SO-exposed cultures might reflect a primarily morphological alteration of neuronal cytoskeleton. In addition, our data support the hypothesis developed by previous authors of reactive oxygen species (ROS) initiating events of SO cytotoxicity

  5. Nonequivalent release sites govern synaptic depression.

    Wen, Hua; McGinley, Matthew J; Mandel, Gail; Brehm, Paul

    2016-01-19

    Synaptic depression is prominent among synapses, but the underlying mechanisms remain uncertain. Here, we use paired patch clamp recording to study neuromuscular transmission between the caudal primary motor neuron and target skeletal muscle in zebrafish. This synapse has an unusually low number of release sites, all with high probabilities of release in response to low-frequency stimulation. During high-frequency stimulation, the synapse undergoes short-term depression and reaches steady-state levels of transmission that sustain the swimming behavior. To determine the release parameters underlying this steady state, we applied variance analysis. Our analysis revealed two functionally distinct subclasses of release sites differing by over 60-fold in rates of vesicle reloading. A slow reloading class requires seconds to recover and contributes to depression onset but not the steady-state transmission. By contrast, a fast reloading class recovers within tens of milliseconds and is solely responsible for steady-state transmission. Thus, in contrast to most current models that assign levels of steady-state depression to vesicle availability, our findings instead assign this function to nonuniform release site kinetics. The duality of active-site properties accounts for the highly nonlinear dependence of steady-state depression levels on frequency. PMID:26715759

  6. A network of autism linked genes stabilizes two pools of synaptic GABA(A) receptors.

    Tong, Xia-Jing; Hu, Zhitao; Liu, Yu; Anderson, Dorian; Kaplan, Joshua M

    2015-01-01

    Changing receptor abundance at synapses is an important mechanism for regulating synaptic strength. Synapses contain two pools of receptors, immobilized and diffusing receptors, both of which are confined to post-synaptic elements. Here we show that immobile and diffusing GABA(A) receptors are stabilized by distinct synaptic scaffolds at C. elegans neuromuscular junctions. Immobilized GABA(A) receptors are stabilized by binding to FRM-3/EPB4.1 and LIN-2A/CASK. Diffusing GABA(A) receptors are stabilized by the synaptic adhesion molecules Neurexin and Neuroligin. Inhibitory post-synaptic currents are eliminated in double mutants lacking both scaffolds. Neurexin, Neuroligin, and CASK mutations are all linked to Autism Spectrum Disorders (ASD). Our results suggest that these mutations may directly alter inhibitory transmission, which could contribute to the developmental and cognitive deficits observed in ASD. PMID:26575289

  7. Synaptic Cell Adhesion Molecules in Alzheimer's Disease

    Leshchyns'ka, Iryna

    2016-01-01

    Alzheimer's disease (AD) is a neurodegenerative brain disorder associated with the loss of synapses between neurons in the brain. Synaptic cell adhesion molecules are cell surface glycoproteins which are expressed at the synaptic plasma membranes of neurons. These proteins play key roles in formation and maintenance of synapses and regulation of synaptic plasticity. Genetic studies and biochemical analysis of the human brain tissue, cerebrospinal fluid, and sera from AD patients indicate that levels and function of synaptic cell adhesion molecules are affected in AD. Synaptic cell adhesion molecules interact with Aβ, a peptide accumulating in AD brains, which affects their expression and synaptic localization. Synaptic cell adhesion molecules also regulate the production of Aβ via interaction with the key enzymes involved in Aβ formation. Aβ-dependent changes in synaptic adhesion affect the function and integrity of synapses suggesting that alterations in synaptic adhesion play key roles in the disruption of neuronal networks in AD. PMID:27242933

  8. Synaptic plasticity functions in an organic electrochemical transistor

    Gkoupidenis, Paschalis; Schaefer, Nathan; Strakosas, Xenofon; Fairfield, Jessamyn A.; Malliaras, George G.

    2015-12-01

    Synaptic plasticity functions play a crucial role in the transmission of neural signals in the brain. Short-term plasticity is required for the transmission, encoding, and filtering of the neural signal, whereas long-term plasticity establishes more permanent changes in neural microcircuitry and thus underlies memory and learning. The realization of bioinspired circuits that can actually mimic signal processing in the brain demands the reproduction of both short- and long-term aspects of synaptic plasticity in a single device. Here, we demonstrate the implementation of neuromorphic functions similar to biological memory, such as short- to long-term memory transition, in non-volatile organic electrochemical transistors (OECTs). Depending on the training of the OECT, the device displays either short- or long-term plasticity, therefore, exhibiting non von Neumann characteristics with merged processing and storing functionalities. These results are a first step towards the implementation of organic-based neuromorphic circuits.

  9. Role of DHA in aging-related changes in mouse brain synaptic plasma membrane proteome.

    Sidhu, Vishaldeep K; Huang, Bill X; Desai, Abhishek; Kevala, Karl; Kim, Hee-Yong

    2016-05-01

    Aging has been related to diminished cognitive function, which could be a result of ineffective synaptic function. We have previously shown that synaptic plasma membrane proteins supporting synaptic integrity and neurotransmission were downregulated in docosahexaenoic acid (DHA)-deprived brains, suggesting an important role of DHA in synaptic function. In this study, we demonstrate aging-induced synaptic proteome changes and DHA-dependent mitigation of such changes using mass spectrometry-based protein quantitation combined with western blot or messenger RNA analysis. We found significant reduction of 15 synaptic plasma membrane proteins in aging brains including fodrin-α, synaptopodin, postsynaptic density protein 95, synaptic vesicle glycoprotein 2B, synaptosomal-associated protein 25, synaptosomal-associated protein-α, N-methyl-D-aspartate receptor subunit epsilon-2 precursor, AMPA2, AP2, VGluT1, munc18-1, dynamin-1, vesicle-associated membrane protein 2, rab3A, and EAAT1, most of which are involved in synaptic transmission. Notably, the first 9 proteins were further reduced when brain DHA was depleted by diet, indicating that DHA plays an important role in sustaining these synaptic proteins downregulated during aging. Reduction of 2 of these proteins was reversed by raising the brain DHA level by supplementing aged animals with an omega-3 fatty acid sufficient diet for 2 months. The recognition memory compromised in DHA-depleted animals was also improved. Our results suggest a potential role of DHA in alleviating aging-associated cognitive decline by offsetting the loss of neurotransmission-regulating synaptic proteins involved in synaptic function. PMID:27103520

  10. The astrocyte as a gatekeeper of synaptic information transfer

    Volman, Vladislav; Ben-Jacob, Eshel; Levine, Herbert

    2006-01-01

    We present a simple biophysical model for the coupling between synaptic transmission and the local calcium concentration on an enveloping astrocytic domain. This interaction enables the astrocyte to modulate the information flow from presynaptic to postsynaptic cells in a manner dependent on previous activity at this and other nearby synapses. Our model suggests a novel, testable hypothesis for the spike timing statistics measured for rapidly-firing cells in culture experiments.

  11. Removal of Synaptic Ca2+-Permeable AMPA Receptors during Sleep.

    Ulrich, Daniel; ROWAN, MICHAEL

    2011-01-01

    PUBLISHED here is accumulating evidence that sleep contributes to memory formation and learning, but the underlying cellular mechanisms are incompletely understood. To investigate the impact of sleep on excitatory synaptic transmission, we obtained whole-cell patch-clamp recordings from layer V pyramidal neurons in acute slices of somatosensory cortex of juvenile rats (postnatal days 21-25). In animals after the dark period, philanthotoxin 74 (PhTx)-sensitive calcium-permeable AMPA recepto...

  12. Super-resolution microscopy of the synaptic active zone

    Markus Sauer; Kittel, Robert J.

    2015-01-01

    Brain function relies on accurate information transfer at chemical synapses. At the presynaptic active zone (AZ) a variety of specialised proteins are assembled to complex architectures, which set the basis for speed, precision and plasticity of synaptic transmission. Calcium (Ca2+) channels are pivotal for the initiation of excitation-secretion coupling and, correspondingly, capture a central position at the AZ. Combining quantitative functional studies with modelling approaches has prov...

  13. Thermal impact on spiking properties in Hodgkin-Huxley neuron with synaptic stimulus

    Shenbing Kuang; Jiafu Wang; Ting Zeng; Aiyin Cao

    2008-01-01

    The effect of environmental temperature on neuronal spiking behaviors is investigated by numerically simulating the temperature dependence of spiking threshold of the Hodgkin-Huxley neuron subject to synaptic stimulus. We find that the spiking threshold exhibits a global minimum in a specific temperature range where spike initiation needs weakest synaptic strength, which form the engineering perspective indicates the occurrence of optimal use of synaptic transmission in the nervous system. We further explore the biophysical origin of this phenomenon associated with ion channel gating kinetics and also discuss its possible biological relevance in information processing in neuronal systems.

  14. Retinal function and morphology are altered in cattle infected with the prion disease transmissible mink encephalopathy.

    Smith, J D; Greenlee, J J; Hamir, A N; Richt, J A; Greenlee, M H West

    2009-09-01

    Transmissible spongiform encephalopathies (TSEs) are a group of diseases that result in progressive and invariably fatal neurologic disease in both animals and humans. TSEs are characterized by the accumulation of an abnormal protease-resistant form of the prion protein in the central nervous system. Transmission of infectious TSEs is believed to occur via ingestion of prion protein-contaminated material. This material is also involved in the transmission of bovine spongiform encephalopathy ("mad cow disease") to humans, which resulted in the variant form of Creutzfeldt-Jakob disease. Abnormal prion protein has been reported in the retina of TSE-affected cattle, but despite these observations, the specific effect of abnormal prion protein on retinal morphology and function has not been assessed. The objective of this study was to identify and characterize potential functional and morphologic abnormalities in the retinas of cattle infected with a bovine-adapted isolate of transmissible mink encephalopathy. We used electroretinography and immunohistochemistry to examine retinas from 10 noninoculated and 5 transmissible mink encephalopathy-inoculated adult Holstein steers. Here we show altered retinal function, as evidenced by prolonged implicit time of the electroretinogram b-wave, in transmissible mink encephalopathy-infected cattle before the onset of clinical illness. We also demonstrate disruption of rod bipolar cell synaptic terminals, indicated by decreased immunoreactivity for the alpha isoform of protein kinase C and vesicular glutamate transporter 1, and activation of Müller glia, as evidenced by increased glial fibrillary acidic protein and glutamine synthetase expression, in the retinas of these cattle at the time of euthanasia due to clinical deterioration. This is the first study to identify both functional and morphologic alterations in the retinas of TSE-infected cattle. Our results support future efforts to focus on the retina for the development of

  15. mGluR-Dependent Synaptic Plasticity in Drug-Seeking

    ManuelMameli; CamillaBellone

    2012-01-01

    A primary feature of drug addiction is the compulsive use despite negative consequences. A general consensus is emerging on the capacity of addictive substances to co-opt synaptic transmission and synaptic plasticity in brain circuits which are involved in reinforcement and reward processing. A current hypothesis is that drug-driven neuroadaptations during learning and memory processes divert the functions of these brain circuits, eventually leading to addictive behaviors. Metabotropic glutam...

  16. Synaptic neuropeptide release induced by octopamine without Ca2+ entry into the nerve terminal

    Shakiryanova, Dinara; Zettel, Geoffrey M.; Gu, Tingting; Hewes, Randall S.; Levitan, Edwin S.

    2011-01-01

    Synaptic release of neurotransmitters is evoked by activity-dependent Ca2+ entry into the nerve terminal. However, here it is shown that robust synaptic neuropeptide release from Drosophila motoneurons is evoked in the absence of extracellular Ca2+ by octopamine, the arthropod homolog to norepinephrine. Genetic and pharmacology experiments demonstrate that this surprising peptidergic transmission requires cAMP-dependent protein kinase, with only a minor contribution of exchange protein activa...

  17. Role of synaptic dynamics and heterogeneity in neuronal learning of temporal code

    Rotman, Ziv; Klyachko, Vitaly A.

    2013-01-01

    Temporal codes are believed to play important roles in neuronal representation of information. Neuronal ability to classify and learn temporal spiking patterns is thus essential for successful extraction and processing of information. Understanding neuronal learning of temporal code has been complicated, however, by the intrinsic stochasticity of synaptic transmission. Using a computational model of a learning neuron, the tempotron, we studied the effects of synaptic unreliability and short-t...

  18. Brief dendritic calcium signals initiate long-lasting synaptic depression in cerebellar Purkinje cells.

    Konnerth, A.; Dreessen, J; Augustine, G J

    1992-01-01

    We have performed experiments designed to test the hypothesis that long-term depression (LTD) of excitatory synaptic transmission in the cerebellar cortex is caused by a rise in postsynaptic Ca concentration. These experiments combined measurements of synaptic efficacy, performed with the thin slice patch clamp technique, with fura-2 measurements of intracellular Ca concentration ([Ca]i) in single cerebellar Purkinje cells. Simultaneous activation of the climbing fiber and parallel fibers inn...

  19. Consumption of palatable food primes food approach behavior by rapidly increasing synaptic density in the VTA

    Liu, Shuai; Globa, Andrea K.; Mills, Fergil; Naef, Lindsay; Qiao, Min; Bamji, Shernaz X.; Borgland, Stephanie L.

    2016-01-01

    Consumption of palatable food or food-related advertising can prime increased food intake, potentially leading to overeating. We show that short-term exposure to palatable foods induces long-lasting synaptic plasticity in mesolimbic dopamine neurons. Furthermore, short-term exposure to sweetened high-fat food can drive food approach behaviors and consumption days after the initial exposure. Suppressing excitatory synaptic transmission in the ventral tegmental area can reverse increased food a...

  20. AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging

    Henley JM; Wilkinson KA

    2013-01-01

    Even in healthy individuals there is an inexorable agerelated decline in cognitive function. This is due, in large part, to reduced synaptic plasticity caused by changes in the molecular composition of the postsynaptic membrane. AMPA receptors (AMPARs) are glutamate-gated cation channels that mediate the overwhelming majority of fast excitatory transmission in the brain. Changes in AMPAR number and/or function are a core feature of synaptic plasticity and age-related cognitive decline, AMPARs...

  1. Glial protein S100B modulates long-term neuronal synaptic plasticity

    NISHIYAMA, HIROSHI; Knöpfel, Thomas; Endo, Shogo; Itohara, Shigeyoshi

    2002-01-01

    Glial cells are traditionally regarded as elements for structural support and ionic homeostasis, but have recently attracted attention as putative integral elements of the machinery involved in synaptic transmission and plasticity. Here, we demonstrate that calcium-binding protein S100B, which is synthesized in considerable amounts in astrocytes (a major glial cell subtype), modulates long-term synaptic plasticity. Mutant mice devoid of S100B developed normally and had no detectable abnormali...

  2. A trans-synaptic nanocolumn aligns neurotransmitter release to receptors.

    Tang, Ai-Hui; Chen, Haiwen; Li, Tuo P; Metzbower, Sarah R; MacGillavry, Harold D; Blanpied, Thomas A

    2016-08-11

    Synaptic transmission is maintained by a delicate, sub-synaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity and pathological disorders. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresponds to the position of receptors in the postsynaptic density. However, while it has long been recognized that this spatial relationship modulates synaptic strength, it has not been precisely described, owing in part to the limited resolution of light microscopy. Using localization microscopy, here we show that key proteins mediating vesicle priming and fusion are mutually co-enriched within nanometre-scale subregions of the presynaptic active zone. Through development of a new method to map vesicle fusion positions within single synapses in cultured rat hippocampal neurons, we find that action-potential-evoked fusion is guided by this protein gradient and occurs preferentially in confined areas with higher local density of Rab3-interacting molecule (RIM) within the active zones. These presynaptic RIM nanoclusters closely align with concentrated postsynaptic receptors and scaffolding proteins, suggesting the existence of a trans-synaptic molecular 'nanocolumn'. Thus, we propose that the nanoarchitecture of the active zone directs action-potential-evoked vesicle fusion to occur preferentially at sites directly opposing postsynaptic receptor-scaffold ensembles. Remarkably, NMDA receptor activation triggered distinct phases of plasticity in which postsynaptic reorganization was followed by trans-synaptic nanoscale realignment. This architecture suggests a simple organizational principle of central nervous system synapses to maintain and modulate synaptic efficiency. PMID:27462810

  3. Kidins220/ARMS is a novel modulator of short-term synaptic plasticity in hippocampal GABAergic neurons.

    Joachim Scholz-Starke

    Full Text Available Kidins220 (Kinase D interacting substrate of 220 kDa/ARMS (Ankyrin Repeat-rich Membrane Spanning is a scaffold protein highly expressed in the nervous system. Previous work on neurons with altered Kidins220/ARMS expression suggested that this protein plays multiple roles in synaptic function. In this study, we analyzed the effects of Kidins220/ARMS ablation on basal synaptic transmission and on a variety of short-term plasticity paradigms in both excitatory and inhibitory synapses using a recently described Kidins220 full knockout mouse. Hippocampal neuronal cultures prepared from embryonic Kidins220(-/- (KO and wild type (WT littermates were used for whole-cell patch-clamp recordings of spontaneous and evoked synaptic activity. Whereas glutamatergic AMPA receptor-mediated responses were not significantly affected in KO neurons, specific differences were detected in evoked GABAergic transmission. The recovery from synaptic depression of inhibitory post-synaptic currents in WT cells showed biphasic kinetics, both in response to paired-pulse and long-lasting train stimulation, while in KO cells the respective slow components were strongly reduced. We demonstrate that the slow recovery from synaptic depression in WT cells is caused by a transient reduction of the vesicle release probability, which is absent in KO neurons. These results suggest that Kidins220/ARMS is not essential for basal synaptic transmission and various forms of short-term plasticity, but instead plays a novel role in the mechanisms regulating the recovery of synaptic strength in GABAergic synapses.

  4. Adolescent Alcohol Exposure: Burden of Epigenetic Reprogramming, Synaptic Remodeling, and Adult Psychopathology

    Kyzar, Evan J.; Floreani, Christina; Teppen, Tara L.; Pandey, Subhash C.

    2016-01-01

    Adolescence represents a crucial phase of synaptic maturation characterized by molecular changes in the developing brain that shape normal behavioral patterns. Epigenetic mechanisms play an important role in these neuromaturation processes. Perturbations of normal epigenetic programming during adolescence by ethanol can disrupt these molecular events, leading to synaptic remodeling and abnormal adult behaviors. Repeated exposure to binge levels of alcohol increases the risk for alcohol use disorder (AUD) and comorbid psychopathology including anxiety in adulthood. Recent studies in the field clearly suggest that adolescent alcohol exposure causes widespread and persistent changes in epigenetic, neurotrophic, and neuroimmune pathways in the brain. These changes are manifested by altered synaptic remodeling and neurogenesis in key brain regions leading to adult psychopathology such as anxiety and alcoholism. This review details the molecular mechanisms underlying adolescent alcohol exposure-induced changes in synaptic plasticity and the development of alcohol addiction-related phenotypes in adulthood. PMID:27303256

  5. Adolescent alcohol exposure: Burden of epigenetic reprogramming, synaptic remodeling, and adult psychopathology

    Evan J Kyzar

    2016-05-01

    Full Text Available Adolescence represents a crucial phase of synaptic maturation characterized by molecular changes in the developing brain that shape normal behavioral patterns. Epigenetic mechanisms play an important role in these neuromaturation processes. Perturbations of normal epigenetic programming during adolescence by ethanol can delay these molecular events, leading to synaptic remodeling and abnormal adult behaviors. Repeated exposure to binge levels of alcohol increases the risk for alcohol use disorder (AUD and comorbid psychopathology including anxiety in adulthood. Recent studies in the field clearly suggest that adolescent alcohol exposure causes widespread and persistent changes in epigenetic, neurotrophic, and neuroimmune pathways in the brain. These changes are manifested by altered synaptic remodeling and neurogenesis in key brain regions leading to adult psychopathology such as anxiety and alcoholism. This review details the molecular mechanisms underlying adolescent alcohol exposure-induced changes in synaptic plasticity and the development of alcohol addiction-related phenotypes in adulthood.

  6. NMDA-receptor activation but not ion flux is required for amyloid-beta induced synaptic depression.

    Albert Tamburri

    Full Text Available Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ in the etiology of Alzheimer's disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

  7. 神经电活动稳态调控抑制性突触传递的分子机制%Molecular Mechanisms Underlying Activity-induced Homeostatic Regulation of Inhibitory Synaptic Transmission

    彭懿蓉; 于翔

    2011-01-01

    excitatory synapses, relatively little is known about the mechanism mediating homeostatic plasticity of inhibitory synapses, especially that following activity elevation. Here, we found that elevating neuronal activity in cultured hippocampal neurons for 4h significantly increased the frequency and amplitude of mlPSCs, before detectable change at excitatory synapses. Consistently, we observed increases in presynaptic and postsynaptic proteins of GABAergic synapses, including GAD65,vGAT, and GABAARal. By suppressing activity-induced increase of neuronal firing with expression of the inward rectifier potassium channel Kir2. 1 in individual neurons, we showed that elevation in postsynaptic spiking activity is required for activity-dependent increase in the frequency and amplitude of mlPSCs. Importantly, directly elevating spiking in individual postsynaptic neurons, by capsaicin activation of overexpressed TR-PV1 channels, was sufficient to induce increased mlP-SC amplitude and frequency, mimicking the effect of elevated neuronal activity. Downregulating BDNF expression in the postsynaptic neuron or its extracellular scavenging prevented activity-induced increase in mlPSC frequency, consistent with a role of BDNF-dependent retrograde signaling in this process. Finally, elevating activity in vivo by kainate injection increased both mIP-SC amplitude and frequency in CA1 pyramidal neurons. Thus, spiking-induced, cell-autonomous upregulation of GABAergic synaptic inputs, through retrograde BDNF signaling, represents an early adaptive response of neural circuits to elevated network activity.

  8. Synaptic protein levels altered in vascular dementia

    Sinclair, Lindsey I; Tayler, Hannah M; Love, Seth

    2015-01-01

    Introduction Cerebral ischaemia is the defining pathophysiological abnormality in most forms of vascular dementia (VAD), but the pathogenesis of the dementia remains poorly understood. In Alzheimer's disease (AD), there is early loss of synaptic proteins, but these have been little studied in VAD. Materials and Methods We measured synaptophysin, postsynaptic density protein 95 (PSD-95), drebrin, synaptosomal-associated protein 25 (SNAP-25) and vascular endothelial growth factor (VEGF) by enzyme-linked immunosorbent assays in superior temporal cortex from 11 patients with VAD and, initially, 11 non-dementia controls. We corrected for neuronal content by measurement of neuron-specific enolase. A further 11 controls were subsequently used in a validation study. Simulation of post-mortem delay found that PSD-95 was stable at 4°C but declined slightly at RT. SNAP-25 and drebrin showed good post-mortem stability. Previous studies had shown good post-mortem preservation of synaptophysin and VEGF. Results The VAD cases had lower synaptophysin (but P > 0.05 in initial study), significantly lower SNAP-25 (P = 0.024) and significantly higher drebrin (P = 0.020). On comparison with the second control group, the reduction in synaptophysin was significant (P = 0.008), and the other results were confirmed. Conclusion There is probably a reduction in presynaptic proteins in the temporal cortex in VAD, although not as marked as in AD. In VAD, there is also an increase in drebrin, which may be a response to reduced synaptic input. PMID:25559750

  9. ELECTRON MICROSCOPY OF SYNAPTIC STRUCTURE OF OCTOPUS BRAIN.

    GRAY, E G; YOUNG, J Z

    1964-04-01

    The well known type of synapse between a presynaptic process containing vesicles and a "clear" postsynaptic process can be commonly observed in the various lobes of the brain of Octopus. The presynaptic vesicles are aggregated near regions of the synaptic membranes which show specialisation and asymmetric "thickening" indicating functional polarisation, and here chemical transmission is presumed to take place. In addition, in the vertical lobe a very interesting serial arrangement of synaptic contacts occurs. Presynaptic bags, formed from varicosities of fibres from the superior frontal lobe, contact the trunks of amacrine cells in the manner just described. The trunks, however, although apparently postsynaptic are themselves packed with synaptic vesicles. The trunks, in turn, make "presynaptic" contacts with clear spinous processes of other neurons of yet undetermined origin. Typical polarised membrane specialisations occur at the contact regions. The trunk vesicles aggregated closest to the contact regions have a shell of particles round their walls. At present, there is no way of telling whether the membrane conductance to the various ions is differently affected at either of the transmission sites, and, if an inhibitory mechanism is involved, whether it is of the presynaptic or postsynaptic variety. PMID:14154498

  10. Huperzine A enhances excitatory synaptic transmission in CA1 pyramidal neurons of adult rat hippocampal slices%石杉碱甲增强大鼠海马脑片CA1锥体神经元的兴奋性突触传递

    吴小未; 王邦安; 汪萌芽

    2012-01-01

    AIM: To observe the effects of huperzine A (Hup-A) on excitatory synaptic transmission in CA1 pyramidal neurons of adult rat hippocampal slices and to gain an insight into the cellular electrophysiological mechanisms underlying the potentiation of learning and memory by Hup-A. METHODS: The intracellular recordings from CA1 pyramidal neurons in hippocampal slices related to learning and memory were made to analyze mechanisms of Hup-A actions on cell electrophysiological properties and excitatory postsynaptic potential (EPSP) evoked by stimulating Schaffer collaterals. RESULTS; (1) During bath of Hup-A (1 μmol/L), the changes of cell electrophysiological properties were not significant (P>0. 05). (2) Superfu-sion of Hup-A (0. 3 - 3. 0 μmol/L, 15 min) in- creased amplitude, duration and area under curve of EPSPs, which was concentration-dependent, recoverable, but sensitive to atropine pretreatment (10 μmol/L, n = 4). (3) Hup-A did not result in remarkable changes of depolarizing response induced by exogenous glutamate (n=5). CONCLUSION, By the facilitation of the synaptic transmissions, Hup-A may potentiate the activities of hippocampal CA1 pyramidal neurons, and its actions on EPSP is related to the excitation of muscarinic type of acetylcholin-ergic receptors.%目的:观察石杉碱甲(Hup-A)对海马CA1锥体神经元兴奋性突触传递的影响,以探讨其增强学习记忆功能的神经细胞电生理机制.方法:应用大鼠海马脑片CA1锥体神经元细胞内记录技术,观察Hup-A对大鼠海马CA1锥体神经元膜电性质和刺激Schaffer侧支诱发的兴奋性突触后电位( EPSP)的影响.结果:(1) Hup-A(1 μmol/L)灌流15 min对CA1锥体神经元的膜电性质没有显著性影响.(2) Hup-A (0.3~3.0 μmol/L)浓度依赖性使EPSP幅度升高、时程延长、曲线下面积增大,该作用可被阿托品(10μmol/L)预处理取消.(3)Hup-A对外源性谷氨酸诱导的去极化反应无明显影响.结论:Hup-A可增强CA1

  11. Synaptic plasticity, neural circuits and the emerging role of altered short-term information processing in schizophrenia

    Gregg W. Crabtree

    2014-11-01

    Full Text Available Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point towards a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders may be due to a combination of both short-term and long-term synaptic plasticity alterations.

  12. Role of the origin of glutamatergic synaptic inputs in controlling synaptic plasticity and its modulation by alcohol in mice nucleus accumbens

    Gilles Erwann Martin

    2015-07-01

    Full Text Available It is widely accepted that long-lasting changes of synaptic strength in the nucleus accumbens, a brain region involved in drug reward, mediate acute and chronic effects of alcohol. However, our understanding of the mechanisms underlying the effects of alcohol on synaptic plasticity is limited by the fact that the nucleus accumbens receives glutamatergic inputs from distinct brain regions (e.g. the prefrontal cortex, the amygdala and the hippocampus, each region providing different information (e.g. spatial, emotional and cognitive. Combining whole-cell patch-clamp recordings and the optogenetic technique, we examined synaptic plasticity, and its regulation by alcohol, at cortical, hippocampal and amygdala inputs in fresh slices of mouse tissue. We showed that the origin of synaptic inputs determines the basic properties of glutamatergic synaptic transmission, the expression of spike-timing dependent long-term depression (tLTD and long-term potentiation (tLTP and their regulation by alcohol. While we observed both tLTP and tLTD at amygadala and hippocampal synapses, we showed that cortical inputs only undergo tLTD. Functionally, we provide evidence that acute EtOH has little effects on higher order information coming from the prefrontal cortex (PFCx, while severely impacting the ability of emotional and contextual information to induce long-lasting changes of synaptic strength.

  13. Super-resolution microscopy of the synaptic active zone

    Markus Sauer

    2015-01-01

    Full Text Available Brain function relies on accurate information transfer at chemical synapses. At the presynaptic active zone (AZ a variety of specialised proteins are assembled to complex architectures, which set the basis for speed, precision and plasticity of synaptic transmission. Calcium (Ca2+ channels are pivotal for the initiation of excitation-secretion coupling and, correspondingly, capture a central position at the AZ. Combining quantitative functional studies with modelling approaches has provided predictions of channel properties, numbers and even positions on the nanometre scale. However, elucidating the nanoscopic organisation of the surrounding protein network requires direct ultrastructural access. Without this information, knowledge of molecular synaptic structure-function relationships remains incomplete. Recently, super-resolution microscopy techniques have begun to enter the neurosciences. These approaches combine high spatial resolution with the molecular specificity of fluorescence microscopy. Here, we discuss how super-resolution microscopy can be used to obtain information on the organisation of AZ proteins.

  14. Statistical Modelling of Synaptic Vesicles Distribution and Analysing their Physical Characteristics

    Khanmohammadi, Mahdieh

    transmission electron microscopy is used to acquire images from two experimental groups of rats: 1) rats subjected to a behavioral model of stress and 2) rats subjected to sham stress as the control group. The synaptic vesicle distribution and interactions are modeled by employing a point process approach. The......This Ph.D. thesis deals with mathematical and statistical modeling of synaptic vesicle distribution, shape, orientation and interactions. The first major part of this thesis treats the problem of determining the effect of stress on synaptic vesicle distribution and interactions. Serial section...... differences of statistical measures in section and the same measures in between sections. Three-dimensional (3D) datasets are reconstructed by using image registration techniques and estimated thicknesses. We distinguish the effect of stress by estimating the synaptic vesicle densities and modeling their...

  15. Open Syntaxin Docks Synaptic Vesicles

    Marc Hammarlund; Mark T Palfreyman; Shigeki Watanabe; Shawn Olsen; Erik M. Jorgensen

    2007-01-01

    Author Summary Like Olympic swimmers crouched on their starting blocks, synaptic vesicles prepare for fusion with the neuronal plasma membrane long before the starting gun fires. This preparation enables vesicles to fuse rapidly, synchronously, and in the correct place when the signal finally arrives. A well-known but poorly understood part of vesicle preparation is docking, in which vesicles prepare for release by attaching to the plasma membrane at the eventual site of release. Here, we out...

  16. Wnts in adult brain: from synaptic plasticity to cognitive deficiencies

    Oliva, Carolina A.; Vargas, Jessica Y.; Inestrosa, Nibaldo C.

    2013-01-01

    During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer’s disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts. PMID:24348327

  17. Synaptic strength modulation after cortical trauma: a role in epileptogenesis.

    Avramescu, Sinziana; Timofeev, Igor

    2008-07-01

    Traumatic brain injuries are often followed by abnormal hyperexcitability, leading to acute seizures and epilepsy. Previous studies documented the rewiring capacity of neocortical neurons in response to various cortical and subcortical lesions. However, little information is available on the functional consequences of these anatomical changes after cortical trauma and the adaptation of synaptic connectivity to a decreased input produced by chronic deafferentation. In this study, we recorded intracellular (IC) activities of cortical neurons simultaneously with extracellular (EC) unit activities and field potentials of neighboring cells in cat cortex, after a large transection of the white matter underneath the suprasylvian gyrus, in acute and chronic conditions (at 2, 4, and 6 weeks) in ketamine-xylazine-anesthetized cats. Using EC spikes to compute the spike-triggered averages of IC membrane potential, we found an increased connection probability and efficacy between cortical neurons weeks after cortical trauma. Inhibitory interactions showed no significant changes in the traumatized cortex compared with control. The increased synaptic efficacy was accompanied by enhanced input resistance and intrinsic excitability of cortical neurons, as well as by increased duration of silent network periods. Our electrophysiological data revealed functional consequences of previously reported anatomical changes in the injured cortex. We suggest that homeostatic synaptic plasticity compensating the decreased activity in the undercut cortex leads to an uncontrollable cortical hyperexcitability and seizure generation. PMID:18596152

  18. BACE1 Is Necessary for Experience-Dependent Homeostatic Synaptic Plasticity in Visual Cortex

    Emily Petrus

    2014-01-01

    Full Text Available Alzheimer’s disease (AD is the most common form of age-related dementia, which is thought to result from overproduction and/or reduced clearance of amyloid-beta (Aβ peptides. Studies over the past few decades suggest that Aβ is produced in an activity-dependent manner and has physiological relevance to normal brain functions. Similarly, physiological functions for β- and γ-secretases, the two key enzymes that produce Aβ by sequentially processing the amyloid precursor protein (APP, have been discovered over recent years. In particular, activity-dependent production of Aβ has been suggested to play a role in homeostatic regulation of excitatory synaptic function. There is accumulating evidence that activity-dependent immediate early gene Arc is an activity “sensor,” which acts upstream of Aβ production and triggers AMPA receptor endocytosis to homeostatically downregulate the strength of excitatory synaptic transmission. We previously reported that Arc is critical for sensory experience-dependent homeostatic reduction of excitatory synaptic transmission in the superficial layers of visual cortex. Here we demonstrate that mice lacking the major neuronal β-secretase, BACE1, exhibit a similar phenotype: stronger basal excitatory synaptic transmission and failure to adapt to changes in visual experience. Our results indicate that BACE1 plays an essential role in sensory experience-dependent homeostatic synaptic plasticity in the neocortex.

  19. Urine - abnormal color

    ... medlineplus.gov/ency/article/003139.htm Urine - abnormal color To use the sharing features on this page, please enable JavaScript. The usual color of urine is straw-yellow. Abnormally colored urine ...

  20. Synaptic Mitochondria in Synaptic Transmission and Organization of Vesicle Pools in Health and Disease

    Vos, Melissa; Lauwers, Elsa; Verstreken, Patrik

    2010-01-01

    Cell types rich in mitochondria, including neurons, display a high energy demand and a need for calcium buffering. The importance of mitochondria for proper neuronal function is stressed by the occurrence of neurological defects in patients suffering from a great variety of diseases caused by mutations in mitochondrial genes. Genetic and pharmacological evidence also reveal a role of these organelles in various aspects of neuronal physiology and in the pathogenesis of neurodegenerative disord...

  1. Synaptic mitochondria in synaptic transmission and organization of vesicle pools in health and disease

    Melissa Vos; Elsa Lauwers; Patrik Verstreken

    2010-01-01

    Cell types rich in mitochondria, including neurons, display a high energy demand and a need for calcium buffering. The importance of mitochondria for proper neuronal function is stressed by the occurrence of neurological defects in patients suffering from a great variety of diseases caused by mutations in mitochondrial genes. Genetic and pharmacological evidence also reveal a role of these organelles in various aspects of neuronal physiology and in the pathogenesis of neurodegenerative disord...

  2. Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity.

    Brassai, A; Suvanjeiev, R-G; Bán, E-Gy; Lakatos, M

    2015-03-01

    In acute ischaemic brain injury and chronic neurodegeneration, the first step leading to excitotoxicity and cell death is the excessive release of Glu and the prolonged activation of Glu receptors, followed by intracellular calcium overload. There is apparent agreement that glutamatergic transmission via synaptic NMDA receptors (composed of GluN2A subunits) is neuroprotective, whereas transmission via non-synaptic NMDA receptors (composed of GluN2B subunits) is excitotoxic. Extrasynaptic NMDARs activate cell death pathways and may play a key role in Glu-induced excitotoxic neurodegeneration and apoptosis. Accordingly, the function of protective pathways may be impaired by the concomitant blockade of GluN2A-containing receptors. In contrast, the selective inhibition of non-synaptic GluN2B-containing NMDARs may be beneficial in neuroprotection because it can prevent neuronal cell death and thus maintain protective pathways. PMID:25540918

  3. Nootropic dipeptide noopept enhances inhibitory synaptic transmission in the hippocampus.

    Povarov, I S; Kondratenko, R V; Derevyagin, V I; Ostrovskaya, R U; Skrebitskii, V G

    2015-01-01

    Application of nootropic agent Noopept on hippocampal slices from Wistar rats enhanced the inhibitory component of total current induced by stimulation of Shaffer collaterals in CA1 pyramidal neurons, but did not affect the excitatory component. A direct correlation between the increase in the amplitude of inhibitory current and agent concentration was found. The substance did not affect the release of inhibitory transmitters from terminals in the pyramidal neurons, which indicated changes in GABAergic interneurons. PMID:25573367

  4. Calcium-sensing receptor activation depresses synaptic transmission

    Phillips, Cecilia G.; Harnett, Mark T.; Chen, Wenyan; Smith, Stephen M.

    2008-01-01

    At excitatory synapses, decreases in cleft [Ca] arising from activity-dependent transmembrane Ca flux reduce the probability of subsequent transmitter release. Intense neural activity, induced by physiological and pathological stimuli, disturb the external microenvironment reducing extracellular [Ca] ([Ca]o) and thus may impair neurotransmission. Increases in [Ca]o activate the extracellular calcium sensing receptor (CaSR) which in turn inhibits non-selective cation channels (NSCC) at the maj...

  5. Cholinergic Mechanisms in the Cerebral Cortex: Beyond Synaptic Transmission.

    Ovsepian, Saak V; O'Leary, Valerie B; Zaborszky, Laszlo

    2016-06-01

    Functional overviews of cholinergic mechanisms in the cerebral cortex have traditionally focused on the release of acetylcholine with modulator and transmitter effects. Recently, however, data have emerged that extend the role of acetylcholine and cholinergic innervations to a range of housekeeping and metabolic functions. These include regulation of amyloid precursor protein (APP) processing with production of amyloid β (Aβ) and other APP fragments and control of the phosphorylation of microtubule-associated protein (MAP) tau. Evidence has been also presented for receptor-ligand like interactions of cholinergic receptors with soluble Aβ peptide and MAP tau, with modulator and signaling effects. Moreover, high-affinity binding of Aβ to the neurotrophin receptor p75 (p75NTR) enriched in basalo-cortical cholinergic projections has been implicated in clearance of Aβ and nucleation of amyloid plaques. Here, we critically evaluate these unorthodox cholinergic mechanisms and discuss their role in neuronal physiology and the biology of Alzheimer's disease. PMID:26002948

  6. Regulation of synaptic connectivity by glia

    Eroglu, Cagla; Barres, Ben A

    2010-01-01

    The human brain contains more than 100 trillion (1014) synaptic connections, which form all of its neural circuits. Neuroscientists have long been interested in how this complex synaptic web is weaved during development and remodelled during learning and disease. Recent studies have uncovered that glial cells are important regulators of synaptic connectivity. These cells are far more active than was previously thought and are powerful controllers of synapse formation, function, plasticity and...

  7. Modulation of synaptic depression of the calyx of Held synapse by GABAB receptors and spontaneous activity

    Wang, T.; Rusu, S. I.; Hrušková, Bohdana; Tureček, Rostislav; Borst, J. G.

    2013-01-01

    Roč. 591, č. 19 (2013), s. 4877-4894. ISSN 0022-3751 R&D Projects: GA ČR(CZ) GAP303/11/0131 Institutional support: RVO:68378041 Keywords : GABAB * synaptic transmission * auditory Subject RIV: FH - Neurology Impact factor: 4.544, year: 2013

  8. Abnormal glutamate release in aged BTBR mouse model of autism

    Wei, Hongen; Ding, Caiyun; Jin, Guorong; Yin, Haizhen; Liu, Jianrong; Hu, Fengyun

    2015-01-01

    Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. Most of the available research on autism is focused on children and young adults and little is known about the pathological alternation of autism in older adults. In order to investigate the neurobiological alternation of autism in old age stage, we compared the morphology and synaptic function of excitatory synapses betw...

  9. Altered hippocampus synaptic function in selenoprotein P deficient mice

    Peters Melinda M

    2006-09-01

    Full Text Available Abstract Selenium is an essential micronutrient that function through selenoproteins. Selenium deficiency results in lower concentrations of selenium and selenoproteins. The brain maintains it's selenium better than other tissues under low-selenium conditions. Recently, the selenium-containing protein selenoprotein P (Sepp has been identified as a possible transporter of selenium. The targeted disruption of the selenoprotein P gene (Sepp1 results in decreased brain selenium concentration and neurological dysfunction, unless selenium intake is excessive However, the effect of selenoprotein P deficiency on the processes of memory formation and synaptic plasticity is unknown. In the present studies Sepp1(-/- mice and wild type littermate controls (Sepp1(+/+ fed a high-selenium diet (1 mg Se/kg were used to characterize activity, motor coordination, and anxiety as well as hippocampus-dependent learning and memory. Normal associative learning, but disrupted spatial learning was observed in Sepp1(-/- mice. In addition, severe alterations were observed in synaptic transmission, short-term plasticity and long-term potentiation in hippocampus area CA1 synapses of Sepp1(-/- mice on a 1 mg Se/kg diet and Sepp1(+/+ mice fed a selenium-deficient (0 mg Se/kg diet. Taken together, these data suggest that selenoprotein P is required for normal synaptic function, either through presence of the protein or delivery of required selenium to the CNS.

  10. Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate

    Schotten, Sebastiaan; Meijer, Marieke; Walter, Alexander Matthias;

    2015-01-01

    supralinear effects on the fusion rate. To test this prediction experimentally, we developed a method to assess the number of releasable vesicles, rate constants for vesicle priming, unpriming, and fusion, and the activation energy for fusion by fitting a vesicle state model to synaptic responses induced by......-linear effects of genetic/pharmacological perturbations on synaptic transmission and a novel interpretation of the cooperative nature of Ca2+-dependent release....

  11. Kidins220/ARMS Is a Novel Modulator of Short-Term Synaptic Plasticity in Hippocampal GABAergic Neurons

    Joachim Scholz-Starke; Fabrizia Cesca; Giampietro Schiavo; Fabio Benfenati; Pietro Baldelli

    2012-01-01

    Kidins220 (Kinase D interacting substrate of 220 kDa)/ARMS (Ankyrin Repeat-rich Membrane Spanning) is a scaffold protein highly expressed in the nervous system. Previous work on neurons with altered Kidins220/ARMS expression suggested that this protein plays multiple roles in synaptic function. In this study, we analyzed the effects of Kidins220/ARMS ablation on basal synaptic transmission and on a variety of short-term plasticity paradigms in both excitatory and inhibitory synapses using a r...

  12. Synaptic Impairment in Layer 1 of the Prefrontal Cortex Induced by Repeated Stress During Adolescence is Reversed in Adulthood

    Negrón-Oyarzo, Ignacio; Dagnino-Subiabre, Alexies; Muñoz Carvajal, Pablo

    2015-01-01

    Chronic stress is a risk factor for the development of psychiatric disorders, some of which involve dysfunction of the prefrontal cortex (PFC). There is a higher prevalence of these chronic stress-related psychiatric disorders during adolescence, when the PFC has not yet fully matured. In the present work we studied the effect of repeated stress during adolescence on synaptic function in the PFC in adolescence and adulthood. To this end, adolescent Sprague-Dawley rats were subjected to seven consecutive days of restraint stress. Afterward, both synaptic transmission and short- and long-term synaptic plasticity were evaluated in layer 1 of medial-PFC (mPFC) slices from adolescent and adult rats. We found that repeated stress significantly reduced the amplitude of evoked field excitatory post-synaptic potential (fEPSP) in the mPFC. Isolation of excitatory transmission reveled that lower-amplitude fEPSPs were associated with a reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated transmission. We also found that repeated stress significantly decreased long-term depression (LTD). Interestingly, AMPA/kainate receptor-mediated transmission and LTD were recovered in adult animals that experienced a three-week stress-free recovery period. The data indicates that the changes in synaptic transmission and plasticity in the mPFC induced by repeated stress during adolescence are reversed in adulthood after a stress-free period. PMID:26617490

  13. MOLECULAR MACHINES DETERMINING THE FATE OF ENDOCYTOSED SYNAPTIC VESICLES IN NERVE TERMINALS

    Anna Fassio

    2016-05-01

    Full Text Available The cycle of a synaptic vesicle (SV within the nerve terminal is a step-by-step journey with the final goal of ensuring the proper synaptic strength under changing environmental conditions.The SV cycle is a precisely regulated membrane traffic event in cells and, because of this, a plethora of membrane-bound and cytosolic proteins are devoted to assist SVs in each step of the journey. The cycling fate of endocytosed SVs determines both the availability for subsequent rounds of release and the lifetime of SVs in the terminal and is therefore crucial for synaptic function and plasticity. Molecular players that determine the destiny of SVs in nerve terminals after a round of exo-endocytosis are largely unknown. Here we review the functional role in SV fate of phosphorylation/dephosphorylation of SV proteins and of small GTPases acting on membrane trafficking at the synapse, as they are emerging as key molecules in determining the recycling route of SVs within the nerve terminal. In particular, we focus on (i the cyclin-dependent kinase-5 and calcineurin control of the recycling pool of SVs; (ii the role of small GTPases of the Rab and ADP-ribosylation factor (Arf families in defining the route followed by SV in their nerve terminal cycle. These regulatory proteins together with their synaptic regulators and effectors, are molecular nanomachines mediating homeostatic responses in synaptic plasticity and potential targets of drugs modulating the efficiency of synaptic transmission.

  14. Presynaptic protein synthesis required for NT-3-induced long-term synaptic modulation

    Je H

    2011-01-01

    Full Text Available Abstract Background Neurotrophins elicit both acute and long-term modulation of synaptic transmission and plasticity. Previously, we demonstrated that the long-term synaptic modulation requires the endocytosis of neurotrophin-receptor complex, the activation of PI3K and Akt, and mTOR mediated protein synthesis. However, it is unclear whether the long-term synaptic modulation by neurotrophins depends on protein synthesis in pre- or post-synaptic cells. Results Here we have developed an inducible protein translation blocker, in which the kinase domain of protein kinase R (PKR is fused with bacterial gyrase B domain (GyrB-PKR, which could be dimerized upon treatment with a cell permeable drug, coumermycin. By genetically targeting GyrB-PKR to specific cell types, we show that NT-3 induced long-term synaptic modulation requires presynaptic, but not postsynaptic protein synthesis. Conclusions Our results provide mechanistic insights into the cell-specific requirement for protein synthesis in the long-term synaptic modulation by neurotrophins. The GyrB-PKR system may be useful tool to study protein synthesis in a cell-specific manner.

  15. Molecular Machines Determining the Fate of Endocytosed Synaptic Vesicles in Nerve Terminals

    Fassio, Anna; Fadda, Manuela; Benfenati, Fabio

    2016-01-01

    The cycle of a synaptic vesicle (SV) within the nerve terminal is a step-by-step journey with the final goal of ensuring the proper synaptic strength under changing environmental conditions. The SV cycle is a precisely regulated membrane traffic event in cells and, because of this, a plethora of membrane-bound and cytosolic proteins are devoted to assist SVs in each step of the journey. The cycling fate of endocytosed SVs determines both the availability for subsequent rounds of release and the lifetime of SVs in the terminal and is therefore crucial for synaptic function and plasticity. Molecular players that determine the destiny of SVs in nerve terminals after a round of exo-endocytosis are largely unknown. Here we review the functional role in SV fate of phosphorylation/dephosphorylation of SV proteins and of small GTPases acting on membrane trafficking at the synapse, as they are emerging as key molecules in determining the recycling route of SVs within the nerve terminal. In particular, we focus on: (i) the cyclin-dependent kinase-5 (cdk5) and calcineurin (CN) control of the recycling pool of SVs; (ii) the role of small GTPases of the Rab and ADP-ribosylation factor (Arf) families in defining the route followed by SV in their nerve terminal cycle. These regulatory proteins together with their synaptic regulators and effectors, are molecular nanomachines mediating homeostatic responses in synaptic plasticity and potential targets of drugs modulating the efficiency of synaptic transmission. PMID:27242505

  16. Presynaptic active zone density during development and synaptic plasticity.

    Gwenaëlle L Clarke

    2012-02-01

    Full Text Available Neural circuits transmit information through synapses, and the efficiency of synaptic transmission is closely related to the density of presynaptic active zones, where synaptic vesicles are released. The goal of this review is to highlight recent insights into the molecular mechanisms that control the number of active zones per presynaptic terminal (active zone density during developmental and stimulus-dependent changes in synaptic efficacy. At the neuromuscular junctions (NMJs, the active zone density is preserved across species, remains constant during development, and is the same between synapses with different activities. However, the NMJ active zones are not always stable, as exemplified by the change in active zone density during acute experimental manipulation or as a result of aging. Therefore, a mechanism must exist to maintain its density. In the central nervous system (CNS, active zones have restricted maximal size, exist in multiple numbers in larger presynaptic terminals, and maintain a constant density during development. These findings suggest that active zone density in the CNS is also controlled. However, in contrast to the NMJ, active zone density in the CNS can also be increased, as observed in hippocampal synapses in response to synaptic plasticity. Although the numbers of known active zone proteins and protein interactions have increased, less is known about the mechanism that controls the number or spacing of active zones. The following molecules are known to control active zone density and will be discussed herein: extracellular matrix laminins and voltage-dependent calcium channels, amyloid precursor proteins, the small GTPase Rab3, an endocytosis mechanism including synaptojanin, cytoskeleton protein spectrins and β-adducin, and a presynaptic web including spectrins. The molecular mechanisms that organize the active zone density are just beginning to be elucidated.

  17. A Mathematical Model of Tripartite Synapse: Astrocyte Induced Synaptic Plasticity

    Tewari, Shivendra; Majumdar, Kaushik

    2011-01-01

    In this paper we present a biologically detailed mathematical model of tripartite synapses, where astrocytes modulate short-term synaptic plasticity. The model consists of a pre-synaptic bouton, a post-synaptic dendritic spine-head, a synaptic cleft and a peri-synaptic astrocyte controlling Ca2+ dynamics inside the synaptic bouton. This in turn controls glutamate release dynamics in the cleft. As a consequence of this, glutamate concentration in the cleft has been modeled, in which glutamate ...

  18. Learning and reconsolidation implicate different synaptic mechanisms.

    Li, Yan; Meloni, Edward G; Carlezon, William A; Milad, Mohammed R; Pitman, Roger K; Nader, Karim; Bolshakov, Vadim Y

    2013-03-19

    Synaptic mechanisms underlying memory reconsolidation after retrieval are largely unknown. Here we report that synapses in projections to the lateral nucleus of the amygdala implicated in auditory fear conditioning, which are potentiated by learning, enter a labile state after memory reactivation, and must be restabilized through a postsynaptic mechanism implicating the mammalian target of rapamycin kinase-dependent signaling. Fear-conditioning-induced synaptic enhancements were primarily presynaptic in origin. Reconsolidation blockade with rapamycin, inhibiting mammalian target of rapamycin kinase activity, suppressed synaptic potentiation in slices from fear-conditioned rats. Surprisingly, this reduction of synaptic efficacy was mediated by post- but not presynaptic mechanisms. These findings suggest that different plasticity rules may apply to the processes underlying the acquisition of original fear memory and postreactivational stabilization of fear-conditioning-induced synaptic enhancements mediating fear memory reconsolidation. PMID:23487762

  19. Programmable synaptic chip for electronic neural networks

    Moopenn, A.; Langenbacher, H.; Thakoor, A. P.; Khanna, S. K.

    1988-01-01

    A binary synaptic matrix chip has been developed for electronic neural networks. The matrix chip contains a programmable 32X32 array of 'long channel' NMOSFET binary connection elements implemented in a 3-micron bulk CMOS process. Since the neurons are kept off-chip, the synaptic chip serves as a 'cascadable' building block for a multi-chip synaptic network as large as 512X512 in size. As an alternative to the programmable NMOSFET (long channel) connection elements, tailored thin film resistors are deposited, in series with FET switches, on some CMOS test chips, to obtain the weak synaptic connections. Although deposition and patterning of the resistors require additional processing steps, they promise substantial savings in silicon area. The performance of synaptic chip in a 32-neuron breadboard system in an associative memory test application is discussed.

  20. Synaptic control of motoneuronal excitability

    Rekling, J C; Funk, G D; Bayliss, D A;

    2000-01-01

    Movement, the fundamental component of behavior and the principal extrinsic action of the brain, is produced when skeletal muscles contract and relax in response to patterns of action potentials generated by motoneurons. The processes that determine the firing behavior of motoneurons are therefore...... important in understanding the transformation of neural activity to motor behavior. Here, we review recent studies on the control of motoneuronal excitability, focusing on synaptic and cellular properties. We first present a background description of motoneurons: their development, anatomical organization......, cationic inward current, hyperpolarization-activated inward current, Ca(2+) channels, or presynaptic release processes. Together, these numerous inputs mediate and modify incoming motor commands, ultimately generating the coordinated firing patterns that underlie muscle contractions during motor behavior....

  1. Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement

    Knafo, Shira; Venero, César; Sánchez-Puelles, Cristina;

    2012-01-01

    ) that enhances spatial learning and memory in rats. We have now investigated the cellular and molecular basis of this cognitive enhancement, using biochemical, morphological, electrophysiological, and behavioral analyses. We have found that FGL triggers a long-lasting enhancement of synaptic...... transmission in hippocampal CA1 neurons. This effect is mediated by a facilitated synaptic delivery of AMPA receptors, which is accompanied by enhanced NMDA receptor-dependent long-term potentiation (LTP). Both LTP and cognitive enhancement are mediated by an initial PKC activation, which is followed by...

  2. Synaptic changes in Alzheimer's disease in vivo

    The article describes the current knowledge on biochemical changes in Alzheimer's disease. Following a summary on post mortem findings, results from positron emission tomography will be focused on. This synopsis shows that patients with Alzheimer's disease show very consistently changes in the cholinergic transmission. In addition to this, changes of the dopaminergic, noradrenergic and serotonergic system are observed. It is possible, that clinical, pathological and functional differences in Alzheimer's disease between different patients reflect variations of a single disease process. It is also thinkable, that there are subclassifications in Alzheimer's disease which are reflected in the above described biochemical abnormalities. In this case it is important in therapeutical terms to investigate these subtypes. (orig.)

  3. Urine - abnormal color

    The usual color of urine is straw-yellow. Abnormally colored urine may be cloudy, dark, or blood-colored. ... Abnormal urine color may be caused by infection, disease, medicines, or food you eat. Cloudy or milky urine is a sign ...

  4. Involvement of ClC-3 chloride/proton exchangers in controlling glutamatergic synaptic strength in cultured hippocampal neurons

    Raul Enrique Guzman

    2014-05-01

    Full Text Available ClC-3 is a member of the CLC family of anion channels and transporters that localizes to early and late endosomes as well as to synaptic vesicles. Its genetic disruption in mouse models results in pronounced hippocampal and retinal neurodegeneration, suggesting that ClC-3 might be important for normal excitatory and/or inhibitory neurotransmission in central neurons. To characterize the role of ClC-3 in glutamate accumulation in synaptic vesicles we compared glutamatergic synaptic transmission in cultured hippocampal neurons from WT and Clcn3-/- mice. In Clcn3-/- neurons the amplitude and frequency of miniature as well as the amplitudes of action-potential evoked EPSCs were significantly increased as compared to WT neurons. The low-affinity competitive AMPA receptor antagonist -DGG reduced the quantal size of synaptic events more effectively in WT than in Clcn3-/- neurons, whereas no difference was observed for the high-affinity competitive non-NMDA antagonist NBQX. Paired pulse ratios of evoked EPSCs were significantly reduced, whereas the size of the readily releasable pool was not affected by the genetic ablation of ClC-3. Electron microscopy revealed increased volumes of synaptic vesicles in hippocampi of Clcn3-/- mice. Our findings demonstrate that ClC-3 controls fast excitatory synaptic transmission by regulating the amount of neurotransmitter as well as the release probability of synaptic vesicles. These results provide novel insights into the role of ClC-3 in synaptic transmission and identify excessive glutamate release as a likely basis of neurodegeneration in Clcn3-/-.

  5. Late onset deficits in synaptic plasticity in the valproic acid rat model of autism

    Henry Giles Stratten Martin; Olivier eManzoni

    2014-01-01

    Valproic acid (VPA) is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC) physiology and synaptic connectivity...

  6. Spike timing regulation on the millisecond scale by distributed synaptic plasticity at the cerebellum input stage: a simulation study

    Jesus A Garrido

    2013-05-01

    Full Text Available The way long-term synaptic plasticity regulates neuronal spike patterns is not completely understood. This issue is especially relevant for the cerebellum, which is endowed with several forms of long-term synaptic plasticity and has been predicted to operate as a timing and a learning machine. Here we have used a computational model to simulate the impact of multiple distributed synaptic weights in the cerebellar granular layer network. In response to mossy fiber bursts, synaptic weights at multiple connections played a crucial role to regulate spike number and positioning in granule cells. The weight at mossy fiber to granule cell synapses regulated the delay of the first spike and the weight at mossy fiber and parallel fiber to Golgi cell synapses regulated the duration of the time-window during which the first-spike could be emitted. Moreover, the weights of synapses controlling Golgi cell activation regulated the intensity of granule cell inhibition and therefore the number of spikes that could be emitted. First spike timing was regulated with millisecond precision and the number of spikes ranged from 0 to 3. Interestingly, different combinations of synaptic weights optimized either first-spike timing precision or spike number, efficiently controlling transmission and filtering properties. These results predict that distributed synaptic plasticity regulates the emission of quasi-digital spike patterns on the millisecond time scale and allows the cerebellar granular layer to flexibly control burst transmission along the mossy fiber pathway.

  7. The role of microglia in synaptic stripping and synaptic degeneration: a revised perspective

    Perry, V. Hugh; O'Connor, Vincent

    2010-01-01

    Chronic neurodegenerative diseases of the CNS (central nervous system) are characterized by the loss of neurons. There is, however, growing evidence to show that an early stage of this process involves degeneration of presynaptic terminals prior to the loss of the cell body. Synaptic plasticity in CNS pathology has been associated with microglia and the phenomenon of synaptic stripping. We review here the evidence for the involvement of microglia in synaptic stripping and synapse degeneration...

  8. Prenatal cocaine reduces AMPA receptor synaptic expression through hyperphosphorylation of the synaptic anchoring protein GRIP

    Bakshi, Kalindi; Gennaro, Serena; Chan, Christopher Y.; Kosciuk, Mary; Liu, Jingjing; Stucky, Andres; Trenkner, Ekkehart; FRIEDMAN, EITAN; Nagele, Robert G; Wang, Hoau-Yan

    2009-01-01

    Prenatal cocaine exposure produces sustained neurobehavioral and brain synaptic changes closely resembling those of animals with defective alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamatergic receptors (AMPARs). We hypothesized that prenatal cocaine exposure attenuates AMPAR signaling by interfering with AMPAR synaptic targeting. AMPAR function is governed by receptor cycling on and off the synaptic membrane through its interaction with GRIP, a PDZ domain protein that i...

  9. Prefrontal synaptic markers of cocaine addiction-like behavior in rats.

    Kasanetz, F; Lafourcade, M; Deroche-Gamonet, V; Revest, J-M; Berson, N; Balado, E; Fiancette, J-F; Renault, P; Piazza, P-V; Manzoni, O J

    2013-06-01

    Defining the drug-induced neuroadaptations specifically associated with the behavioral manifestation of addiction is a daunting task. To address this issue, we used a behavioral model that differentiates rats controlling their drug use (Non-Addict-like) from rats undergoing transition to addiction (Addict-like). Dysfunctions in prefrontal cortex (PFC) synaptic circuits are thought to be responsible for the loss of control over drug taking that characterizes addicted individuals. Here, we studied the synaptic alterations in prelimbic PFC (pPFC) circuits associated with transition to addiction. We discovered that some of the changes induced by cocaine self-administration (SA), such as the impairment of the endocannabinoid-mediated long-term synaptic depression (eCB-LTD) was similarly abolished in Non-Addict- and Addict-like rats and thus unrelated to transition to addiction. In contrast, metabotropic glutamate receptor 2/3-mediated LTD (mGluR2/3-LTD) was specifically suppressed in Addict-like rats, which also show a concomitant postsynaptic plasticity expressed as a change in the relative contribution of AMPAR and NMDAR to basal glutamate-mediated synaptic transmission. Addiction-associated synaptic alterations in the pPFC were not fully developed at early stages of cocaine SA, when addiction-like behaviors are still absent, suggesting that pathological behaviors appear once the pPFC is compromised. These data identify specific synaptic impairments in the pPFC associated with addiction and support the idea that alterations of synaptic plasticity are core markers of drug dependence. PMID:22584869

  10. Chromosomal Abnormalities in ADHD

    J Gordon Millichap

    2002-07-01

    Full Text Available The prevalence of fragile X syndrome, velocardiofacial syndrome (VCFS, and other cytogenetic abnormalities among 100 children (64 boys with combined type ADHD and normal intelligence was assessed at the NIMH and Georgetown University Medical Center.

  11. Chromosomal abnormalities and autism

    Farida El-Baz

    2016-01-01

    Conclusion: Chromosomal abnormalities were not detected in the studied autistic children, and so the relation between the genetics and autism still needs further work up with different study methods and techniques.

  12. Programmable synaptic devices for electronic neural nets

    Moopenn, A.; Thakoor, A. P.

    1990-01-01

    The architecture, design, and operational characteristics of custom VLSI and thin film synaptic devices are described. The devices include CMOS-based synaptic chips containing 1024 reprogrammable synapses with a 6-bit dynamic range, and nonvolatile, write-once, binary synaptic arrays based on memory switching in hydrogenated amorphous silicon films. Their suitability for embodiment of fully parallel and analog neural hardware is discussed. Specifically, a neural network solution to an assignment problem of combinatorial global optimization, implemented in fully parallel hardware using the synaptic chips, is described. The network's ability to provide optimal and near optimal solutions over a time scale of few neuron time constants has been demonstrated and suggests a speedup improvement of several orders of magnitude over conventional search methods.

  13. Brain circuitry outside the synaptic cleft

    Rusakov, Dmitri A.; Alexander E Dityatev

    2014-01-01

    A growing body of experimental evidence suggests that astroglia, and possibly microglia, play an important part in regulating synaptic networking of the brain. It has also emerged that extracellular matrix (ECM) structures that enwrap synaptic connections can generate molecular signals affecting both neuronal and glial activity. Thus it appears that the mechanism of information processing in the brain, which has hitherto been associated almost exclusively with neural circuits, could also invo...

  14. Protein tyrosine phosphorylation in synaptic vesicles.

    Pang, D T; Wang, J K; Valtorta, F; Benfenati, F; Greengard, P.

    1988-01-01

    Protein tyrosine phosphorylation in purified synaptic vesicles from rat forebrain has been studied in the presence of Mn2+ and orthovanadate. High levels of endogenous protein tyrosine phosphorylation were observed. Four major phosphoproteins, with apparent molecular masses of 105, 94, 38, and 30 kDa, were shown to contain phosphotyrosine. The 38-kDa phosphoprotein was identified as synaptophysin (p38), a well-characterized integral membrane protein of synaptic vesicles. The three other phosp...

  15. Stress, trauma and PTSD: translational insights into the core synaptic circuitry and its modulation.

    Bennett, Maxwell R; Hatton, Sean N; Lagopoulos, Jim

    2016-06-01

    Evidence is considered as to whether behavioral criteria for diagnosis of post-traumatic stress disorder (PTSD) are applicable to that of traumatized animals and whether the phenomena of acquisition, extinction and reactivation of fear behavior in animals are also successfully applicable to humans. This evidence suggests an affirmative answer in both cases. Furthermore, the deficits in gray matter found in PTSD, determined with magnetic resonance imaging, are also observed in traumatized animals, lending neuropsychological support to the use of animals to probe what has gone awry in PTSD. Such animal experiments indicate that the core synaptic circuitry mediating behavior following trauma consists of the amygdala, ventral-medial prefrontal cortex and hippocampus, all of which are modulated by the basal ganglia. It is not clear if this is the case in PTSD as the observations using fMRI are equivocal and open to technical objections. Nevertheless, the effects of the basal ganglia in controlling glutamatergic synaptic transmission through dopaminergic and serotonergic synaptic mechanisms in the core synaptic circuitry provides a ready explanation for why modifying these mechanisms delays extinction in animal models and predisposes towards PTSD. In addition, changes of brain-derived neurotrophic factor (BDNF) in the core synaptic circuitry have significant effects on acquisition and extinction in animal experiments with single nucleotide polymorphisms in the BDNF gene predisposing to PTSD. PMID:25985955

  16. Spatiotemporal discrimination in neural networks with short-term synaptic plasticity

    Shlaer, Benjamin; Miller, Paul

    2015-03-01

    Cells in recurrently connected neural networks exhibit bistability, which allows for stimulus information to persist in a circuit even after stimulus offset, i.e. short-term memory. However, such a system does not have enough hysteresis to encode temporal information about the stimuli. The biophysically described phenomenon of synaptic depression decreases synaptic transmission strengths due to increased presynaptic activity. This short-term reduction in synaptic strengths can destabilize attractor states in excitatory recurrent neural networks, causing the network to move along stimulus dependent dynamical trajectories. Such a network can successfully separate amplitudes and durations of stimuli from the number of successive stimuli. Stimulus number, duration and intensity encoding in randomly connected attractor networks with synaptic depression. Front. Comput. Neurosci. 7:59., and so provides a strong candidate network for the encoding of spatiotemporal information. Here we explicitly demonstrate the capability of a recurrent neural network with short-term synaptic depression to discriminate between the temporal sequences in which spatial stimuli are presented.

  17. Glucose rapidly induces different forms of excitatory synaptic plasticity in hypothalamic POMC neurons.

    Jun Hu

    Full Text Available Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+, EPSC(-, and EPSC(+/- based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs, using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+ neurons, but increased it in EPSC(- neurons. Unlike EPSC(+ and EPSC(- neurons, EPSC(+/- neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/- neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals.

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

    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.

  19. Calcineurin, Synaptic Plasticity, and Memory

    Carl Weitlauf

    2001-01-01

    Full Text Available A long-held hypothesis in neuroscience holds that learning and memory mechanisms involve lasting changes in synaptic weights. Multiple mechanisms for producing such changes exist, of which NMDA-receptor–dependent long-term potentiation (LTP is the most widely studied. Curiously, the relatively simple hypothesis that LTP plays a role in learning and memory has proven difficult to test. A current experimental strategy is to generate genetically altered mice with mutations in genes thought to be involved in LTP and assess the effects of these mutations both on LTP and animal behavior[1,2]. A difficulty associated with these approaches has been that they are not temporally or spatially refined. To alleviate this problem, Dr. Isabelle Mansuy and colleagues used an inducible and reversible transgene expression system in which transgene expression could be controlled on a week-to-week timescale to assess the effects of genetic reduction of the activity of a protein phosphatase known as calcineurin or PP2B in adult mouse forebrain[3,4].

  20. Chromosomal abnormalities in patients with sperm disorders

    L. Y. Pylyp

    2013-02-01

    Full Text Available Chromosomal abnormalities are among the most common genetic causes of spermatogenic disruptions. Carriers of chromosomal abnormalities are at increased risk of infertility, miscarriage or birth of a child with unbalanced karyotype due to the production of unbalanced gametes. The natural selection against chromosomally abnormal sperm usually prevents fertilization with sperm barring in cases of serious chromosomal abnormalities. However, assisted reproductive technologies in general and intracytoplasmic sperm injection in particular, enable the transmission of chromosomal abnormalities to the progeny. Therefore, cytogenetic studies are important in patients with male factor infertility before assisted reproduction treatment. The purpose of the current study was to investigate the types and frequencies of chromosomal abnormalities in 724 patients with infertility and to estimate the risk of chromosomal abnormalities detection in subgroups of patients depending on the severity of spermatogenic disruption, aiming at identifying groups of patients in need of cytogenetic studies. Karyotype analysis was performed in 724 blood samples of men attending infertility clinic. Chromosomal preparation was performed by standard techniques. At least 20 GTG-banded metaphase plates with the resolution from 450 to 750 bands per haploid set were analysed in each case. When chromosomal mosaicism was suspected, this number was increased to 50. Abnormal karyotypes were observed in 48 (6.6% patients, including 67% of autosomal abnormalities and 33% of gonosomal abnormalities. Autosomal abnormalities were represented by structural rearrangements. Reciprocal translocations were the most common type of structural chromosomal abnormalities in the studied group, detected with the frequency of 2.6% (n = 19, followed by Robertsonian translocation, observed with the frequency of 1.2% (n = 9. The frequency of inversions was 0.6% (n = 4. Gonosomal abnormalities included 14 cases

  1. Brain Cholesterol Metabolism and Its Defects: Linkage to Neurodegenerative Diseases and Synaptic Dysfunction.

    Petrov, A M; Kasimov, M R; Zefirov, A L

    2016-01-01

    Cholesterol is an important constituent of cell membranes and plays a crucial role in the compartmentalization of the plasma membrane and signaling. Brain cholesterol accounts for a large proportion of the body's total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes . Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized. Many neurodegenerative diseases are characterized by impaired cholesterol turnover in the brain. However, at which stage the cholesterol biosynthetic pathway is perturbed and how this contributes to pathogenesis remains unknown. Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction. Defects in cholesterol biosynthesis can trigger dysfunction of synaptic transmission. In this review, an overview of cholesterol turnover under physiological and pathological conditions is presented (Huntington's, Niemann-Pick type C diseases, Smith-Lemli-Opitz syndrome). We will discuss possible mechanisms by which cholesterol content in the plasma membrane influences synaptic processes. Changes in cholesterol metabolism in Alzheimer's disease, Parkinson's disease, and autistic disorders are beyond the scope of this review and will be summarized in our next paper. PMID:27099785

  2. Lavandula angustifolia extract improves deteriorated synaptic plasticity in an animal model of Alzheimer’s disease

    Masoud Soheili

    2015-11-01

    Full Text Available Objective(s:Neurodegenerative Alzheimer’s disease (AD is associated with profound deficits in synaptic transmission and synaptic plasticity. Long-term potentiation (LTP, an experimental form of synaptic plasticity, is intensively examined in hippocampus. In this study we evaluated the effect of aqueous extract of lavender (Lavandula angustifolia on induction of LTP in the CA1 area of hippocampus. In response to stimulation of the Schaffer collaterals the baseline or tetanized field extracellular postsynaptic potentials (fEPSPs were recorded in the CA1 area. Materials and Methods: The electrophysiological recordings were carried out in four groups of rats; two control groups including the vehicle (CON and lavender (CE treated rats and two Alzheimeric groups including the vehicle (ALZ and lavender (AE treated animals. Results: The extract inefficiently affected the baseline responses in the four testing groups. While the fEPSPs displayed a considerable LTP in the CON animals, no potentiation was evident in the tetanized responses in the ALZ rats. The herbal medicine effectively restored LTP in the AE group and further potentiated fEPSPs in the CE group. Conclusion:The positive effect of the lavender extract on the plasticity of synaptic transmission supports its previously reported behavioral effects on improvement of impaired spatial memory in the Alzheimeric animals.

  3. Consumption of palatable food primes food approach behavior by rapidly increasing synaptic density in the VTA.

    Liu, Shuai; Globa, Andrea K; Mills, Fergil; Naef, Lindsay; Qiao, Min; Bamji, Shernaz X; Borgland, Stephanie L

    2016-03-01

    In an environment with easy access to highly palatable and energy-dense food, food-related cues drive food-seeking regardless of satiety, an effect that can lead to obesity. The ventral tegmental area (VTA) and its mesolimbic projections are critical structures involved in the learning of environmental cues used to predict motivationally relevant outcomes. Priming effects of food-related advertising and consumption of palatable food can drive food intake. However, the mechanism by which this effect occurs, and whether these priming effects last days after consumption, is unknown. Here, we demonstrate that short-term consumption of palatable food can prime future food approach behaviors and food intake. This effect is mediated by the strengthening of excitatory synaptic transmission onto dopamine neurons that is initially offset by a transient increase in endocannabinoid tone, but lasts days after an initial 24-h exposure to sweetened high-fat food (SHF). This enhanced synaptic strength is mediated by a long-lasting increase in excitatory synaptic density onto VTA dopamine neurons. Administration of insulin into the VTA, which suppresses excitatory synaptic transmission onto dopamine neurons, can abolish food approach behaviors and food intake observed days after 24-h access to SHF. These results suggest that even a short-term exposure to palatable foods can drive future feeding behavior by "rewiring" mesolimbic dopamine neurons. PMID:26884159

  4. DREAM (downstream regulatory element antagonist modulator) contributes to synaptic depression and contextual fear memory.

    Wu, Long-Jun; Mellström, Britt; Wang, Hansen; Ren, Ming; Domingo, Sofia; Kim, Susan S; Li, Xiang-Yao; Chen, Tao; Naranjo, Jose R; Zhuo, Min

    2010-01-01

    The downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking advantage of transgenic mice overexpressing a Ca2+-insensitive DREAM mutant (TgDREAM), we used integrative methods including electrophysiology, biochemistry, immunostaining, and behavior tests to study the function of DREAM in synaptic transmission, long-term plasticity and fear memory in hippocampal CA1 region. We found that NMDA receptor but not AMPA receptor-mediated current was decreased in TgDREAM mice. Moreover, synaptic plasticity, such as long-term depression (LTD) but not long-term potentiation (LTP), was impaired in TgDREAM mice. Biochemical experiments found that DREAM interacts with PSD-95 and may inhibit NMDA receptor function through this interaction. Contextual fear memory was significantly impaired in TgDREAM mice. By contrast, sensory responses to noxious stimuli were not affected. Our results demonstrate that DREAM plays a novel role in postsynaptic modulation of the NMDA receptor, and contributes to synaptic plasticity and behavioral memory. PMID:20205763

  5. DREAM (Downstream Regulatory Element Antagonist Modulator contributes to synaptic depression and contextual fear memory

    Wu Long-Jun

    2010-01-01

    Full Text Available Abstract The downstream regulatory element antagonist modulator (DREAM, a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking advantage of transgenic mice overexpressing a Ca2+-insensitive DREAM mutant (TgDREAM, we used integrative methods including electrophysiology, biochemistry, immunostaining, and behavior tests to study the function of DREAM in synaptic transmission, long-term plasticity and fear memory in hippocampal CA1 region. We found that NMDA receptor but not AMPA receptor-mediated current was decreased in TgDREAM mice. Moreover, synaptic plasticity, such as long-term depression (LTD but not long-term potentiation (LTP, was impaired in TgDREAM mice. Biochemical experiments found that DREAM interacts with PSD-95 and may inhibit NMDA receptor function through this interaction. Contextual fear memory was significantly impaired in TgDREAM mice. By contrast, sensory responses to noxious stimuli were not affected. Our results demonstrate that DREAM plays a novel role in postsynaptic modulation of the NMDA receptor, and contributes to synaptic plasticity and behavioral memory.

  6. Drosophila neuroligin 4 regulates sleep through modulating GABA transmission.

    Li, Yi; Zhou, Zikai; Zhang, Xinwang; Tong, Huawei; Li, Peipei; Zhang, Zi Chao; Jia, Zhengping; Xie, Wei; Han, Junhai

    2013-09-25

    Sleep is an essential and evolutionarily conserved behavior that is closely related to synaptic function. However, whether neuroligins (Nlgs), which are cell adhesion molecules involved in synapse formation and synaptic transmission, are involved in sleep is not clear. Here, we show that Drosophila Nlg4 (DNlg4) is highly expressed in large ventral lateral clock neurons (l-LNvs) and that l-LNv-derived DNlg4 is essential for sleep regulation. GABA transmission is impaired in mutant l-LNv, and sleep defects in dnlg4 mutant flies can be rescued by genetic manipulation of GABA transmission. Furthermore, dnlg4 mutant flies exhibit a severe reduction in GABAA receptor RDL clustering, and DNlg4 associates with RDLs in vivo. These results demonstrate that DNlg4 regulates sleep through modulating GABA transmission in l-LNvs, which provides the first known link between a synaptic adhesion molecule and sleep in Drosophila. PMID:24068821

  7. Transcranial magnetic stimulation, synaptic plasticity and network oscillations

    Volpe Bruce T

    2009-03-01

    Full Text Available Abstract Transcranial magnetic stimulation (TMS has quickly progressed from a technical curiosity to a bona-fide tool for neurological research. The impetus has been due to the promising results obtained when using TMS to uncover neural processes in normal human subjects, as well as in the treatment of intractable neurological conditions, such as stroke, chronic depression and epilepsy. The basic principle of TMS is that most neuronal axons that fall within the volume of magnetic stimulation become electrically excited, trigger action potentials and release neurotransmitter into the postsynaptic neurons. What happens afterwards remains elusive, especially in the case of repeated stimulation. Here we discuss the likelihood that certain TMS protocols produce long-term changes in cortical synapses akin to long-term potentiation and long-term depression of synaptic transmission. Beyond the synaptic effects, TMS might have consequences on other neuronal processes, such as genetic and protein regulation, and circuit-level patterns, such as network oscillations. Furthermore, TMS might have non-neuronal effects, such as changes in blood flow, which are still poorly understood.

  8. Neurological abnormalities predict disability

    Poggesi, Anna; Gouw, Alida; van der Flier, Wiesje;

    2014-01-01

    To investigate the role of neurological abnormalities and magnetic resonance imaging (MRI) lesions in predicting global functional decline in a cohort of initially independent-living elderly subjects. The Leukoaraiosis And DISability (LADIS) Study, involving 11 European centres, was primarily aimed...... at evaluating age-related white matter changes (ARWMC) as an independent predictor of the transition to disability (according to Instrumental Activities of Daily Living scale) or death in independent elderly subjects that were followed up for 3 years. At baseline, a standardized neurological examination...... abnormality independently predicted transition to disability or death [HR (95 % CI) 1.53 (1.01-2.34)]. The hazard increased with increasing number of abnormalities. Among MRI lesions, only ARWMC of severe grade independently predicted disability or death [HR (95 % CI) 2.18 (1.37-3.48)]. In our cohort...

  9. Unbiased View of Synaptic and Neuronal Gene Complement in Ctenophores: Are There Pan-neuronal and Pan-synaptic Genes across Metazoa?

    Moroz, Leonid L; Kohn, Andrea B

    2015-12-01

    Hypotheses of origins and evolution of neurons and synapses are controversial, mostly due to limited comparative data. Here, we investigated the genome-wide distribution of the bilaterian "synaptic" and "neuronal" protein-coding genes in non-bilaterian basal metazoans (Ctenophora, Porifera, Placozoa, and Cnidaria). First, there are no recognized genes uniquely expressed in neurons across all metazoan lineages. None of the so-called pan-neuronal genes such as embryonic lethal abnormal vision (ELAV), Musashi, or Neuroglobin are expressed exclusively in neurons of the ctenophore Pleurobrachia. Second, our comparative analysis of about 200 genes encoding canonical presynaptic and postsynaptic proteins in bilaterians suggests that there are no true "pan-synaptic" genes or genes uniquely and specifically attributed to all classes of synapses. The majority of these genes encode receptive and secretory complexes in a broad spectrum of eukaryotes. Trichoplax (Placozoa) an organism without neurons and synapses has more orthologs of bilaterian synapse-related/neuron-related genes than do ctenophores-the group with well-developed neuronal and synaptic organization. Third, the majority of genes encoding ion channels and ionotropic receptors are broadly expressed in unicellular eukaryotes and non-neuronal tissues in metazoans. Therefore, they cannot be viewed as neuronal markers. Nevertheless, the co-expression of multiple types of ion channels and receptors does correlate with the presence of neural and synaptic organization. As an illustrative example, the ctenophore genomes encode a greater diversity of ion channels and ionotropic receptors compared with the genomes of the placozoan Trichoplax and the demosponge Amphimedon. Surprisingly, both placozoans and sponges have a similar number of orthologs of "synaptic" proteins as we identified in the genomes of two ctenophores. Ctenophores have a distinct synaptic organization compared with other animals. Our analysis of

  10. Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels.

    Lv, Caixia; Stewart, William J; Akanyeti, Otar; Frederick, Courtney; Zhu, Jie; Santos-Sacchi, Joseph; Sheets, Lavinia; Liao, James C; Zenisek, David

    2016-06-21

    Synaptic ribbons are structures made largely of the protein Ribeye that hold synaptic vesicles near release sites in non-spiking cells in some sensory systems. Here, we introduce frameshift mutations in the two zebrafish genes encoding for Ribeye and thus remove Ribeye protein from neuromast hair cells. Despite Ribeye depletion, vesicles collect around ribbon-like structures that lack electron density, which we term "ghost ribbons." Ghost ribbons are smaller in size but possess a similar number of smaller vesicles and are poorly localized to synapses and calcium channels. These hair cells exhibit enhanced exocytosis, as measured by capacitance, and recordings from afferent neurons post-synaptic to hair cells show no significant difference in spike rates. Our results suggest that Ribeye makes up most of the synaptic ribbon density in neuromast hair cells and is necessary for proper localization of calcium channels and synaptic ribbons. PMID:27292637

  11. Dysregulated Expression of Neuregulin-1 by Cortical Pyramidal Neurons Disrupts Synaptic Plasticity

    Amit Agarwal

    2014-08-01

    Full Text Available Neuregulin-1 (NRG1 gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an “optimal” level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect.

  12. Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies.

    Giovanoli, Sandra; Weber-Stadlbauer, Ulrike; Schedlowski, Manfred; Meyer, Urs; Engler, Harald

    2016-07-01

    Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre- and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced an adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1β levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation. PMID:26408796

  13. Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity.

    Agarwal, Amit; Zhang, Mingyue; Trembak-Duff, Irina; Unterbarnscheidt, Tilmann; Radyushkin, Konstantin; Dibaj, Payam; Martins de Souza, Daniel; Boretius, Susann; Brzózka, Magdalena M; Steffens, Heinz; Berning, Sebastian; Teng, Zenghui; Gummert, Maike N; Tantra, Martesa; Guest, Peter C; Willig, Katrin I; Frahm, Jens; Hell, Stefan W; Bahn, Sabine; Rossner, Moritz J; Nave, Klaus-Armin; Ehrenreich, Hannelore; Zhang, Weiqi; Schwab, Markus H

    2014-08-21

    Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect. PMID:25131210

  14. In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders

    Harry Pantazopoulos

    2016-01-01

    Full Text Available Rapidly emerging evidence implicates perineuronal nets (PNNs and extracellular matrix (ECM molecules that compose or interact with PNNs, in the pathophysiology of several psychiatric disorders. Studies on schizophrenia, autism spectrum disorders, mood disorders, Alzheimer’s disease, and epilepsy point to the involvement of ECM molecules such as chondroitin sulfate proteoglycans, Reelin, and matrix metalloproteases, as well as their cell surface receptors. In many of these disorders, PNN abnormalities have also been reported. In the context of the “quadripartite” synapse concept, that is, the functional unit composed of the pre- and postsynaptic terminals, glial processes, and ECM, and of the role that PNNs and ECM molecules play in regulating synaptic functions and plasticity, these findings resonate with one of the most well-replicated aspects of the pathology of psychiatric disorders, that is, synaptic abnormalities. Here we review the evidence for PNN/ECM-related pathology in these disorders, with particular emphasis on schizophrenia, and discuss the hypothesis that such pathology may significantly contribute to synaptic dysfunction.

  15. In Sickness and in Health: Perineuronal Nets and Synaptic Plasticity in Psychiatric Disorders.

    Pantazopoulos, Harry; Berretta, Sabina

    2016-01-01

    Rapidly emerging evidence implicates perineuronal nets (PNNs) and extracellular matrix (ECM) molecules that compose or interact with PNNs, in the pathophysiology of several psychiatric disorders. Studies on schizophrenia, autism spectrum disorders, mood disorders, Alzheimer's disease, and epilepsy point to the involvement of ECM molecules such as chondroitin sulfate proteoglycans, Reelin, and matrix metalloproteases, as well as their cell surface receptors. In many of these disorders, PNN abnormalities have also been reported. In the context of the "quadripartite" synapse concept, that is, the functional unit composed of the pre- and postsynaptic terminals, glial processes, and ECM, and of the role that PNNs and ECM molecules play in regulating synaptic functions and plasticity, these findings resonate with one of the most well-replicated aspects of the pathology of psychiatric disorders, that is, synaptic abnormalities. Here we review the evidence for PNN/ECM-related pathology in these disorders, with particular emphasis on schizophrenia, and discuss the hypothesis that such pathology may significantly contribute to synaptic dysfunction. PMID:26839720

  16. Synaptic transfer of dynamic motion information between identified neurons in the visual system of the blowfly

    Warzecha, Anne-Kathrin; Kurtz, Rafael; Egelhaaf, Martin

    2003-01-01

    Synaptic transmission is usually studied in vitro with electrical stimulation replacing the natural input of the system. In contrast, we analyzed in vivo transfer of visual motion information from graded-potential presynaptic to spiking postsynaptic neurons in the fly. Motion in the null direction leads to hyperpolarization of the presynaptic neuron but does not much influence the postsynaptic cell, because its firing rate is already low during rest, giving only little scope for further reduc...

  17. Volterra representation enables modeling of complex synaptic nonlinear dynamics in large-scale simulations

    Hu, Eric Y.; Jean-Marie C Bouteiller; Song, Dong; Baudry, Michel; Theodore W. Berger

    2015-01-01

    Chemical synapses are comprised of a wide collection of intricate signaling pathways involving complex dynamics. These mechanisms are often reduced to simple spikes or exponential representations in order to enable computer simulations at higher spatial levels of complexity. However, these representations cannot capture important nonlinear dynamics found in synaptic transmission. Here, we propose an input-output (IO) synapse model capable of generating complex nonlinear dynamics while maintai...

  18. Prolonged synaptic currents increase relay neuron firing at the developing retinogeniculate synapse

    Hauser, Jessica L.; Liu, Xiaojin; Litvina, Elizabeth Y.; Chen, Chinfei

    2014-01-01

    The retinogeniculate synapse, the connection between retinal ganglion cells (RGC) and thalamic relay neurons, undergoes robust changes in connectivity over development. This process of synapse elimination and strengthening of remaining inputs is thought to require synapse specificity. Here we show that glutamate spillover and asynchronous release are prominent features of retinogeniculate synaptic transmission during this period. The immature excitatory postsynaptic currents exhibit a slow de...

  19. Hydrogen sulfide augments synaptic neurotransmission in the nucleus of the solitary tract

    Austgen, James R.; Hermann, Gerlinda E.; Dantzler, Heather A.; Richard C Rogers; Kline, David D.

    2011-01-01

    Within the brain stem, the nucleus tractus solitarii (NTS) serves as a principal central site for sensory afferent integration from the cardiovascular and respiratory reflexes. Neuronal activity and synaptic transmission in the NTS are highly pliable and subject to neuromodulation. In the central nervous system, hydrogen sulfide (H2S) is a gasotransmitter generated primarily by the enzyme cystathionine-β-synthase (CBS). We sought to determine the role of H2S, and its generation by CBS, in NTS...

  20. The Interplay between Synaptic Activity and Neuroligin Function in the CNS

    2015-01-01

    Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previous in vitro and in vivo studies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum ...

  1. DREAM (Downstream Regulatory Element Antagonist Modulator) contributes to synaptic depression and contextual fear memory

    Wu Long-Jun; Mellström Britt; Wang Hansen; Ren Ming; Domingo Sofia; Kim Susan S; Li Xiang-Yao; Chen Tao; Naranjo Jose R; Zhuo Min

    2010-01-01

    Abstract The downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking...

  2. Synaptic vesicle recycling at the calyx of Held

    Lei XUE; Yan-ai MEI

    2011-01-01

    Efficient endocytosis is crucial for maintaining synaptic transmission because of its role in retrieving constituent membrane and associated proteins. In the past three decades three modes of endocytosis have been proposed involving the central nervous system: clathrin-mediated endocytosis, kiss-and-run endocytosis and bulk endocytosis. These forms of endocytosis can be induced under different conditions, but their detailed molecular mechanisms and functions are largely unknown. Here, we review the existence and initiation of all three modes of endocytosis at a giant glutamatergic synapse, the calyx of Held. The possibility of direct electrophysiology recording in this synapse allows for accurate tracking of exocytosis and endocytosis via capacitance measurements. Future aims will be focused on identifying the molecules that undergo the different mechanisms of endocytosis and the conditions under which different forms of endocytosis predominate.

  3. CT of pleural abnormalities

    Briefly discussed were CT diagnosis of pleural thickening, CT technique for examining the pleura or pleuro-pulmonary disease, diagnosis of pleural collections, diagnosis of pleural fluid abnormalities in patients with pneumonia, pleural neoplasms, malignant (diffuse) mesothelioma, metastases, local fibrous tumor of the pleura (benign mesothelioma) (21 refs.)

  4. Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila

    Friedman, Samuel H.; Dani, Neil; Rushton, Emma; Broadie, Kendal

    2013-01-01

    SUMMARY Fragile X syndrome (FXS), the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1) gene product (FMRP), an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1) null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs): GPI-anchored glypican Dally-like protein (Dlp) and transmembrane Syndecan (Sdc). Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg) ligand abundance and downstream Frizzled-2 (Fz2) receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb), and downstream ERK phosphorylation (dpERK) are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb) and downstream signaling via phosphorylation of the transcription factor MAD (pMAD) seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1) Wg and Jeb trans-synaptic signaling, and (2) synaptic architecture and transmission strength back to wild-type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS

  5. Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila

    Samuel H. Friedman

    2013-11-01

    Fragile X syndrome (FXS, the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1 gene product (FMRP, an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1 null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs: GPI-anchored glypican Dally-like protein (Dlp and transmembrane Syndecan (Sdc. Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg ligand abundance and downstream Frizzled-2 (Fz2 receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb, and downstream ERK phosphorylation (dpERK are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb and downstream signaling via phosphorylation of the transcription factor MAD (pMAD seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1 Wg and Jeb trans-synaptic signaling, and (2 synaptic architecture and transmission strength back to wild-type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS disease state.

  6. Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology.

    Sheng, Yanghui; Zhang, Lei; Su, Susan C; Tsai, Li-Huei; Julius Zhu, J

    2016-07-01

    Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase implicated in synaptic plasticity, behavior, and cognition, yet its synaptic function remains poorly understood. Here, we report that physiological Cdk5 signaling in rat hippocampal CA1 neurons regulates homeostatic synaptic transmission using an unexpectedly rapid mechanism that is different from all known slow homeostatic regulators, such as beta amyloid (Aβ) and activity-regulated cytoskeleton-associated protein (Arc, aka Arg3.1). Interestingly, overproduction of the potent Cdk5 activator p25 reduces synapse density, and dynamically regulates synaptic size by suppressing or enhancing Aβ/Arc production. Moreover, chronic overproduction of p25, seen in Alzheimer's patients, induces initially concurrent reduction in synapse density and increase in synaptic size characteristic of the early Alzheimer-like pathology, and later persistent synapse elimination in intact brains. These results identify Cdk5 as the regulator of a novel rapid form of homeostasis at central synapses and p25 as the first molecule capable of initiating the early Alzheimer's synaptic pathology. PMID:26088971

  7. Synaptic Effects of Munc18-1 Alternative Splicing in Excitatory Hippocampal Neurons.

    Marieke Meijer

    Full Text Available The munc18-1 gene encodes two splice-variants that vary at the C-terminus of the protein and are expressed at different levels in different regions of the adult mammalian brain. Here, we investigated the expression pattern of these splice variants within the brainstem and tested whether they are functionally different. Munc18-1a is expressed in specific nuclei of the brainstem including the LRN, VII and SOC, while Munc18-1b expression is relatively low/absent in these regions. Furthermore, Munc18-1a is the major splice variant in the Calyx of Held. Synaptic transmission was analyzed in autaptic hippocampal munc18-1 KO neurons re-expressing either Munc18-1a or Munc18-1b. The two splice variants supported synaptic transmission to a similar extent, but Munc18-1b was slightly more potent in sustaining synchronous release during high frequency stimulation. Our data suggest that alternative splicing of Munc18-1 support synaptic transmission to a similar extent, but could modulate presynaptic short-term plasticity.

  8. Synaptic Effects of Munc18-1 Alternative Splicing in Excitatory Hippocampal Neurons.

    Meijer, Marieke; Cijsouw, Tony; Toonen, Ruud F; Verhage, Matthijs

    2015-01-01

    The munc18-1 gene encodes two splice-variants that vary at the C-terminus of the protein and are expressed at different levels in different regions of the adult mammalian brain. Here, we investigated the expression pattern of these splice variants within the brainstem and tested whether they are functionally different. Munc18-1a is expressed in specific nuclei of the brainstem including the LRN, VII and SOC, while Munc18-1b expression is relatively low/absent in these regions. Furthermore, Munc18-1a is the major splice variant in the Calyx of Held. Synaptic transmission was analyzed in autaptic hippocampal munc18-1 KO neurons re-expressing either Munc18-1a or Munc18-1b. The two splice variants supported synaptic transmission to a similar extent, but Munc18-1b was slightly more potent in sustaining synchronous release during high frequency stimulation. Our data suggest that alternative splicing of Munc18-1 support synaptic transmission to a similar extent, but could modulate presynaptic short-term plasticity. PMID:26407320

  9. Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca2+ influx, not Ca2+-exocytosis coupling.

    Baumgart, Joel P; Zhou, Zhen-Yu; Hara, Masato; Cook, Daniel C; Hoppa, Michael B; Ryan, Timothy A; Hemmings, Hugh C

    2015-09-22

    Identifying presynaptic mechanisms of general anesthetics is critical to understanding their effects on synaptic transmission. We show that the volatile anesthetic isoflurane inhibits synaptic vesicle (SV) exocytosis at nerve terminals in dissociated rat hippocampal neurons through inhibition of presynaptic Ca(2+) influx without significantly altering the Ca(2+) sensitivity of SV exocytosis. A clinically relevant concentration of isoflurane (0.7 mM) inhibited changes in [Ca(2+)]i driven by single action potentials (APs) by 25 ± 3%, which in turn led to 62 ± 3% inhibition of single AP-triggered exocytosis at 4 mM extracellular Ca(2+) ([Ca(2+)]e). Lowering external Ca(2+) to match the isoflurane-induced reduction in Ca(2+) entry led to an equivalent reduction in exocytosis. These data thus indicate that anesthetic inhibition of neurotransmitter release from small SVs occurs primarily through reduced axon terminal Ca(2+) entry without significant direct effects on Ca(2+)-exocytosis coupling or on the SV fusion machinery. Isoflurane inhibition of exocytosis and Ca(2+) influx was greater in glutamatergic compared with GABAergic nerve terminals, consistent with selective inhibition of excitatory synaptic transmission. Such alteration in the balance of excitatory to inhibitory transmission could mediate reduced neuronal interactions and network-selective effects observed in the anesthetized central nervous system. PMID:26351670

  10. NMDA receptors mediate synaptic competition in culture.

    Kevin She

    Full Text Available BACKGROUND: Activity through NMDA type glutamate receptors sculpts connectivity in the developing nervous system. This topic is typically studied in the visual system in vivo, where activity of inputs can be differentially regulated, but in which individual synapses are difficult to visualize and mechanisms governing synaptic competition can be difficult to ascertain. Here, we develop a model of NMDA-receptor dependent synaptic competition in dissociated cultured hippocampal neurons. METHODOLOGY/PRINCIPAL FINDINGS: GluN1 -/- (KO mouse hippocampal neurons lacking the essential NMDA receptor subunit were cultured alone or cultured in defined ratios with wild type (WT neurons. The absence of functional NMDA receptors did not alter neuron survival. Synapse development was assessed by immunofluorescence for postsynaptic PSD-95 family scaffold and apposed presynaptic vesicular glutamate transporter VGlut1. Synapse density was specifically enhanced onto minority wild type neurons co-cultured with a majority of GluN1 -/- neighbour neurons, both relative to the GluN1 -/- neighbours and relative to sister pure wild type cultures. This form of synaptic competition was dependent on NMDA receptor activity and not conferred by the mere physical presence of GluN1. In contrast to these results in 10% WT and 90% KO co-cultures, synapse density did not differ by genotype in 50% WT and 50% KO co-cultures or in 90% WT and 10% KO co-cultures. CONCLUSIONS/SIGNIFICANCE: The enhanced synaptic density onto NMDA receptor-competent neurons in minority coculture with GluN1 -/- neurons represents a cell culture paradigm for studying synaptic competition. Mechanisms involved may include a retrograde 'reward' signal generated by WT neurons, although in this paradigm there was no 'punishment' signal against GluN1 -/- neurons. Cell culture assays involving such defined circuits may help uncover the rules and mechanisms of activity-dependent synaptic competition in the

  11. Flexible Proton-Gated Oxide Synaptic Transistors on Si Membrane.

    Zhu, Li Qiang; Wan, Chang Jin; Gao, Ping Qi; Liu, Yang Hui; Xiao, Hui; Ye, Ji Chun; Wan, Qing

    2016-08-24

    Ion-conducting materials have received considerable attention for their applications in fuel cells, electrochemical devices, and sensors. Here, flexible indium zinc oxide (InZnO) synaptic transistors with multiple presynaptic inputs gated by proton-conducting phosphorosilicate glass-based electrolyte films are fabricated on ultrathin Si membranes. Transient characteristics of the proton gated InZnO synaptic transistors are investigated, indicating stable proton-gating behaviors. Short-term synaptic plasticities are mimicked on the proposed proton-gated synaptic transistors. Furthermore, synaptic integration regulations are mimicked on the proposed synaptic transistor networks. Spiking logic modulations are realized based on the transition between superlinear and sublinear synaptic integration. The multigates coupled flexible proton-gated oxide synaptic transistors may be interesting for neuroinspired platforms with sophisticated spatiotemporal information processing. PMID:27471861

  12. Abnormal ionization in sonoluminescence

    张文娟; 安宇

    2015-01-01

    Sonoluminescence is a complex phenomenon, the mechanism of which remains unclear. The present study reveals that an abnormal ionization process is likely to be present in the sonoluminescing bubble. To fit the experimental data of previous studies, we assume that the ionization energies of the molecules and atoms in the bubble decrease as the gas density increases and that the decrease of the ionization energy reaches about 60%–70%as the bubble flashes, which is difficult to explain by using previous models.

  13. Ultrasonography of splenic abnormalities

    Ming-Jen Chen; Ming-Jer Huang; Wen-Hsiung Chang; Tsang-En Wang; Horng-Yuan Wang; Cheng-Hsin Chu; Shee-Chan Lin; Shou-Chuan Shih

    2005-01-01

    AIM: This report gives a comprehensive overview of ultrasonography of splenic abnormalities. Certain ultrasonic features are also discussed with pathologic correlation.METHODS: We review the typical ultrasonic characteristics of a wide range of splenic lesions, illustrating them with images obtained in our institution from 2000 to 2003.One hundred and three patients (47 men, 56 women),with a mean age of 54 years (range 9-92 years), were found to have an abnormal ultrasonic pattern of spleen.RESULTS: We describe the ultrasonic features of various splenic lesions such as accessory spleen, splenomegaly,cysts, cavernous hemangiomas, lymphomas, abscesses,metastatic tumors, splenic infarctions, hematomas, and rupture, based on traditional gray-scale and color Doppler sonography.CONCLUSION: Ultrasound is a widely available, noninvasive,and useful means of diagnosing splenic abnormalities. A combination of ultrasonic characteristics and clinical data may provide an accurate diagnosis. If the US appearance alone is not enough, US may also be used to guide biopsy of suspicious lesions.

  14. Synaptic dynamics contribute to long-term single neuron response fluctuations

    Sebastian eReinartz

    2014-07-01

    Full Text Available Firing rate variability at the single neuron level is characterized by long-memory processes and complex statistics over a wide range of time scales (from milliseconds up to several hours. Here, we focus on the contribution of non-stationary efficacy of the ensemble of synapses-activated in response to a given stimulus-on single neuron response variability. We present and validate a method tailored for controlled and specific long-term activation of a single cortical neuron in vitro via synaptic or antidromic stimulation, enabling a clear separation between two determinants of neuronal response variability: membrane excitability dynamics vs. synaptic dynamics. Applying this method we show that, within the range of physiological activation frequencies, the synaptic ensemble of a given neuron is a key contributor to the neuronal response variability, long-memory processes and complex statistics observed over extended time scales. Synaptic transmission dynamics impact on response variability in stimulation rates that are substantially lower compared to stimulation rates that drive excitability resources to fluctuate. Implications to network embedded neurons are discussed.

  15. INVOLVEMENT OF SYNAPTIC GENES IN THE PATHOGENESIS OF AUTISM SPECTRUM DISORDERS: THE CASE OF SYNAPSINS

    Silvia eGiovedi

    2014-09-01

    Full Text Available Autism spectrum disorders (ASDs are heterogeneous neurodevelopmental disorders characterized by deficits in social interaction and social communication, restricted interests and repetitive behaviors. Many synaptic protein genes are linked to the pathogenesis of ASDs, making them prototypical synaptopathies. An array of mutations in the synapsin (Syn genes in humans have been recently associated with ASD and epilepsy, diseases that display a frequent comorbidity. Synapsins are presynaptic proteins regulating synaptic vesicle traffic, neurotransmitter release and short-term synaptic plasticity. In doing so, Syn isoforms control the tone of activity of neural circuits and the balance between excitation and inhibition. As ASD pathogenesis is believed to result from dysfunctions in the balance between excitatory and inhibitory transmissions in neocortical areas, Syns are novel ASD candidate genes. Accordingly, deletion of single Syn genes in mice, in addition to epilepsy, causes core symptoms of ASD by affecting social behavior, social communication and repetitive behaviors. Thus, Syn knockout mice represent a good experimental model to define synaptic alterations involved in the pathogenesis of ASD and epilepsy.

  16. Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement.

    Shira Knafo

    2012-02-01

    Full Text Available Cell adhesion molecules and downstream growth factor-dependent signaling are critical for brain development and synaptic plasticity, and they have been linked to cognitive function in adult animals. We have previously developed a mimetic peptide (FGL from the neural cell adhesion molecule (NCAM that enhances spatial learning and memory in rats. We have now investigated the cellular and molecular basis of this cognitive enhancement, using biochemical, morphological, electrophysiological, and behavioral analyses. We have found that FGL triggers a long-lasting enhancement of synaptic transmission in hippocampal CA1 neurons. This effect is mediated by a facilitated synaptic delivery of AMPA receptors, which is accompanied by enhanced NMDA receptor-dependent long-term potentiation (LTP. Both LTP and cognitive enhancement are mediated by an initial PKC activation, which is followed by persistent CaMKII activation. These results provide a mechanistic link between facilitation of AMPA receptor synaptic delivery and improved hippocampal-dependent learning, induced by a pharmacological cognitive enhancer.

  17. Spinal cord explants use carbon nanotube interfaces to enhance neurite outgrowth and to fortify synaptic inputs.

    Fabbro, Alessandra; Villari, Ambra; Laishram, Jummi; Scaini, Denis; Toma, Francesca M; Turco, Antonio; Prato, Maurizio; Ballerini, Laura

    2012-03-27

    New developments in nanotechnology are increasingly designed to modulate relevant interactions between nanomaterials and neurons, with the aim of exploiting the physical properties of synthetic materials to tune desired and specific biological processes. Carbon nanotubes have been applied in several areas of nerve tissue engineering to study cell behavior or to instruct the growth and organization of neural networks. Recent reports show that nanotubes can sustain and promote electrical activity in networks of cultured neurons. However, such results are usually limited to carbon nanotube/neuron hybrids formed on a monolayer of dissociated brain cells. In the present work, we used organotypic spinal slices to model multilayer tissue complexity, and we interfaced such spinal segments to carbon nanotube scaffolds for weeks. By immunofluorescence, scanning and transmission electronic microscopy, and atomic force microscopy, we investigated nerve fiber growth when neuronal processes exit the spinal explant and develop in direct contact to the substrate. By single-cell electrophysiology, we investigated the synaptic activity of visually identified ventral interneurons, within the ventral area of the explant, thus synaptically connected, but located remotely, to the substrate/network interface. Here we show that spinal cord explants interfaced for weeks to purified carbon nanotube scaffolds expand more neuronal fibers, characterized by different mechanical properties and displaying higher growth cones activity. On the other hand, exploring spontaneous and evoked synaptic activity unmasks an increase in synaptic efficacy in neurons located at as far as 5 cell layers from the cell-substrate interactions. PMID:22339712

  18. AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging.

    Henley, Jeremy M; Wilkinson, Kevin A

    2013-03-01

    Even in healthy individuals there is an inexorable agerelated decline in cognitive function. This is due, in large part, to reduced synaptic plasticity caused by changes in the molecular composition of the postsynaptic membrane. AMPA receptors (AMPARs) are glutamate-gated cation channels that mediate the overwhelming majority of fast excitatory transmission in the brain. Changes in AMPAR number and/or function are a core feature of synaptic plasticity and age-related cognitive decline, AMPARs are highly dynamic proteins that are subject to highly controlled trafficking, recycling, and/or degradation and replacement. This active regulation of AMPAR synthesis, targeting, synaptic dwell time, and degradation is fundamentally important for memory formation and storage. Further, aberrant AMPAR trafficking and consequent detrimental changes in synapses are strongly implicated in many brain diseases, which represent a vast social and economic burden. The purpose of this article is to provide an overview of the molecular and cellular AMPA receptor trafficking events that control synaptic responsiveness and plasticity, and highlight what is known currently known about how these processes change with age and disease. PMID:23576886

  19. P2X Receptors and Synaptic Plasticity

    Pankratov, Y.; Lalo, U.; Krishtal, A.; Verkhratsky, Alexei

    2009-01-01

    Roč. 158, č. 1 (2009), s. 137-148. ISSN 0306-4522 Institutional research plan: CEZ:AV0Z50390512 Keywords : ATP * P2X receptors * synaptic plasticity Subject RIV: FH - Neurology Impact factor: 3.292, year: 2009

  20. Retinal synaptic regeneration via microfluidic guiding channels.

    Su, Ping-Jung; Liu, Zongbin; Zhang, Kai; Han, Xin; Saito, Yuki; Xia, Xiaojun; Yokoi, Kenji; Shen, Haifa; Qin, Lidong

    2015-01-01

    In vitro culture of dissociated retinal neurons is an important model for investigating retinal synaptic regeneration (RSR) and exploring potentials in artificial retina. Here, retinal precursor cells were cultured in a microfluidic chip with multiple arrays of microchannels in order to reconstruct the retinal neuronal synapse. The cultured retinal cells were physically connected through microchannels. Activation of electric signal transduction by the cells through the microchannels was demonstrated by administration of glycinergic factors. In addition, an image-based analytical method was used to quantify the synaptic connections and to assess the kinetics of synaptic regeneration. The rate of RSR decreased significantly below 100 μM of inhibitor glycine and then approached to a relatively constant level at higher concentrations. Furthermore, RSR was enhanced by chemical stimulation with potassium chloride. Collectively, the microfluidic synaptic regeneration chip provides a novel tool for high-throughput investigation of RSR at the cellular level and may be useful in quality control of retinal precursor cell transplantation. PMID:26314276

  1. Synaptic plasticity and the warburg effect

    Magistretti, Pierre J.

    2014-01-01

    Functional brain imaging studies show that in certain brain regions glucose utilization exceeds oxygen consumption, indicating the predominance of aerobic glycolysis. In this issue, Goyal et al. (2014) report that this metabolic profile is associated with an enrichment in the expression of genes involved in synaptic plasticity and remodeling processes. © 2014 Elsevier Inc.

  2. Fragile X mental retardation protein and synaptic plasticity

    Sidorov, Michael S.; Auerbach, Benjamin D.; Bear, Mark F.

    2013-01-01

    Loss of the translational repressor FMRP causes Fragile X syndrome. In healthy neurons, FMRP modulates the local translation of numerous synaptic proteins. Synthesis of these proteins is required for the maintenance and regulation of long-lasting changes in synaptic strength. In this role as a translational inhibitor, FMRP exerts profound effects on synaptic plasticity.

  3. Differential Modulation of Synaptic Strength and Timing Regulate Synaptic Efficacy in a Motor Network

    Bruce R Johnson; Brown, Jessica M; Kvarta, Mark D.; Lu, Jay Y. J.; Schneider, Lauren R.; Nadim, Farzan; Harris-Warrick, Ronald M

    2010-01-01

    Neuromodulators modify network output by altering neuronal firing properties and synaptic strength at multiple sites; however, the functional importance of each site is often unclear. We determined the importance of monoamine modulation of a single synapse for regulation of network cycle frequency in the oscillatory pyloric network of the lobster. The pacemaker kernel of the pyloric network receives only one chemical synaptic feedback, an inhibitory synapse from the lateral pyloric (LP) neuro...

  4. Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer’s disease brain

    Kurbatskaya, Ksenia; Phillips, Emma Claire; Croft, Cara Louise; Dentoni, Giacomo; Hughes, Martina; Wade, Matthew Austen James; Al-Sarraj, Safa; Troakes, Claire; O'Neill, Michael; Gomez Perez-Nievas, Beatriz; Hanger, Diane Pamela; Noble, Wendy Jane

    2016-01-01

    Alterations in calcium homeostasis are widely reported to contribute to synaptic degeneration and neuronal loss in Alzheimer’s disease. Elevated cytosolic calcium concentrations lead to activation of the calcium-sensitive cysteine protease, calpain, which has a number of substrates known to be abnormally regulated in disease. Analysis of human brain has shown that calpain activity is elevated in AD compared to controls, and that calpain-mediated proteolysis regulates the activity of important...

  5. Endocannabinoids differentially modulate synaptic plasticity in rat hippocampal CA1 pyramidal neurons.

    Jian-Yi Xu

    Full Text Available BACKGROUND: Hippocampal CA1 pyramidal neurons receive two excitatory glutamatergic synaptic inputs: their most distal dendritic regions in the stratum lacunosum-moleculare (SLM are innervated by the perforant path (PP, originating from layer III of the entorhinal cortex, while their more proximal regions of the apical dendrites in the stratum radiatum (SR are innervated by the Schaffer-collaterals (SC, originating from hippocampal CA3 neurons. Endocannabinoids (eCBs are naturally occurring mediators capable of modulating both GABAergic and glutamatergic synaptic transmission and plasticity via the CB1 receptor. Previous work on eCB modulation of excitatory synapses in the CA1 region largely focuses on the SC pathway. However, little information is available on whether and how eCBs modulate glutamatergic synaptic transmission and plasticity at PP synapses. METHODOLOGY/PRINCIPAL FINDINGS: By employing somatic and dendritic patch-clamp recordings, Ca(2+ uncaging, and immunostaining, we demonstrate that there are significant differences in low-frequency stimulation (LFS- or DHPG-, an agonist of group I metabotropic glutamate receptors (mGluRs, induced long-term depression (LTD of excitatory synaptic transmission between SC and PP synapses in the same pyramidal neurons. These differences are eliminated by pharmacological inhibition with selective CB1 receptor antagonists or genetic deletion of the CB1 receptor, indicating that these differences likely result from differential modulation via a CB1 receptor-dependent mechanism. We also revealed that depolarization-induced suppression of excitation (DSE, a form of short-term synaptic plasticity, and photolysis of caged Ca(2+-induced suppression of Excitatory postsynaptic currents (EPSCs were less at the PP than that at the SC. In addition, application of WIN55212 (WIN induced a more pronounced inhibition of EPSCs at the SC when compared to that at the PP. CONCLUSIONS/SIGNIFICANCE: Our results suggest

  6. Bilinearity in spatiotemporal integration of synaptic inputs.

    Songting Li

    2014-12-01

    Full Text Available Neurons process information via integration of synaptic inputs from dendrites. Many experimental results demonstrate dendritic integration could be highly nonlinear, yet few theoretical analyses have been performed to obtain a precise quantitative characterization analytically. Based on asymptotic analysis of a two-compartment passive cable model, given a pair of time-dependent synaptic conductance inputs, we derive a bilinear spatiotemporal dendritic integration rule. The summed somatic potential can be well approximated by the linear summation of the two postsynaptic potentials elicited separately, plus a third additional bilinear term proportional to their product with a proportionality coefficient [Formula: see text]. The rule is valid for a pair of synaptic inputs of all types, including excitation-inhibition, excitation-excitation, and inhibition-inhibition. In addition, the rule is valid during the whole dendritic integration process for a pair of synaptic inputs with arbitrary input time differences and input locations. The coefficient [Formula: see text] is demonstrated to be nearly independent of the input strengths but is dependent on input times and input locations. This rule is then verified through simulation of a realistic pyramidal neuron model and in electrophysiological experiments of rat hippocampal CA1 neurons. The rule is further generalized to describe the spatiotemporal dendritic integration of multiple excitatory and inhibitory synaptic inputs. The integration of multiple inputs can be decomposed into the sum of all possible pairwise integration, where each paired integration obeys the bilinear rule. This decomposition leads to a graph representation of dendritic integration, which can be viewed as functionally sparse.

  7. THE STUDY OF HUMAN PARVOVIRUS B19 INFECTION IN PERINATAL TRANSMISSION AND ABNORMAL FETUSES AND NEONATES IN GUANGDONG%广东地区人微小病毒B19母婴传播及异常胎儿和新生儿人微小病毒B19感染的研究

    曹虹; 张文炳; 王香云; 钟梅

    2000-01-01

    This study was undertaken to investigate mother-to-infant transmission of human parvovirus B19 and the significance of prevalence of B19 virus in abnormal fetuses in Guandong. The polymerase chain reaction (PCR)was established to detect parvovirus B19 DNA in 700 sera from 350 maternal-infant pair groups. The prevalence of B19 virus DNA was 1.14% (4/350)and 0.28%(1/350)in the sera of pregnant women and cord blood of their neonates respectively. Parvovirus B19 DNA sequences were also detected in abnormal fetuses and new-born by PCR. The positive results were obtained in 5 samples of fetal tissues from 17 abnormal fetuses and in 3 those of neonatal tissues from 7 cases of neonatal death. The amplified products of PCR were identified to be the target DNA with Hae Ⅲ digestion. By in situ hybridization ,parvovirus DNA could be detected mainly in the nuclei of immature hematopoetic cells within fetal brain or spleen whose PCR tests were positive. The study results suggest that human parvovirus B19 infection does exist in maternal-infant transmission in Guangdong and might lead to harm on fetuses,but the prevalence rate of B19 virus may be very low. The evaluation of B19 virus infection might depend on reliable assay to determine present infection or past infection.%目的为研究人微小病毒B19在广东地区母婴及异常胎儿和新生儿中的感染状况。方法应用PCR方法检测700份孕妇外周血和新生儿脐血,PCR结合限制性内切酶分析以及原位杂交检测24份异常胎儿和新生儿组织。结果孕妇和胎儿血清中B19病毒的检出率分别为1.14%(4/350)和0.28%(1/350);17例异常胎儿和7例新生儿中,分别有5份胎儿和3份新生儿组织PCR结果阳性。PCR产物经限制性内切酶HaeI酶切分析,证实为PVB19特异的DNA片段。用原位杂交的方法,在部分异常胎儿的脑或脾组织小血管内或周围的原始红细胞核中检测到DNA阳性颗粒。结论广东地区孕妇B19病

  8. Multiple personalities: synaptic target cells as introverts and extroverts.

    Ritzenthaler, S; Chiba, A

    2001-10-01

    The intricate process of wiring a neuronetwork requires a high degree of accuracy in the communication between pre- and post-synaptic cells. While presynaptic cells have been widely recognized for their dynamic role in synaptic matchmaking, post-synaptic cells have historically been overlooked as passive targets. Recent studies in the Drosophila embryonic neuromuscular system provide compelling evidence that post-synaptic cells participate actively in the synaptogenic process. Endocytosis allows them to quickly modify the array of molecular cues they provide on their surfaces and the extension of dynamic filopodia allows post-synaptic cells to engage in direct long-distance communication. By making use of familiar cellular mechanisms such as endocytosis and filopodia formation, post-synaptic cells may be able to communicate more effectively with potential synaptic partners. PMID:11576167

  9. SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development.

    Choi, Yeonsoo; Nam, Jungyong; Whitcomb, Daniel J; Song, Yoo Sung; Kim, Doyoun; Jeon, Sangmin; Um, Ji Won; Lee, Seong-Gyu; Woo, Jooyeon; Kwon, Seok-Kyu; Li, Yan; Mah, Won; Kim, Ho Min; Ko, Jaewon; Cho, Kwangwook; Kim, Eunjoon

    2016-01-01

    Synaptogenic adhesion molecules play critical roles in synapse formation. SALM5/Lrfn5, a SALM/Lrfn family adhesion molecule implicated in autism spectrum disorders (ASDs) and schizophrenia, induces presynaptic differentiation in contacting axons, but its presynaptic ligand remains unknown. We found that SALM5 interacts with the Ig domains of LAR family receptor protein tyrosine phosphatases (LAR-RPTPs; LAR, PTPδ, and PTPσ). These interactions are strongly inhibited by the splice insert B in the Ig domain region of LAR-RPTPs, and mediate SALM5-dependent presynaptic differentiation in contacting axons. In addition, SALM5 regulates AMPA receptor-mediated synaptic transmission through mechanisms involving the interaction of postsynaptic SALM5 with presynaptic LAR-RPTPs. These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength. PMID:27225731

  10. Unitary synaptic connections among substantia nigra pars reticulata neurons.

    Higgs, Matthew H; Wilson, Charles J

    2016-06-01

    Neurons in substantia nigra pars reticulata (SNr) are synaptically coupled by local axon collaterals, providing a potential mechanism for local signal processing. Because SNr neurons fire spontaneously, these synapses are constantly active. To investigate their properties, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) from SNr neurons in brain slices, in which afferents from upstream nuclei are severed, and the cells fire rhythmically. The sIPSC trains contained a mixture of periodic and aperiodic events. Autocorrelation analysis of sIPSC trains showed that a majority of cells had one to four active unitary inputs. The properties of the unitary IPSCs (uIPSCs) were analyzed for cells with one unitary input, using a model of periodic presynaptic firing and stochastic synaptic transmission. The inferred presynaptic firing rates and coefficient of variation of interspike intervals (ISIs) corresponded well with direct measurements of spiking in SNr neurons. Methods were developed to estimate the success probability, amplitude distributions, and kinetics of the uIPSCs, while removing the contribution from aperiodic sIPSCs. The sIPSC amplitudes were not increased upon release from halorhodopsin silencing, suggesting that most synapses were not depressed at the spontaneous firing rate. Gramicidin perforated-patch recordings indicated that the average reversal potential of spontaneous inhibitory postsynaptic potentials was -64 mV. Because of the change in driving force across the ISI, the unitary inputs are predicted to have a larger postsynaptic impact when they arrive late in the ISI. Simulations of network activity suggest that this very sparse inhibitory coupling may act to desynchronize the activity of SNr neurons while having only a small effect on firing rate. PMID:26961101

  11. Modulation of swimming behavior in the medicinal leech. IV. Serotonin-induced alteration of synaptic interactions between neurons of the swim circuit.

    Mangan, P S; Cometa, A K; Friesen, W O

    1994-12-01

    Serotonin enhances the expression of swimming in the medicinal leech Hirudo medicinalis. These two reports examine the physiological causes underlying this modulation. The initial paper (Mangan et al. 1994) demonstrated that serotonin enhanced the participation of inhibitory swim motor neurons (MNs) in the generation of the swimming rhythm in the isolated nerve cord. In experiments reported here, we examined whether synaptic interactions between neurons of the swim circuit are altered by serotonin. Following exposure to 50 microM serotonin, pairwise intracellular recording revealed the presence of a time-dependent synaptic decrement. Synaptic decrement was characterized by: 1) a substantial decline in synaptic inhibition (half-decay time about 0.4 s) during constant presynaptic excitation; 2) a reduced half-time of recovery from synaptic inhibition; and 3) a strong dependence on the presynaptic neuron's membrane potential. We found little alteration in the physiology of synaptic transmission involving MNs following amine depletion in leech nerve cords. We propose that alterations in synaptic interactions resulting from exposure to elevated serotonin levels, coupled with the changes in MN cellular properties described earlier, are crucial to the increased efficacy of MNs in participating in generating and expressing the leech swimming rhythm. PMID:7807416

  12. Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo.

    Thomas M Wishart

    Full Text Available Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in

  13. Role of mast cell- and non-mast cell-derived inflammatory mediators in immunologic induction of synaptic plasticity

    Albuquerque A.A.C.

    1997-01-01

    Full Text Available We have previously discovered a long-lasting enhancement of synaptic transmission in mammal autonomic ganglia caused by immunological activation of ganglionic mast cells. Subsequent to mast cell activation, lipid and peptide mediators are released which may modulate synaptic function. In this study we determined whether some mast cell-derived mediators, prostaglandin D2 (PGD2; 1.0 µM, platelet aggregating factor (PAF; 0.3 µM and U44619 (a thromboxane analogue; 1.0 µM, and also endothelin-1 (ET-1; 0.5 µM induce synaptic potentiation in the guinea pig superior cervical ganglion (SCG, and compared their effects on synaptic transmission with those induced by a sensitizing antigen, ovalbumin (OVA; 10 µg/ml. The experiments were carried out on SCGs isolated from adult male guinea pigs (200-250 g actively sensitized to OVA, maintained in oxygenated Locke solution at 37oC. Synaptic potentiation was measured through alterations of the integral of the post-ganglionic compound action potential (CAP. All agents tested caused long-term (LTP; duration ³30 min or short-term (STP; <30 min potentiation of synaptic efficacy, as measured by the increase in the integral of the post-ganglionic CAP. The magnitude of mediator-induced potentiation was never the same as the antigen-induced long-term potentiation (A-LTP. The agent that best mimicked the antigen was PGD2, which induced a 75% increase in CAP integral for LTP (antigen: 94% and a 34% increase for STP (antigen: 91%. PAF-, U44619-, and ET-1-induced increases in CAP integral ranged for LTP from 34 to 47%, and for STP from 0 to 26%. These results suggest that the agents investigated may participate in the induction of A-LTP

  14. Synaptic and blood-brain barrier structural changes in a rat epilepsy model induced by coriaria lacton

    Jiyan Cheng; Jichun Huang; Yi Han; Guangyi Liu; Ling Yin; Furong Zheng

    2008-01-01

    synaptic interface, length of active zones, thickness of postsynaptic density, and percentage of perforation synapses increased significantly. ②There was significant edema in the endothelium, basement membrane, and the pericyte of the epilepsy group; the electron density of the basement membrane was reduced.CONCLUSION: ①The coriaria lacton treatment altered synaptic ultrastructure, as well as BBB characteristics, in the epileptic rat model, and also improved synaptic transmission efficiency, as well as BBB permeability; ②Synaptic and BBB ultrastructural changes might play an important role in the mechanism of epilepsy.

  15. Synaptic devices based on purely electronic memristors

    Pan, Ruobing [Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201 (China); Institute of Materials Science, School of Materials Science and Engineering, Shanghai University, Shanghai 200072 (China); Li, Jun; Zhuge, Fei, E-mail: zhugefei@nimte.ac.cn, E-mail: h-cao@nimte.ac.cn; Zhu, Liqiang; Liang, Lingyan; Zhang, Hongliang; Gao, Junhua; Cao, Hongtao, E-mail: zhugefei@nimte.ac.cn, E-mail: h-cao@nimte.ac.cn; Fu, Bing; Li, Kang [Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201 (China)

    2016-01-04

    Memristive devices have been widely employed to emulate biological synaptic behavior. In these cases, the memristive switching generally originates from electrical field induced ion migration or Joule heating induced phase change. In this letter, the Ti/ZnO/Pt structure was found to show memristive switching ascribed to a carrier trapping/detrapping of the trap sites (e.g., oxygen vacancies or zinc interstitials) in ZnO. The carrier trapping/detrapping level can be controllably adjusted by regulating the current compliance level or voltage amplitude. Multi-level conductance states can, therefore, be realized in such memristive device. The spike-timing-dependent plasticity, an important Hebbian learning rule, has been implemented in this type of synaptic device. Compared with filamentary-type memristive devices, purely electronic memristors have potential to reduce their energy consumption and work more stably and reliably, since no structural distortion occurs.

  16. Filamentary Switching: Synaptic Plasticity through Device Volatility

    La Barbera, Selina; Alibart, Fabien

    2015-01-01

    Replicating the computational functionalities and performances of the brain remains one of the biggest challenges for the future of information and communication technologies. Such an ambitious goal requires research efforts from the architecture level to the basic device level (i.e., investigating the opportunities offered by emerging nanotechnologies to build such systems). Nanodevices, or, more precisely, memory or memristive devices, have been proposed for the implementation of synaptic functions, offering the required features and integration in a single component. In this paper, we demonstrate that the basic physics involved in the filamentary switching of electrochemical metallization cells can reproduce important biological synaptic functions that are key mechanisms for information processing and storage. The transition from short- to long-term plasticity has been reported as a direct consequence of filament growth (i.e., increased conductance) in filamentary memory devices. In this paper, we show tha...

  17. Synaptic devices based on purely electronic memristors

    Memristive devices have been widely employed to emulate biological synaptic behavior. In these cases, the memristive switching generally originates from electrical field induced ion migration or Joule heating induced phase change. In this letter, the Ti/ZnO/Pt structure was found to show memristive switching ascribed to a carrier trapping/detrapping of the trap sites (e.g., oxygen vacancies or zinc interstitials) in ZnO. The carrier trapping/detrapping level can be controllably adjusted by regulating the current compliance level or voltage amplitude. Multi-level conductance states can, therefore, be realized in such memristive device. The spike-timing-dependent plasticity, an important Hebbian learning rule, has been implemented in this type of synaptic device. Compared with filamentary-type memristive devices, purely electronic memristors have potential to reduce their energy consumption and work more stably and reliably, since no structural distortion occurs

  18. Gender differences in human cortical synaptic density

    Alonso-Nanclares, L.; Gonzalez-Soriano, J.; Rodriguez, J. R.; DeFelipe, J

    2008-01-01

    Certain cognitive functions differ in men and women, although the anatomical and functional substrates underlying these differences remain unknown. Because neocortical activity is directly related with higher brain function, numerous studies have focused on the cerebral cortex when searching for possible structural correlates of cognitive gender differences. However, there are no studies on possible gender differences at the synaptic level. In the present work we have used stereological and c...

  19. Morphological plasticity of astroglia: Understanding synaptic microenvironment

    Heller, J. P.; Rusakov, D. A.

    2015-01-01

    Memory formation in the brain is thought to rely on the remodeling of synaptic connections which eventually results in neural network rewiring. This remodeling is likely to involve ultrathin astroglial protrusions which often occur in the immediate vicinity of excitatory synapses. The phenomenology, cellular mechanisms, and causal relationships of such astroglial restructuring remain, however, poorly understood. This is in large part because monitoring and probing of the underpinning molecula...

  20. Signaling for Vesicle Mobilization and Synaptic Plasticity

    Levitan, Edwin S.

    2008-01-01

    The hypothesis that release of classical neurotransmitters and neuropeptides is facilitated by increasing the mobility of small synaptic vesicles (SSVs) and dense core vesicles (DCVs) could not be tested until the advent of methods for visualizing these secretory vesicles in living nerve terminals. In fact, fluorescence imaging studies have only since 2005 established that activity increases secretory vesicle mobility in motoneuron terminals and chromaffin cells. Mobilization of DCVs and SSVs...

  1. Cellular and synaptic network defects in autism

    Peça, João; Feng, Guoping

    2012-01-01

    Many candidate genes are now thought to confer susceptibility to autism spectrum disorders (ASDs). Here we review four interrelated complexes, each composed of multiple families of genes that functionally coalesce on common cellular pathways. We illustrate a common thread in the organization of glutamatergic synapses and suggest a link between genes involved in Tuberous Sclerosis Complex, Fragile X syndrome, Angelman syndrome and several synaptic ASD candidate genes. When viewed in this conte...

  2. Matrix metalloproteinases, synaptic injury, and multiple sclerosis

    ArekSzklarczyk

    2010-10-01

    Full Text Available Multiple sclerosis (MS is a disease of the central nervous system in which immune mediated damage to myelin is characteristic. For an overview of this condition and its pathophysiology, please refer to one of many excellent published reviews. To follow, is a discussion focused on the possibility that synaptic injury occurs in at least a subset of patients, and that matrix metalloproteinases (MMPs play a role in such.

  3. Retinal synaptic regeneration via microfluidic guiding channels

    Ping-Jung Su; Zongbin Liu; Kai Zhang; Xin Han; Yuki Saito; Xiaojun Xia; Kenji Yokoi; Haifa Shen; Lidong Qin

    2015-01-01

    In vitro culture of dissociated retinal neurons is an important model for investigating retinal synaptic regeneration (RSR) and exploring potentials in artificial retina. Here, retinal precursor cells were cultured in a microfluidic chip with multiple arrays of microchannels in order to reconstruct the retinal neuronal synapse. The cultured retinal cells were physically connected through microchannels. Activation of electric signal transduction by the cells through the microchannels was demon...

  4. Matrix Metalloproteinases, Synaptic Injury, and Multiple Sclerosis

    Szklarczyk, Arek; Conant, Katherine

    2010-01-01

    Multiple sclerosis (MS) is a disease of the central nervous system in which immune mediated damage to myelin is characteristic. For an overview of this condition and its pathophysiology, please refer to one of many excellent published reviews (Sorensen and Ransohoff, 1998; Weiner, 2009). To follow, is a discussion focused on the possibility that synaptic injury occurs in at least a subset of patients, and that matrix metalloproteinases (MMPs) play a role in such.

  5. Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease.

    D'Arcangelo, G; Grossi, D; Racaniello, M; Cardinale, A; Zaratti, A; Rufini, S; Cutarelli, A; Tancredi, V; Merlo, D; Frank, C

    2016-01-01

    Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1-/- mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1-/- mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1-/- mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia. PMID:26885401

  6. Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease

    G. D’Arcangelo

    2016-01-01

    Full Text Available Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1−/− mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1−/− mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1−/− mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia.

  7. Synaptic theory of Replicator-like melioration

    Yonatan Loewenstein

    2010-06-01

    Full Text Available According to the theory of Melioration, organisms in repeated choice settings shift their choice preference in favor of the alternative that provides the highest return. The goal of this paper is to explain how this learning behavior can emerge from microscopic changes in the efficacies of synapses, in the context of two-alternative repeated-choice experiment. I consider a large family of synaptic plasticity rules in which changes in synaptic efficacies are driven by the covariance between reward and neural activity. I construct a general framework that predicts the learning dynamics of any decision-making neural network that implements this synaptic plasticity rule and show that melioration naturally emerges in such networks. Moreover, the resultant learning dynamics follows the Replicator equation which is commonly used to phenomenologically describe changes in behavior in operant conditioning experiments. Several examples demonstrate how the learning rate of the network is affected by its properties and by the specifics of the plasticity rule. These results help bridge the gap between cellular physiology and learning behavior.

  8. Characterization and extraction of the synaptic apposition surface for synaptic geometry analysis

    Morales, Juan; Rodríguez, Angel; Rodríguez, José-Rodrigo; DeFelipe, Javier; Merchán-Pérez, Angel

    2013-01-01

    Geometrical features of chemical synapses are relevant to their function. Two critical components of the synaptic junction are the active zone (AZ) and the postsynaptic density (PSD), as they are related to the probability of synaptic release and the number of postsynaptic receptors, respectively. Morphological studies of these structures are greatly facilitated by the use of recent electron microscopy techniques, such as combined focused ion beam milling and scanning electron microscopy (FIB/SEM), and software tools that permit reconstruction of large numbers of synapses in three dimensions. Since the AZ and the PSD are in close apposition and have a similar surface area, they can be represented by a single surface—the synaptic apposition surface (SAS). We have developed an efficient computational technique to automatically extract this surface from synaptic junctions that have previously been three-dimensionally reconstructed from actual tissue samples imaged by automated FIB/SEM. Given its relationship with the release probability and the number of postsynaptic receptors, the surface area of the SAS is a functionally relevant measure of the size of a synapse that can complement other geometrical features like the volume of the reconstructed synaptic junction, the equivalent ellipsoid size and the Feret's diameter. PMID:23847474

  9. Characterization and extraction of the synaptic apposition surface for synaptic geometry analysis.

    Juan Morales

    2013-07-01

    Full Text Available Geometrical features of chemical synapses are relevant to their function. Two critical components of the synaptic junction are the active zone and the postsynaptic density, as they are related to the probability of synaptic release and the number of postsynaptic receptors, respectively. Morphological studies of these structures are greatly facilitated by the use of recent electron microscopy techniques, such as combined focused ion beam milling and scanning electron microscopy (FIB/SEM, and software tools that permit reconstruction of large numbers of synapses in three dimensions. Since the active zone and the postsynaptic density are in close apposition and have a similar surface area, they can be represented by a single surface — the synaptic apposition surface (SAS. We have developed an efficient computational technique to automatically extract this surface from synaptic junctions that have previously been three-dimensionally reconstructed from actual tissue samples imaged by automated FIB/SEM. Given its relationship with the release probability and the number of postsynaptic receptors, the surface area of the SAS is a functionally relevant measure of the size of a synapse that can complement other geometrical features like the volume of the reconstructed synaptic junction, the equivalent ellipsoid size and the Feret’s diameter.

  10. Differential regulation of synaptic vesicle tethering and docking by UNC-18 and TOM-1

    Elena O Gracheva

    2010-10-01

    Full Text Available The assembly of SNARE complexes between syntaxin, SNAP-25 and synaptobrevin is required to prime synaptic vesicles for fusion. Since Munc18 and tomosyn compete for syntaxin interactions, the interplay between these proteins is predicted to be important in regulating synaptic transmission. We explored this possibility, by examining genetic interactions between C. elegans unc-18(Munc18, unc-64(syntaxin and tom-1(tomosyn. We have previously demonstrated that unc-18 mutants have reduced synaptic transmission, whereas tom-1 mutants exhibit enhanced release. Here we show that the unc-18 mutant release defect is associated with loss of two morphologically distinct vesicle pools; those tethered within 25nm of the plasma membrane and those docked with the plasma membrane. In contrast, priming defective unc-13 mutants accumulate tethered vesicles, while docked vesicles are greatly reduced, indicating tethering is UNC-18-dependent and occurs in the absence of priming. C. elegans unc-64 mutants phenocopy unc-18 mutants, losing both tethered and docked vesicles, whereas overexpression of open syntaxin preferentially increases vesicle docking, suggesting UNC-18/closed syntaxin interactions are responsible for vesicle tethering. Given the competition between vertebrate tomosyn and Munc18, for syntaxin binding, we hypothesized that C. elegans TOM-1 may inhibit both UNC-18-dependent vesicle targeting steps. Consistent with this hypothesis, tom-1 mutants exhibit enhanced UNC-18 plasma membrane localization and a concomitant increase in both tethered and docked synaptic vesicles. Furthermore, in tom-1;unc-18 double mutants the docked, primed vesicle pool is preferentially rescued relative to unc-18 single mutants. Together these data provide evidence for the differential regulation of two vesicle targeting steps by UNC-18 and TOM-1 through competitive interactions with syntaxin

  11. Impaired hippocampal synaptic plasticity and NR2A/2B expression ratio in remifentanil withdrawal rats.

    Wang, Yi-Yi; Liu, Shichang; Zhang, Nan; Yang, Jing; Zhang, Yinguo

    2016-03-01

    Remifentanil is a kind of synthetic opioid which has gained wide clinical acceptance by anesthesiologists. In this study, we attempted to test whether withdrawal effects on learning mechanisms can be triggered by repeated low-dose remifentanil treatment. Male Sprague-Dawley (SD) rats were subjected to remifentanil (50μg/kgs.c.) twice per day at 12h intervals for 15 days. When the animals of remifentanil group were withdrawn from remifentanil at 10h after the last injection, changes in open field test, Morris water maze test (MWM) and synaptic efficacy were examined in each group. We demonstrated that repeated exposure to 50μg/kg remifentanil produced enhanced locomotor activity indicating that a remifentanil addiction animal model in rats was established. MWM results showed that exposure to remifentanil had no influence on the spatial cognition. After withdrawal of remifentanil rats showed impaired spatial cognition. In electrophysiology test, remifentanil group rats showed a trend for a rightward shift of input/output relationship and significant deficits in maintenance of STP and LTP. Immunohistochemistry results demonstrated increased NR2A/NR2B ratio that should be included depression of LTP. In the whole-cell patch-clamp recording, after elimination from remifentanil incubation, mEPSC frequency was down regulated in hippocampal CA1 neurons, indicating that basal synaptic transmission were affected by remifentanil withdrawal. Taken together, the current findings demonstrate that the remifentanil withdrawn rats exhibit obvious impairment of hippocampus-dependent memory and synaptic plasticity. Increased hippocampal NR2A/NR2B expression ratio and the changes of basal synaptic transmission may participate in the impairment of LTP. PMID:26777139

  12. The presence of synaptic and chromosome disjunction mutants in Cenchrus ciliaris (Poaceae: Paniceae

    N. C. Visser

    1999-12-01

    Full Text Available Synaptic mutants are present in  Cenchrus ciliaris L This species, due to the presence of linear bivalents and occasion­al trivalents and quadrivalents, is an intermediate desynaptic species. In addition, geographical distribution and environmental factors, such as high temperatures and low humidity, could also have had an influence on the desynapsis observed.The disjunction of chromosomes during anaphase I was mostly abnormal in this desynaptic species. Precocious disjunction of chromosomes into chromatids occurred during anaphase I Due to the high incidence of this chromosome abnormality, a mutant gene,  'pc'  responsible for the disjunction of chromosomes, must be present. The absence of cytokinesis in one specimen indicates a recessive mutant gene,  'va' to be active in this species.

  13. Abnormal fear conditioning and amygdala processing in an animal model of autism

    Markram, Kamila; Rinaldi, Tania; La Mendola, Deborah; Sandi, Carmen; Markram, Henry

    2008-01-01

    A core feature of autism spectrum disorders is the impairment in social interactions. Among other brain regions, a deficit in amygdala processing has been suggested to underlie this impairment, but whether the amygdala is processing fear abnormally in autism, is yet not clear. We used the valproic acid (VPA) rat model of autism to (a) screen for autism-like symptoms in rats, (b) test for alterations in amygdala-dependent fear processing, and (c) evaluate neuronal reactivity and synaptic plast...

  14. Realistic modelling of receptor activation in hippocampal excitatory synapses: analysis of multivesicular release, release location, temperature and synaptic cross-talk.

    Boucher, Jérôme; Kröger, Helmut; Sík, Attila

    2010-07-01

    Chemically mediated synaptic transmission results from fusion of synaptic vesicles with the presynaptic plasma membrane, subsequent release of the vesicular content into the cleft and binding to postsynaptic receptors. Previous modelling studies of excitatory neurotransmitter glutamate were based on simplified geometries failing to account for the biologically realistic synaptic environment, in particular, the presence of astrocytes, the geometry of extracellular space, and the neurotransmitter uptake mechanism. Using 3-dimensional reconstructions of hippocampal glutamatergic synapses including the surrounding astrocytic processes we have developed a biologically realistic model to analyse receptor activation in different conditions. We used the finite element method to simulate glutamate release, analyse glutamate diffusion following single and multiple vesicle release and binding at the postsynaptic site to AMPA and NMDA receptors. We demonstrate that: (1) the transmitter diffusion is highly temperature-sensitive; (2) release conditions and geometry more specifically affect AMPARs than NMDARs; (3) the sensitivities of AMPARs and NMDARs to simultaneous vesicular release are different; (4) in the case of multivesicle neurotransmitter release with variable delays, the binding of glutamate to AMPARs is additive up to 1 ms after the release, then becomes independent, but to NMDARs the binding is additive up to 33 ms; (5) the number of AMPARs varies more than the number of NMDRs in response to the input firing patterns; (6) the presence of astrocytes effectively blocks synaptic cross-talk; and (7) synaptic cross-talk, mediated by NMDARs but not AMPARs, is only possible after quasi-simultaneous multivesicular release at physiological temperature (35 degrees C) without intervening astrocytes, but not at 25 degrees C. Our simulations demonstrate the importance of temperature and ultrastructural synaptic environment in synaptic transmission and synaptic cross-talk. PMID

  15. Streptavidin-conjugated CdSe/ZnS quantum dots impaired synaptic plasticity and spatial memory process

    Gao Xiaoyan [Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf (Germany); Tang Mingliang [Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences (China); Li Zhifeng; Zha Yingying [University of Science and Technology of China, CAS Key Laboratory of Brain Function and Disease, and School of Life Sciences (China); Cheng Guosheng [Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences (China); Yin Shuting [Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf (Germany); Chen Jutao; Ruan Diyun; Chen Lin; Wang Ming, E-mail: wming@ustc.edu.cn [University of Science and Technology of China, CAS Key Laboratory of Brain Function and Disease, and School of Life Sciences (China)

    2013-04-15

    Studies reported that quantum dots (QDs), as a novel probe, demonstrated a promising future for in vivo imaging, but also showed potential toxicity. This study is mainly to investigate in vivo response in the central nervous system (CNS) after exposure to QDs in a rat model of synaptic plasticity and spatial memory. Adult rats were exposed to streptavidin-conjugated CdSe/ZnS QDs (Qdots 525, purchased from Molecular Probes Inc.) by intraperitoneal injection for 7 days, followed by behavioral, electrophysiological, and biochemical examinations. The electrophysiological results show that input/output (I/O) functions were increased, while the peak of paired-pulse reaction and long-term potentiation were decreased after QDs insult, indicating synaptic transmission was enhanced and synaptic plasticity in the hippocampus was impaired. Meanwhile, behavioral experiments provide the evidence that QDs could impair rats' spatial memory process. All the results present evidences of interference of synaptic transmission and plasticity in rat hippocampal dentate gyrus area by QDs insult and suggest potential adverse issues which should be considered in QDs applications.

  16. Streptavidin-conjugated CdSe/ZnS quantum dots impaired synaptic plasticity and spatial memory process

    Studies reported that quantum dots (QDs), as a novel probe, demonstrated a promising future for in vivo imaging, but also showed potential toxicity. This study is mainly to investigate in vivo response in the central nervous system (CNS) after exposure to QDs in a rat model of synaptic plasticity and spatial memory. Adult rats were exposed to streptavidin-conjugated CdSe/ZnS QDs (Qdots 525, purchased from Molecular Probes Inc.) by intraperitoneal injection for 7 days, followed by behavioral, electrophysiological, and biochemical examinations. The electrophysiological results show that input/output (I/O) functions were increased, while the peak of paired-pulse reaction and long-term potentiation were decreased after QDs insult, indicating synaptic transmission was enhanced and synaptic plasticity in the hippocampus was impaired. Meanwhile, behavioral experiments provide the evidence that QDs could impair rats’ spatial memory process. All the results present evidences of interference of synaptic transmission and plasticity in rat hippocampal dentate gyrus area by QDs insult and suggest potential adverse issues which should be considered in QDs applications.

  17. Temporal requirements of the fragile X mental retardation protein in modulating circadian clock circuit synaptic architecture

    Cheryl L Gatto

    2009-08-01

    Full Text Available Loss of fragile X mental retardation 1 (FMR1 gene function is the most common cause of inherited mental retardation and autism spectrum disorders, characterized by attention disorder, hyperactivity and disruption of circadian activity cycles. Pursuit of effective intervention strategies requires determining when the FMR1 product (FMRP is required in the regulation of neuronal circuitry controlling these behaviors. In the well-characterized Drosophila disease model, loss of the highly conserved dFMRP causes circadian arrhythmicity and conspicuous abnormalities in the circadian clock circuitry. Here, a novel Sholl Analysis was used to quantify over-elaborated synaptic architecture in dfmr1-null small ventrolateral neurons (sLNvs, a key subset of clock neurons. The transgenic Gene-Switch system was employed to drive conditional neuronal dFMRP expression in the dfmr1-null mutant background in order to dissect temporal requirements within the clock circuit. Introduction of dFMRP during early brain development, including the stages of neurogenesis, neuronal fate specification and early pathfinding, provided no rescue of dfmr1 mutant phenotypes. Similarly, restoring normal dFMRP expression in the adult failed to restore circadian circuit architecture. In sharp contrast, supplying dFMRP during a transient window of very late brain development, wherein synaptogenesis and substantial subsequent synaptic reorganization (e.g. use-dependent pruning occur, provided strong morphological rescue to reestablish normal sLNvs synaptic arbors. We conclude that dFMRP plays a developmentally restricted role in sculpting synaptic architecture in these neurons that cannot be compensated for by later reintroduction of the protein at maturity.

  18. Transmission issues

    This session on transmission issues focused on the role that transmission plays in electricity markets and the importance of getting the market structure right in terms of generation divestiture with buy back contracts, demand side responsive programs, transmission upgrades and long term contracts. The difficulties of distinguishing between market power and scarcity were examined along with some of the complications that ensue if transmission experiences congestion, as exemplified by the August 2003 blackout in eastern North America. The presentations described the best ways to handle transmission issues, and debated whether transmission should be deregulated or follow market forces. Issues of interconnections and reliability of connections were also debated along with the attempt to integrate renewables into the grid. Some presentations identified what new transmission must be built and what must be done to ensure that transmission gets built. The challenges and business opportunities for transmission in Alberta were discussed with reference to plans to invest in new infrastructure, where it is going outside of the province and how it works with other jurisdictions. Manitoba's Conawapa Hydro Project and its 2000 MW tie line to Ontario was also discussed. Some examples of non-optimal use of interconnections in Europe were also discussed in an effort to learn from these mistakes and avoid them in Canada. tabs., figs

  19. Transmission line protection relay : an overview

    Gupta, R.P. [Compton Greaves Ltd., Mumbai (India). Global Research and Development Centre

    2008-07-01

    A protective relay senses abnormal conditions in power transmission grid and issues an alarm or trip signal. This paper described various functions in a transmission line protection relay. These functions use the voltages and currents at the relay location. Transmission line protection is based on the measurement of impedance. Various algorithms are used by different manufacturers to issue trip signal within a cycle. There is much scope in the transmission line protection with the incorporation of FACTS devices into the transmission system. This paper included a description of the protection functions, secondary supervision functions, as well as control and monitoring functions 5 refs., 2 figs.

  20. Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation

    Sara Calafate

    2015-05-01

    Full Text Available Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer’s disease (AD. Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation. These findings can have implications for synaptic repair therapies, which may turn out to have adverse effects by promoting propagation of Tau pathology.

  1. Quantifying Repetitive Transmission at Chemical Synapses: A Generative-Model Approach123

    Barri, Alessandro; Wang, Yun; Hansel, David

    2016-01-01

    Abstract The dependence of the synaptic responses on the history of activation and their large variability are both distinctive features of repetitive transmission at chemical synapses. Quantitative investigations have mostly focused on trial-averaged responses to characterize dynamic aspects of the transmission—thus disregarding variability—or on the fluctuations of the responses in steady conditions to characterize variability—thus disregarding dynamics. We present a statistically principled framework to quantify the dynamics of the probability distribution of synaptic responses under arbitrary patterns of activation. This is achieved by constructing a generative model of repetitive transmission, which includes an explicit description of the sources of stochasticity present in the process. The underlying parameters are then selected via an expectation-maximization algorithm that is exact for a large class of models of synaptic transmission, so as to maximize the likelihood of the observed responses. The method exploits the information contained in the correlation between responses to produce highly accurate estimates of both quantal and dynamic parameters from the same recordings. The method also provides important conceptual and technical advances over existing state-of-the-art techniques. In particular, the repetition of the same stimulation in identical conditions becomes unnecessary. This paves the way to the design of optimal protocols to estimate synaptic parameters, to the quantitative comparison of synaptic models over benchmark datasets, and, most importantly, to the study of repetitive transmission under physiologically relevant patterns of synaptic activation. PMID:27200414

  2. Emotional enhancement of memory: how norepinephrine enables synaptic plasticity

    Tully Keith; Bolshakov Vadim Y

    2010-01-01

    Abstract Changes in synaptic strength are believed to underlie learning and memory. We explore the idea that norepinephrine is an essential modulator of memory through its ability to regulate synaptic mechanisms. Emotional arousal leads to activation of the locus coeruleus with the subsequent release of norepineprine in the brain, resulting in the enhancement of memory. Norepinephrine activates both pre- and post-synaptic adrenergic receptors at central synapses with different functional outc...

  3. The impact of synapsins on synaptic plasticity and cognitive behaviors

    Lin ZHANG; Zhong-Xin ZHAO

    2006-01-01

    Synapsins are a family of phosphoproteins specifically associated with the cytoplasmic surface of the synaptic vesicle membrane, appearing to regulate neurotransmitter release, the formation and maintenance of synaptic contacts.They could induce the change of the synaptic plasticity to regulate various adaptation reactions, and change the cognitive behaviors. So we presume that if some cognitive behavior are damaged, synapsins would be changed as well. This gives us a new recognition of better diagnosis and therapy of cognitive disorder desease.

  4. Synaptic tagging and capture in a biophysical model

    Benjamin Auffarth

    2014-01-01

    There is wide consensus that synaptic plasticity (prominently long-term potentiation; LTP) is the underlying mechanism for learning and memory storage (cf Nabavi 2014). Open issues include the molecular pathways and networks and structural processes leading to functional and structural changes at the synaptic and dendritic levels in terms of channels and spines. Synaptic tagging and capture (STC; Frey and Morris 1997; Redondo and Morris 2011) is a predominant model for investigating LTP. Acco...

  5. A Voltage Mode Memristor Bridge Synaptic Circuit with Memristor Emulators

    Leon Chua; Maheshwar Pd. Sah; Hyongsuk Kim; Changju Yang

    2012-01-01

    A memristor bridge neural circuit which is able to perform signed synaptic weighting was proposed in our previous study, where the synaptic operation was verified via software simulation of the mathematical model of the HP memristor. This study is an extension of the previous work advancing toward the circuit implementation where the architecture of the memristor bridge synapse is built with memristor emulator circuits. In addition, a simple neural network which performs both synaptic weighti...

  6. Restoration of synaptic function in sight for degenerative retinal disease

    Schubert, Timm; Wissinger, Bernd

    2015-01-01

    Synaptic disorganization is a prominent feature of many neurological diseases of the CNS, including Parkinson’s disease, intellectual development disorders, and autism. Although synaptic plasticity is critical for learning and memory, it is unclear whether this innate property helps restore synaptic function in disease once the primary cause of disease is abrogated. An answer to this question may come from a recent investigation in X-linked retinoschisis, a currently untreatable retinopathy. ...

  7. Neuroligins and Neurexins Link Synaptic Function to Cognitive Disease

    Südhof, Thomas C.

    2008-01-01

    The brain processes information by transmitting signals at synapses, which connect neurons into vast networks of communicating cells. In these networks, synapses not only transmit, but also process and refine information. Neurexins and neuroligins are synaptic cell-adhesion molecules that connect pre- and postsynaptic neurons at synapses, mediate trans-synaptic signaling, and shape neural network properties by specifying synaptic functions. In humans, alterations in neurexin or neuroligin gen...

  8. Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.

    Tracy, Tara E; Sohn, Peter Dongmin; Minami, S Sakura; Wang, Chao; Min, Sang-Won; Li, Yaqiao; Zhou, Yungui; Le, David; Lo, Iris; Ponnusamy, Ravikumar; Cong, Xin; Schilling, Birgit; Ellerby, Lisa M; Huganir, Richard L; Gan, Li

    2016-04-20

    Tau toxicity has been implicated in the emergence of synaptic dysfunction in Alzheimer's disease (AD), but the mechanism by which tau alters synapse physiology and leads to cognitive decline is unclear. Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein. Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA. These findings suggest a novel mechanism by which pathogenic tau causes synaptic dysfunction and cognitive decline in AD pathogenesis. PMID:27041503

  9. Analysis and treatment for abnormal loss of RCP motor lubrication

    RCP, as the 'heat' of a nuclear power plant, is one of the vital equipment of RCP Coolant System, ensuring the regular coolant flow for core heat transmission. In this case, it is a must to ensure the safety and reliability of RCP operation. During the 11th cycle of QNPC, the lubrication of RCP-A motor lost abnormally. To ensure normal operation of the motor, we performed 5 emergency lubrication-feeding. Against this problem, we analyzed the cause of abnormal lubrication loss of RCP motor and the transfer pathway for oil-gas, and according to the analysis we performed RCP motor disassembly maintenance during refueling overhaul. The paper discusses the specific treatment for the abnormal lubrication loss. It was testified useful to control the abnormal lubrication loss by the specific treatment. (authors)

  10. Statistical mechanics of attractor neural network models with synaptic depression

    Synaptic depression is known to control gain for presynaptic inputs. Since cortical neurons receive thousands of presynaptic inputs, and their outputs are fed into thousands of other neurons, the synaptic depression should influence macroscopic properties of neural networks. We employ simple neural network models to explore the macroscopic effects of synaptic depression. Systems with the synaptic depression cannot be analyzed due to asymmetry of connections with the conventional equilibrium statistical-mechanical approach. Thus, we first propose a microscopic dynamical mean field theory. Next, we derive macroscopic steady state equations and discuss the stabilities of steady states for various types of neural network models.

  11. Experimental Implementation of a Biometric Laser Synaptic Sensor

    Alexander N. Pisarchik

    2013-12-01

    Full Text Available We fabricate a biometric laser fiber synaptic sensor to transmit information from one neuron cell to the other by an optical way. The optical synapse is constructed on the base of an erbium-doped fiber laser, whose pumped diode current is driven by a pre-synaptic FitzHugh–Nagumo electronic neuron, and the laser output controls a post-synaptic FitzHugh–Nagumo electronic neuron. The implemented laser synapse displays very rich dynamics, including fixed points, periodic orbits with different frequency-locking ratios and chaos. These regimes can be beneficial for efficient biorobotics, where behavioral flexibility subserved by synaptic connectivity is a challenge.

  12. A pivotal role of GSK-3 in synaptic plasticity

    Clarrisa A Bradley

    2012-02-01

    Full Text Available Glycogen synthase kinase-3 (GSK-3 has many cellular functions. Recent evidence suggests that it plays a key role in certain types of synaptic plasticity, in particular a form of long-term depression (LTD that is induced by the synaptic activation of N-methyl-D-aspartate (NMDA receptors. In the present article we summarise what is currently known concerning the roles of GSK-3 in synaptic plasticity at both glutamatergic and GABAergic synapses. We summarise its role in cognition and speculate on how alterations in the synaptic functioning of GSK-3 may be a major factor in certain neurodegenerative disorders.

  13. Multi-gate synergic modulation in laterally coupled synaptic transistors

    Zhu, Li Qiang; Xiao, Hui; Liu, Yang Hui; Wan, Chang Jin; Shi, Yi; Wan, Qing

    2015-10-01

    Laterally coupled oxide-based synaptic transistors with multiple gates are fabricated on phosphorosilicate glass electrolyte films. Electrical performance of the transistor can be evidently improved when the device is operated in a tri-gate synergic modulation mode. Excitatory post-synaptic current and paired pulse facilitation (PPF) behavior of biological synapses are mimicked, and PPF index can be effectively tuned by the voltage applied on the modulatory terminal. At last, superlinear to sublinear synaptic integration regulation is also mimicked by applying a modulatory pulse on the third modulatory terminal. The multi-gate oxide-based synaptic transistors may find potential applications in biochemical sensors and neuromorphic systems.

  14. Systemic abnormalities in liver disease

    Minemura, Masami; Tajiri, Kazuto; Shimizu, Yukihiro

    2009-01-01

    Systemic abnormalities often occur in patients with liver disease. In particular, cardiopulmonary or renal diseases accompanied by advanced liver disease can be serious and may determine the quality of life and prognosis of patients. Therefore, both hepatologists and non-hepatologists should pay attention to such abnormalities in the management of patients with liver diseases.

  15. Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (DeltaE) TorsinA in transgenic mice.

    Page, Michelle E; Bao, Li; Andre, Pierrette; Pelta-Heller, Joshua; Sluzas, Emily; Gonzalez-Alegre, Pedro; Bogush, Alexey; Khan, Loren E; Iacovitti, Lorraine; Rice, Margaret E; Ehrlich, Michelle E

    2010-09-01

    Early onset torsion dystonia is an autosomal dominant movement disorder of variable penetrance caused by a glutamic acid, i.e. DeltaE, deletion in DYT1, encoding the protein TorsinA. Genetic and structural data implicate basal ganglia dysfunction in dystonia. TorsinA, however, is diffusely expressed, and therefore the primary source of dysfunction may be obscured in pan-neuronal transgenic mouse models. We utilized the tyrosine hydroxylase (TH) promoter to direct transgene expression specifically to dopaminergic neurons of the midbrain to identify cell-autonomous abnormalities. Expression of both the human wild type (hTorsinA) and mutant (DeltaE-hTorsinA) protein resulted in alterations of dopamine release as detected by microdialysis and fast cycle voltammetry. Motor abnormalities detected in these mice mimicked those noted in transgenic mice with pan-neuronal transgene expression. The locomotor response to cocaine in both TH-hTorsinA and TH-DeltaE-hTorsinA, in the face of abnormal extracellular DA levels relative to non-transgenic mice, suggests compensatory, post-synaptic alterations in striatal DA transmission. This is the first cell-subtype-specific DYT1 transgenic mouse that can serve to differentiate between primary and secondary changes in dystonia, thereby helping to target disease therapies. PMID:20460154

  16. Diverse in- and output polarities and high complexity of local synaptic and nonsynaptic signalling within a chemically defined class of peptidergic Drosophila neurons

    Peptidergic neurons are not easily integrated into current connectomics concepts, since their peptide messages can be distributed via non-synaptic paracrine signaling or even via volume transmission. Moreover, and especially in insects, the polarity of peptidergic interneurons in terms of in- and o...

  17. The Role of Insulin Receptor Signaling in Synaptic Plasticity and Cognitive Function

    Chiung-Chun Huang

    2010-06-01

    Full Text Available Insulin is the most abundant peptidergic hormone secretedby the pancreatic islets of Langerhans and plays an importantrole in organic metabolism. In recent years, various functionsfor insulin receptor signaling in the brain have been suggestedin normal neurophysiology, and a dysregulation of insulinsecretion or insulin receptor signaling has been reported inserious mental illnesses. Several lines of work in both laboratoryanimals and humans suggest that when neurons in cognitivebrain regions such as the hippocampus and cerebral cortexdo not make enough insulin or cannot respond to insulin properly,everything from very mild memory loss to severeneorodegenerative diseases can result. On the other hand,administration of insulin exerts memory-enhancing action inboth humans and experimental animals. Insulin has alsorecently been shown to regulate the endocytosis of 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA receptors, which causes long-term depression(LTD of excitatory synaptic transmission. The fact that LTD in the mammalian brain is generallyassumed to be a synaptic mechanism underlying learning during novel experiences,this insulin-induced LTD may therefore serve as an important role in brain informationprocessesing. Recent advances in the knowledge of the biological role of brain insulin receptorsignaling in relation to synaptic plasticity and cognitive function, and of the regulatorysignaling mechanisms involved in these processes will be discussed in the article.

  18. Counting numbers of synaptic proteins: absolute quantification and single molecule imaging techniques.

    Patrizio, Angela; Specht, Christian G

    2016-10-01

    The ability to count molecules is essential to elucidating cellular mechanisms, as these often depend on the absolute numbers and concentrations of molecules within specific compartments. Such is the case at chemical synapses, where the transmission of information from presynaptic to postsynaptic terminals requires complex interactions between small sets of molecules. Be it the subunit stoichiometry specifying neurotransmitter receptor properties, the copy numbers of scaffold proteins setting the limit of receptor accumulation at synapses, or protein packing densities shaping the molecular organization and plasticity of the postsynaptic density, all of these depend on exact quantities of components. A variety of proteomic, electrophysiological, and quantitative imaging techniques have yielded insights into the molecular composition of synaptic complexes. In this review, we compare the different quantitative approaches and consider the potential of single molecule imaging techniques for the quantification of synaptic components. We also discuss specific neurobiological data to contextualize the obtained numbers and to explain how they aid our understanding of synaptic structure and function. PMID:27335891

  19. Importance of being Nernst: Synaptic activity andfunctional relevance in stem cell-derived neurons

    2015-01-01

    Functional synaptogenesis and network emergence aresignature endpoints of neurogenesis. These behaviorsprovide higher-order confirmation that biochemicaland cellular processes necessary for neurotransmitterrelease, post-synaptic detection and network propagation of neuronal activity have been properly expressed andcoordinated among cells. The development of synapticneurotransmission can therefore be considered a definingproperty of neurons. Although dissociated primaryneuron cultures readily form functioning synapsesand network behaviors in vitro , continuously culturedneurogenic cell lines have historically failed to meet thesecriteria. Therefore, in vitro -derived neuron models thatdevelop synaptic transmission are critically needed for awide array of studies, including molecular neuroscience,developmental neurogenesis, disease research andneurotoxicology. Over the last decade, neurons derivedfrom various stem cell lines have shown varying ability todevelop into functionally mature neurons. In this review,we will discuss the neurogenic potential of various stemcells populations, addressing strengths and weaknessesof each, with particular attention to the emergenceof functional behaviors. We will propose methods tofunctionally characterize new stem cell-derived neuron(SCN) platforms to improve their reliability as physiologicalrelevant models. Finally, we will review howsynaptically active SCNs can be applied to accelerateresearch in a variety of areas. Ultimately, emphasizingthe critical importance of synaptic activity and networkresponses as a marker of neuronal maturation is anticipatedto result in in vitro findings that better translateto efficacious clinical treatments.

  20. Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.

    Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

    2016-06-15

    Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26790349

  1. Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states

    Stephens Robert L

    2005-10-01

    Full Text Available Abstract Glutamate is a neurotransmitter critical for spinal excitatory synaptic transmission and for generation and maintenance of spinal states of pain hypersensitivity via activation of glutamate receptors. Understanding the regulation of synaptically and non-synaptically released glutamate associated with pathological pain is important in exploring novel molecular mechanisms and developing therapeutic strategies of pathological pain. The glutamate transporter system is the primary mechanism for the inactivation of synaptically released glutamate and the maintenance of glutamate homeostasis. Recent studies demonstrated that spinal glutamate transporter inhibition relieved pathological pain, suggesting that the spinal glutamate transporter might serve as a therapeutic target for treatment of pathological pain. However, the exact function of glutamate transporter in pathological pain is not completely understood. This report will review the evidence for the role of the spinal glutamate transporter during normal sensory transmission and pathological pain conditions and discuss potential mechanisms by which spinal glutamate transporter is involved in pathological pain.

  2. Modelling bidirectional modulations in synaptic plasticity: A biochemical pathway model to understand the emergence of long term potentiation (LTP) and long term depression (LTD).

    He, Yao; Kulasiri, Don; Samarasinghe, Sandhya

    2016-08-21

    Synaptic plasticity induces bidirectional modulations of the postsynaptic response following a synaptic transmission. The long term forms of synaptic plasticity, named long term potentiation (LTP) and long term depression (LTD), are critical for the antithetic functions of the memory system, memory formation and removal, respectively. A common Ca(2+) signalling upstream triggers both LTP and LTD, and the critical proteins and factors coordinating the LTP/LTD inductions are not well understood. We develop an integrated model based on the sub-models of the indispensable synaptic proteins in the emergence of synaptic plasticity to validate and understand their potential roles in the expression of synaptic plasticity. The model explains Ca(2+)/calmodulin (CaM) complex dependent coordination of LTP/LTD expressions by the interactions among the indispensable proteins using the experimentally estimated kinetic parameters. Analysis of the integrated model provides us with insights into the effective timescales of the key proteins and we conclude that the CaM pool size is critical for the coordination between LTP/LTD expressions. PMID:27185535

  3. Synaptic Democracy and Vesicular Transport in Axons

    Bressloff, Paul C.; Levien, Ethan

    2015-04-01

    Synaptic democracy concerns the general problem of how regions of an axon or dendrite far from the cell body (soma) of a neuron can play an effective role in neuronal function. For example, stimulated synapses far from the soma are unlikely to influence the firing of a neuron unless some sort of active dendritic processing occurs. Analogously, the motor-driven transport of newly synthesized proteins from the soma to presynaptic targets along the axon tends to favor the delivery of resources to proximal synapses. Both of these phenomena reflect fundamental limitations of transport processes based on a localized source. In this Letter, we show that a more democratic distribution of proteins along an axon can be achieved by making the transport process less efficient. This involves two components: bidirectional or "stop-and-go" motor transport (which can be modeled in terms of advection-diffusion), and reversible interactions between motor-cargo complexes and synaptic targets. Both of these features have recently been observed experimentally. Our model suggests that, just as in human societies, there needs to be a balance between "efficiency" and "equality".

  4. Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer.

    Ou, Jingxing; Vijayasarathy, Camasamudram; Ziccardi, Lucia; Chen, Shan; Zeng, Yong; Marangoni, Dario; Pope, Jodie G; Bush, Ronald A; Wu, Zhijian; Li, Wei; Sieving, Paul A

    2015-07-01

    Strategies aimed at invoking synaptic plasticity have therapeutic potential for several neurological conditions. The human retinal synaptic disease X-linked retinoschisis (XLRS) is characterized by impaired visual signal transmission through the retina and progressive visual acuity loss, and mice lacking retinoschisin (RS1) recapitulate human disease. Here, we demonstrate that restoration of RS1 via retina-specific delivery of adeno-associated virus type 8-RS1 (AAV8-RS1) vector rescues molecular pathology at the photoreceptor-depolarizing bipolar cell (photoreceptor-DBC) synapse and restores function in adult Rs1-KO animals. Initial development of the photoreceptor-DBC synapse was normal in the Rs1-KO retina; however, the metabotropic glutamate receptor 6/transient receptor potential melastatin subfamily M member 1-signaling (mGluR6/TRPM1-signaling) cascade was not properly maintained. Specifically, the TRPM1 channel and G proteins Gαo, Gβ5, and RGS11 were progressively lost from postsynaptic DBC dendritic tips, whereas the mGluR6 receptor and RGS7 maintained proper synaptic position. This postsynaptic disruption differed from other murine night-blindness models with an electronegative electroretinogram response, which is also characteristic of murine and human XLRS disease. Upon AAV8-RS1 gene transfer to the retina of adult XLRS mice, TRPM1 and the signaling molecules returned to their proper dendritic tip location, and the DBC resting membrane potential was restored. These findings provide insight into the molecular plasticity of a critical synapse in the visual system and demonstrate potential therapeutic avenues for some diseases involving synaptic pathology. PMID:26098217

  5. The NG2 Protein Is Not Required for Glutamatergic Neuron-NG2 Cell Synaptic Signaling.

    Passlick, Stefan; Trotter, Jacqueline; Seifert, Gerald; Steinhäuser, Christian; Jabs, Ronald

    2016-01-01

    NG2 glial cells (as from now NG2 cells) are unique in receiving synaptic input from neurons. However, the components regulating formation and maintenance of these neuron-glia synapses remain elusive. The transmembrane protein NG2 has been considered a potential mediator of synapse formation and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) clustering, because it contains 2 extracellular Laminin G/Neurexin/Sex Hormone-Binding Globulin domains, which in neurons are crucial for formation of transsynaptic neuroligin-neurexin complexes. NG2 is connected via Glutamate Receptor-Interacting Protein with GluA2/3-containing AMPARs, thereby possibly mediating receptor clustering in glial postsynaptic density. To elucidate the role of NG2 in neuron-glia communication, we investigated glutamatergic synaptic transmission in juvenile and aged hippocampal NG2 cells of heterozygous and homozygous NG2 knockout mice. Neuron-NG2 cell synapses readily formed in the absence of NG2. Short-term plasticity, synaptic connectivity, postsynaptic AMPAR current kinetics, and density were not affected by NG2 deletion. During development, an NG2-independent acceleration of AMPAR current kinetics and decreased synaptic connectivity were observed. Our results indicate that the lack of NG2 does not interfere with genesis and basic properties of neuron-glia synapses. In addition, we demonstrate frequent expression of neuroligins 1-3 in juvenile and aged NG2 cells, suggesting a role of these molecules in synapse formation between NG2 glia and neurons. PMID:25100858

  6. Long-term modifications of synaptic efficacy in the human inferior and middle temporal cortex

    Chen, W. R.; Lee, S.; Kato, K.; Spencer, D. D.; Shepherd, G. M.; Williamson, A.

    1996-01-01

    The primate temporal cortex has been demonstrated to play an important role in visual memory and pattern recognition. It is of particular interest to investigate whether activity-dependent modification of synaptic efficacy, a presumptive mechanism for learning and memory, is present in this cortical region. Here we address this issue by examining the induction of synaptic plasticity in surgically resected human inferior and middle temporal cortex. The results show that synaptic strength in the human temporal cortex could undergo bidirectional modifications, depending on the pattern of conditioning stimulation. High frequency stimulation (100 or 40 Hz) in layer IV induced long-term potentiation (LTP) of both intracellular excitatory postsynaptic potentials and evoked field potentials in layers II/III. The LTP induced by 100 Hz tetanus was blocked by 50-100 microM DL-2-amino-5-phosphonovaleric acid, suggesting that N-methyl-D-aspartate receptors were responsible for its induction. Long-term depression (LTD) was elicited by prolonged low frequency stimulation (1 Hz, 15 min). It was reduced, but not completely blocked, by DL-2-amino-5-phosphonovaleric acid, implying that some other mechanisms in addition to N-methyl-DL-aspartate receptors were involved in LTD induction. LTD was input-specific, i.e., low frequency stimulation of one pathway produced LTD of synaptic transmission in that pathway only. Finally, the LTP and LTD could reverse each other, suggesting that they can act cooperatively to modify the functional state of cortical network. These results suggest that LTP and LTD are possible mechanisms for the visual memory and pattern recognition functions performed in the human temporal cortex.

  7. Mechanisms and consequences of paternally transmitted chromosomal abnormalities

    Marchetti, F; Wyrobek, A J

    2005-04-05

    Paternally transmitted chromosomal damage has been associated with pregnancy loss, developmental and morphological defects, infant mortality, infertility, and genetic diseases in the offspring including cancer. There is epidemiological evidence linking paternal exposure to occupational or environmental agents with an increased risk of abnormal reproductive outcomes. There is also a large body of literature on germ cell mutagenesis in rodents showing that treatment of male germ cells with mutagens has dramatic consequences on reproduction producing effects such as those observed in human epidemiological studies. However, we know very little about the etiology, transmission and early embryonic consequences of paternally-derived chromosomal abnormalities. The available evidence suggests that: (1) there are distinct patterns of germ cell-stage differences in the sensitivity of induction of transmissible genetic damage with male postmeiotic cells being the most sensitive; (2) cytogenetic abnormalities at first metaphase after fertilization are critical intermediates between paternal exposure and abnormal reproductive outcomes; and, (3) there are maternally susceptibility factors that may have profound effects on the amount of sperm DNA damage that is converted into chromosomal aberrations in the zygote and directly affect the risk for abnormal reproductive outcomes.

  8. S-SCAM/MAGI-2 is an essential synaptic scaffolding molecule for the GluA2-containing maintenance pool of AMPA receptors.

    Danielson, Eric; Zhang, Nanyan; Metallo, Jacob; Kaleka, Kanwardeep; Shin, Seung Min; Gerges, Nashaat; Lee, Sang H

    2012-05-16

    Synaptic plasticity, the cellular basis of learning and memory, involves the dynamic trafficking of AMPA receptors (AMPARs) into and out of synapses. One of the remaining key unanswered aspects of AMPAR trafficking is the mechanism by which synaptic strength is preserved despite protein turnover. In particular, the identity of AMPAR scaffolding molecule(s) involved in the maintenance of GluA2-containing AMPARs is completely unknown. Here we report that the synaptic scaffolding molecule (S-SCAM; also called membrane-associated guanylate kinase inverted-2 and atrophin interacting protein-1) plays the critical role of maintaining synaptic strength. Increasing S-SCAM levels in rat hippocampal neurons led to specific increases in the surface AMPAR levels, enhanced AMPAR-mediated synaptic transmission, and enlargement of dendritic spines, without significantly effecting GluN levels or NMDA receptor (NMDAR) EPSC. Conversely, decreasing S-SCAM levels by RNA interference-mediated knockdown caused the loss of synaptic AMPARs, which was followed by a severe reduction in the dendritic spine density. Importantly, S-SCAM regulated synaptic AMPAR levels in a manner, dependent on GluA2 not GluA1, sensitive to N-ethylmaleimide-sensitive fusion protein interaction, and independent of activity. Further, S-SCAM increased surface AMPAR levels in the absence of PSD-95, while PSD-95 was dependent on S-SCAM to increase surface AMPAR levels. Finally, S-SCAM overexpression hampered NMDA-induced internalization of AMPARs and prevented the induction of long term-depression, while S-SCAM knockdown did not. Together, these results suggest that S-SCAM is an essential AMPAR scaffolding molecule for the GluA2-containing pool of AMPARs, which are involved in the constitutive pathway of maintaining synaptic strength. PMID:22593065

  9. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders

    Ryan M Smith; Wolfgang eSadee

    2011-01-01

    Interactions between presynaptic and postsynaptic cellular adhesion molecules drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of cellular adhesion molecule RNAs, which ultimately determines neurotransmitter phenotype. The diverse assortment of RNAs produced by alternative splicing generates countless protein isoforms necessary for guiding specialized cell-to-cell connectivity. Failure to generate the appropriate synaptic ...

  10. Synaptic Tagging, Evaluation of Memories, and the Distal Reward Problem

    Papper, Marc; Kempter, Richard; Leibold, Christian

    2011-01-01

    Long-term synaptic plasticity exhibits distinct phases. The synaptic tagging hypothesis suggests an early phase in which synapses are prepared, or "tagged," for protein capture, and a late phase in which those proteins are integrated into the synapses to achieve memory consolidation. The synapse specificity of the tags is consistent with…

  11. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

    Huib Mansvelder

    2015-01-01

    Full Text Available Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review highlights the synaptic modifications that are induced by in vivo exposure to addictive drugs and describes how these drug-induced synaptic changes may contribute to the different components of addictive behaviour, such as compulsive drug use despite negative consequences and relapse. Initially, exposure to an addictive drug induces synaptic changes in the ventral tegmental area (VTA. This drug-induced synaptic potentiation in the VTA subsequently triggers synaptic changes in downstream areas of the mesocorticolimbic system, such as the nucleus accumbens (NAc and the prefrontal cortex (PFC, with further drug exposure. These glutamatergic synaptic alterations are then thought to mediate many of the behavioural symptoms that characterize addiction. The later stages of glutamatergic synaptic plasticity in the NAc and in particular in the PFC play a role in maintaining addiction and drive relapse to drug-taking induced by drug-associated cues. Remodelling of PFC glutamatergic circuits can persist into adulthood, causing a lasting vulnerability to relapse. We will discuss how these neurobiological changes produced by drugs of abuse may provide novel targets for potential treatment strategies for addiction.

  12. Synaptic Signaling and Aberrant RNA Splicing in Autism Spectrum Disorders

    Smith, Ryan M; Sadee, Wolfgang

    2011-01-01

    Interactions between presynaptic and postsynaptic cellular adhesion molecules (CAMs) drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of CAM RNAs, which ultimately determines neurotransmitter phenotype. The diverse assortment of RNAs produced by alternative splicing generates countless protein isoforms necessary for guiding specialized cell-to-cell connectivity. Failure to generate the appropriate synaptic adhesion proteins i...

  13. The Ubiquitin-Proteasome Pathway and Synaptic Plasticity

    Hegde, Ashok N.

    2010-01-01

    Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for…

  14. Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer's Disease

    Bales, Kelly R.; Plath, Niels; Svenstrup, Niels; Menniti, Frank S.

    Alzheimer's Disease (AD) is a disease of synaptic dysfunction that ultimately proceeds to neuronal death. There is a wealth of evidence that indicates the final common mediator of this neurotoxic process is the formation and actions on synaptotoxic b-amyloid (Aβ). The premise in this review is that synaptic dysfunction may also be an initiating factor in for AD and promote synaptotoxic Aβ formation. This latter hypothesis is consistent with the fact that the most common risk factors for AD, apolipoprotein E (ApoE) allele status, age, education, and fitness, encompass suboptimal synaptic function. Thus, the synaptic dysfunction in AD may be both cause and effect, and remediating synaptic dysfunction in AD may have acute effects on the symptoms present at the initiation of therapy and also slow disease progression. The cyclic nucleotide (cAMP and cGMP) signaling systems are intimately involved in the regulation of synaptic homeostasis. The phosphodiesterases (PDEs) are a superfamily of enzymes that critically regulate spatial and temporal aspects of cyclic nucleotide signaling through metabolic inactivation of cAMP and cGMP. Thus, targeting the PDEs to promote improved synaptic function, or 'synaptic resilience', may be an effective and facile approach to new symptomatic and disease modifying therapies for AD. There continues to be a significant drug discovery effort aimed at discovering PDE inhibitors to treat a variety of neuropsychiatric disorders. Here we review the current status of those efforts as they relate to potential new therapies for AD.

  15. Nicotinic mechanisms influencing synaptic plasticity in the hippocampus

    Andon Nicholas PLACZEK; Tao A ZHANG; John Anthony DANI

    2009-01-01

    Nicotinic acetylcholine receptors (nAChRs) are expressed throughout the hippocampus, and nicotinic signaling plays an important role in neuronal function. In the context of learning and memory related behaviors associated with hippocampal function, a potentially significant feature of nAChR activity is the impact it has on synaptic plasticity. Synaptic plasticity in hippocampal neurons has long been considered a contributing cellular mechanism of learning and memory. These same kinds of cellular mechanisms are a factor in the development of nicotine addiction. Nicotinic signaling has been demonstrated by in vitro studies to affect synaptic plasticity in hippocampal neurons via multiple steps, and the signaling has also been shown to evoke synaptic plasticity in vivo. This review focuses on the nAChRs subtypes that contribute to hippocampal synaptic plasticity at the cellular and circuit level. It also considers nicotinic influences over long-term changes in the hippocampus that may contribute to addiction.

  16. Synaptic pathology: A shared mechanism in neurological disease.

    Henstridge, Christopher M; Pickett, Eleanor; Spires-Jones, Tara L

    2016-07-01

    Synaptic proteomes have evolved a rich and complex diversity to allow the exquisite control of neuronal communication and information transfer. It is therefore not surprising that many neurological disorders are associated with alterations in synaptic function. As technology has advanced, our ability to study the anatomical and physiological function of synapses in greater detail has revealed a critical role for both central and peripheral synapses in neurodegenerative disease. Synapse loss has a devastating effect on cellular communication, leading to wide ranging effects such as network disruption within central neural systems and muscle wastage in the periphery. These devastating effects link synaptic pathology to a diverse range of neurological disorders, spanning Alzheimer's disease to multiple sclerosis. This review will highlight some of the current literature on synaptic integrity in animal models of disease and human post-mortem studies. Synaptic changes in normal brain ageing will also be discussed and finally the current and prospective treatments for neurodegenerative disorders will be summarised. PMID:27108053

  17. Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle.

    Wilfredo Blanco

    2015-05-01

    Full Text Available Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS followed by a rebound during rapid-eye-movement sleep (REM. The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes

  18. Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle.

    Blanco, Wilfredo; Pereira, Catia M; Cota, Vinicius R; Souza, Annie C; Rennó-Costa, César; Santos, Sharlene; Dias, Gabriella; Guerreiro, Ana M G; Tort, Adriano B L; Neto, Adrião D; Ribeiro, Sidarta

    2015-05-01

    Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic

  19. Skin - abnormally dark or light

    ... ency/article/003242.htm Skin - abnormally dark or light To use the sharing features on this page, ... the hands. The bronze color can range from light to dark (in fair-skinned people) with the ...

  20. Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

    Ferron, Laurent; Nieto-Rostro, Manuela; Cassidy, John S.; Dolphin, Annette C.

    2014-04-01

    Fragile X syndrome (FXS), the most common heritable form of mental retardation, is characterized by synaptic dysfunction. Synaptic transmission depends critically on presynaptic calcium entry via voltage-gated calcium (CaV) channels. Here we show that the functional expression of neuronal N-type CaV channels (CaV2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases CaV channel density in somata and in presynaptic terminals. We then show that FMRP controls CaV2.2 surface expression by targeting the channels to the proteasome for degradation. The interaction between FMRP and CaV2.2 occurs between the carboxy-terminal domain of FMRP and domains of CaV2.2 known to interact with the neurotransmitter release machinery. Finally, we show that FMRP controls synaptic exocytosis via CaV2.2 channels. Our data indicate that FMRP is a potent regulator of presynaptic activity, and its loss is likely to contribute to synaptic dysfunction in FXS.

  1. Vesicular glutamate transporter 1 orchestrates recruitment of other synaptic vesicle cargo proteins during synaptic vesicle recycling.

    Pan, Ping-Yue; Marrs, Julia; Ryan, Timothy A

    2015-09-11

    A long standing question in synaptic physiology is how neurotransmitter-filled vesicles are rebuilt after exocytosis. Among the first steps in this process is the endocytic retrieval of the transmembrane proteins that are enriched in synaptic vesicles (SVs). At least six types of transmembrane proteins must be recovered, but the rules for how this multiple cargo selection is accomplished are poorly understood. Among these SV cargos is the vesicular glutamate transporter (vGlut). We show here that vGlut1 has a strong influence on the kinetics of retrieval of half of the known SV cargos and that specifically impairing the endocytosis of vGlut1 in turn slows down other SV cargos, demonstrating that cargo retrieval is a collective cargo-driven process. Finally, we demonstrate that different cargos can be retrieved in the same synapse with different kinetics, suggesting that additional post-endocytic sorting steps likely occur in the nerve terminal. PMID:26224632

  2. Minocycline enhances inhibitory transmission to substantia gelatinosa neurons of the rat spinal dorsal horn.

    Peng, H-Z; Ma, L-X; Lv, M-H; Hu, T; Liu, T

    2016-04-01

    Minocycline, a second-generation tetracycline, is well known for its antibiotic, anti-inflammatory, and antinociceptive effects. Modulation of synaptic transmission is one of the analgesic mechanisms of minocycline. Although it has been reported that minocycline may suppress excitatory glutamatergic synaptic transmission, it remains unclear whether it could affect inhibitory synaptic transmission, which also plays a key role in modulating pain signaling. To examine the effect of minocycline on synaptic transmission in rat spinal substantia gelatinosa (SG) neurons, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) using whole-cell patch-clamp recording at a holding potential of 0 mV. Bath application of minocycline significantly increased the frequency but not the amplitude of sIPSCs in a reversible and concentration-dependent manner with an EC50 of 85. The enhancement of inhibitory synaptic transmission produced by minocycline was not affected by the glutamate receptor antagonists CNQX and D-APV or by the voltage-gated sodium channel blocker tetrodotoxin (TTX). Moreover, the potency of minocycline for facilitating sIPSC frequency was the same in both glycinergic and GABAergic sIPSCs without changing their decay phases. However, the facilitatory effect of minocycline on sIPSCs was eliminated in a Ca(2+)-free Krebs solution or by co-administration with calcium channel blockers. In summary, our data demonstrate that baseline inhibitory synaptic transmission in SG neurons is markedly enhanced by minocycline. This may function to decrease the excitability of SG neurons, thus leading to a modulation of nociceptive transmission. PMID:26826332

  3. Impaired synaptic plasticity in the prefrontal cortex of mice with developmentally decreased number of interneurons.

    Konstantoudaki, X; Chalkiadaki, K; Tivodar, S; Karagogeos, D; Sidiropoulou, K

    2016-05-13

    Interneurons are inhibitory neurons, which protect neural tissue from excessive excitation. They are interconnected with glutamatergic pyramidal neurons in the cerebral cortex and regulate their function. Particularly in the prefrontal cortex (PFC), interneurons have been strongly implicated in regulating pathological states which display deficits in the PFC. The aim of this study is to investigate the adaptations in the adult glutamatergic system, when defects in interneuron development do not allow adequate numbers of interneurons to reach the cerebral cortex. To this end, we used a mouse model that displays ∼50% fewer cortical interneurons due to the Rac1 protein loss from Nkx2.1/Cre expressing cells (Rac1 conditional knockout (cKO) mice), to examine how the developmental loss of interneurons may affect basal synaptic transmission, synaptic plasticity and neuronal morphology in the adult PFC. Despite the decrease in the number of interneurons, basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks, is not altered in the PFC of Rac1 cKO mice. However, there is decreased paired-pulse ratio (PPR) and decreased long-term potentiation (LTP), in response to tetanic stimulation, in the layer II PFC synapses of Rac1 cKO mice. Furthermore, expression of N-methyl-d-aspartate (NMDA) subunits is decreased and dendritic morphology is altered, changes that could underlie the decrease in LTP in the Rac1 cKO mice. Finally, we find that treating Rac1 cKO mice with diazepam in early postnatal life can reverse changes in dendritic morphology observed in non-treated Rac1 cKO mice. Therefore, our data show that disruption in GABAergic inhibition alters glutamatergic function in the adult PFC, an effect that could be reversed by enhancement of GABAergic function during an early postnatal period. PMID:26926965

  4. Synaptic reverberation underlying mnemonic persistent activity.

    Wang, X J

    2001-08-01

    Stimulus-specific persistent neural activity is the neural process underlying active (working) memory. Since its discovery 30 years ago, mnemonic activity has been hypothesized to be sustained by synaptic reverberation in a recurrent circuit. Recently, experimental and modeling work has begun to test the reverberation hypothesis at the cellular level. Moreover, theory has been developed to describe memory storage of an analog stimulus (such as spatial location or eye position), in terms of continuous 'bump attractors' and 'line attractors'. This review summarizes new studies, and discusses insights and predictions from biophysically based models. The stability of a working memory network is recognized as a serious problem; stability can be achieved if reverberation is largely mediated by NMDA receptors at recurrent synapses. PMID:11476885

  5. Alzheimer's disease: synaptic dysfunction and Abeta

    Shankar, Ganesh M

    2009-11-23

    Abstract Synapse loss is an early and invariant feature of Alzheimer\\'s disease (AD) and there is a strong correlation between the extent of synapse loss and the severity of dementia. Accordingly, it has been proposed that synapse loss underlies the memory impairment evident in the early phase of AD and that since plasticity is important for neuronal viability, persistent disruption of plasticity may account for the frank cell loss typical of later phases of the disease. Extensive multi-disciplinary research has implicated the amyloid β-protein (Aβ) in the aetiology of AD and here we review the evidence that non-fibrillar soluble forms of Aβ are mediators of synaptic compromise. We also discuss the possible mechanisms of Aβ synaptotoxicity and potential targets for therapeutic intervention.

  6. Elimination of redundant synaptic inputs in the absence of synaptic strengthening

    Wang, Hao; Liu, Hong; Zhang, Zhong-wei

    2011-01-01

    Synaptic refinement, a developmental process that consists of selective elimination and strengthening of immature synapses, is essential for the formation of precise neuronal circuits and proper brain function. At glutamatergic synapses in the brain, activity-dependent recruitment of AMPA receptors (AMPAR) is a key mechanism underlying the strengthening of immature synapses. Studies using receptor over-expression have shown that the recruitment of AMPARs is subunit specific. With the notable ...

  7. Synaptic variability in a cortical neuromorphic circuit.

    Mahvash, Mohammad; Parker, Alice C

    2013-03-01

    Variable behavior has been observed in several mechanisms found in biological neurons, resulting in changes in neural behavior that might be useful to capture in neuromorphic circuits. This paper presents a neuromorphic cortical neuron with synaptic neurotransmitter-release variability, which is designed to be used in neural networks as part of the Biomimetic Real-Time Cortex project. This neuron has been designed and simulated using carbon nanotube (CNT) transistors, which is one of several nanotechnologies under consideration to meet the challenges of scale presented by the cortex. Some research results suggest that some instances of variability are stochastic, while others indicate that some instances of variability are chaotic. In this paper, both possible sources of variability are considered by embedding either Gaussian noise or a chaotic signal into the neuromorphic or synaptic circuit and observing the simulation results. In order to embed chaotic behavior into the neuromorphic circuit, a chaotic signal generator circuit is presented, implemented with CNT transistors that could be embedded in the electronic neural circuit, and simulated using CNT SPICE models. The circuit uses a chaotic piecewise linear 1-D map implemented by switched-current circuits. The simulation results presented in this paper illustrate that neurotransmitter-release variability plays a beneficial role in the reliability of spike generation. In an examination of this reliability, the precision of spike timing in the CNT circuit simulations is found to be dependent on stimulus (postsynaptic potential) transients. Postsynaptic potentials with low neurotransmitter release variability or without neurotransmitter release variability produce imprecise spike trains, whereas postsynaptic potentials with high neurotransmitter-release variability produce spike trains with reproducible timing. PMID:24808313

  8. Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice

    Ardiles, Alvaro O.; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M.; Palacios, Adrian G.; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C.; Martínez, Agustín D.

    2014-01-01

    The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory. PMID:25360084

  9. Memetics clarification of abnormal behavior

    2007-01-01

    AIM: Biological medicine is hard to fully and scientifically explain the etiological factor and pathogenesis of abnormal behaviors; while, researches on philosophy and psychology (including memetics) are beneficial to better understand and explain etiological factor and pathogenesis of abnormal behaviors. At present, the theory of philosophy and psychology is to investigate the entity of abnormal behavior based on the views of memetics.METHODS: Abnormal behavior was researched in this study based on three aspects, including instinctive behavior disorder, poorly social-adapted behavior disorder and mental or body disease associated behavior disorder. Most main viewpoints of memetics were derived from "The Meme Machine", which was written by Susan Blackmore. When questions about abnormal behaviors induced by mental and psychological diseases and conduct disorder of teenagers were discussed, some researching achievements which were summarized by authors previously were added in this study, such as aggressive behaviors, pathologically aggressive behaviors, etc.RESULTS: The abnormal behaviors mainly referred to a part of people's substandard behaviors which were not according with the realistic social environment, culture background and the pathologic behaviors resulted from people's various psychological diseases. According to the theory of "meme", it demonstrated that the relevant behavioral obstacles of various psychological diseases, for example, the unusual behavior of schizophrenia, were caused, because the old meme was destroyed thoroughly but the new meme was unable to establish; psychoneurosis and personality disorder were resulted in hard establishment of meme; the behavioral obstacles which were ill-adapted to society, for example, various additional and homosexual behaviors, were because of the selfish replications and imitations of "additional meme" and "homosexual meme"; various instinct behavioral and congenital intelligent obstacles were not significance

  10. Overelaborated synaptic architecture and reduced synaptomatrix glycosylation in a Drosophila classic galactosemia disease model.

    Jumbo-Lucioni, Patricia; Parkinson, William; Broadie, Kendal

    2014-12-01

    Classic galactosemia (CG) is an autosomal recessive disorder resulting from loss of galactose-1-phosphate uridyltransferase (GALT), which catalyzes conversion of galactose-1-phosphate and uridine diphosphate (UDP)-glucose to glucose-1-phosphate and UDP-galactose, immediately upstream of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine synthesis. These four UDP-sugars are essential donors for driving the synthesis of glycoproteins and glycolipids, which heavily decorate cell surfaces and extracellular spaces. In addition to acute, potentially lethal neonatal symptoms, maturing individuals with CG develop striking neurodevelopmental, motor and cognitive impairments. Previous studies suggest that neurological symptoms are associated with glycosylation defects, with CG recently being described as a congenital disorder of glycosylation (CDG), showing defects in both N- and O-linked glycans. Here, we characterize behavioral traits, synaptic development and glycosylated synaptomatrix formation in a GALT-deficient Drosophila disease model. Loss of Drosophila GALT (dGALT) greatly impairs coordinated movement and results in structural overelaboration and architectural abnormalities at the neuromuscular junction (NMJ). Dietary galactose and mutation of galactokinase (dGALK) or UDP-glucose dehydrogenase (sugarless) genes are identified, respectively, as critical environmental and genetic modifiers of behavioral and cellular defects. Assaying the NMJ extracellular synaptomatrix with a broad panel of lectin probes reveals profound alterations in dGALT mutants, including depletion of galactosyl, N-acetylgalactosamine and fucosylated horseradish peroxidase (HRP) moieties, which are differentially corrected by dGALK co-removal and sugarless overexpression. Synaptogenesis relies on trans-synaptic signals modulated by this synaptomatrix carbohydrate environment, and dGALT-null NMJs display striking changes in heparan sulfate proteoglycan (HSPG) co-receptor and Wnt ligand levels

  11. Overelaborated synaptic architecture and reduced synaptomatrix glycosylation in a Drosophila classic galactosemia disease model

    Patricia Jumbo-Lucioni

    2014-12-01

    Full Text Available Classic galactosemia (CG is an autosomal recessive disorder resulting from loss of galactose-1-phosphate uridyltransferase (GALT, which catalyzes conversion of galactose-1-phosphate and uridine diphosphate (UDP-glucose to glucose-1-phosphate and UDP-galactose, immediately upstream of UDP–N-acetylgalactosamine and UDP–N-acetylglucosamine synthesis. These four UDP-sugars are essential donors for driving the synthesis of glycoproteins and glycolipids, which heavily decorate cell surfaces and extracellular spaces. In addition to acute, potentially lethal neonatal symptoms, maturing individuals with CG develop striking neurodevelopmental, motor and cognitive impairments. Previous studies suggest that neurological symptoms are associated with glycosylation defects, with CG recently being described as a congenital disorder of glycosylation (CDG, showing defects in both N- and O-linked glycans. Here, we characterize behavioral traits, synaptic development and glycosylated synaptomatrix formation in a GALT-deficient Drosophila disease model. Loss of Drosophila GALT (dGALT greatly impairs coordinated movement and results in structural overelaboration and architectural abnormalities at the neuromuscular junction (NMJ. Dietary galactose and mutation of galactokinase (dGALK or UDP-glucose dehydrogenase (sugarless genes are identified, respectively, as critical environmental and genetic modifiers of behavioral and cellular defects. Assaying the NMJ extracellular synaptomatrix with a broad panel of lectin probes reveals profound alterations in dGALT mutants, including depletion of galactosyl, N-acetylgalactosamine and fucosylated horseradish peroxidase (HRP moieties, which are differentially corrected by dGALK co-removal and sugarless overexpression. Synaptogenesis relies on trans-synaptic signals modulated by this synaptomatrix carbohydrate environment, and dGALT-null NMJs display striking changes in heparan sulfate proteoglycan (HSPG co-receptor and Wnt

  12. HIV Transmission

    ... Abroad Treatment Basic Statistics Get Tested Find an HIV testing site near you. Enter ZIP code or city Follow HIV/AIDS CDC HIV CDC HIV/AIDS See RSS | ... on HIV Syndicated Content Website Feedback HIV/AIDS HIV Transmission Language: English Español (Spanish) Recommend on Facebook ...

  13. Thyroid abnormality in perimenopausal women with abnormal uterine bleeding

    Prasanna Byna

    2015-11-01

    Full Text Available Background: AUB is a common but complicated clinical presentation and occurs in 15-20% of women between menarche to menopause and significantly affects the women's health. Women with thyroid dysfunction often have menstrual irregularities, infertility and increased morbidity during pregnancy. The objective of present study is to find the correlation between thyroid disorders and AUB in perimenopausal women attending gynecology OPD. Methods: In the present study, fifty five patients with AUB were included and were evaluated for the cause including thyroid abnormality. Thyroid function tests were done in all patients. Results: Among 55 patients, 12 patients were diagnosed as hypothyroidism and 7 as hyperthyroidism, women with AUB 36 (65.4% were euthyroid. Among 19 women with thyroid abnormality, heavy menstrual bleeding was seen in 8 (42% women, 6 (31.57% had polymenorrhagia, 5 (26.31% had oligomenorrhoea. The frequent menstrual abnormality in women with hypothyroidism (12 women was heavy menstrual bleeding in 5 (41.6% women, 3 (25% had oligomennorhoea, 4 (33.3% had polymenorrhagia. Out of 7 women with hyperthyroidism, 2 (28.57% had oligomenorrhoea, 3 (42.8% had heavy menstrual bleeding, 2 (28.57% had polymenorrhagia. In a total of 55 patients with AUB, 11 (20% had structural abnormalities in uterus and ovaries. 5 (9% had adenomyosis, 3 (5.4% had ovarian cysts, 3 (5.4% had fibroids. Conclusions: It is important to screen all women for thyroid abnormality who are presenting with AUB especially with non-structural causes of AUB. Correction of thyroid abnormalities also relieves AUB. This will avoid unnecessary hormonal treatment and surgery. [Int J Res Med Sci 2015; 3(11.000: 3250-3253

  14. A Voltage Mode Memristor Bridge Synaptic Circuit with Memristor Emulators

    Leon Chua

    2012-03-01

    Full Text Available A memristor bridge neural circuit which is able to perform signed synaptic weighting was proposed in our previous study, where the synaptic operation was verified via software simulation of the mathematical model of the HP memristor. This study is an extension of the previous work advancing toward the circuit implementation where the architecture of the memristor bridge synapse is built with memristor emulator circuits. In addition, a simple neural network which performs both synaptic weighting and summation is built by combining memristor emulators-based synapses and differential amplifier circuits. The feasibility of the memristor bridge neural circuit is verified via SPICE simulations.

  15. Spikes Synchronization in Neural Networks with Synaptic Plasticity

    Borges, Rafael R; Batista, Antonio M; Caldas, Iberê L; Borges, Fernando S; Lameu, Ewandson L

    2015-01-01

    In this paper, we investigated the neural spikes synchronisation in a neural network with synaptic plasticity and external perturbation. In the simulations the neural dynamics is described by the Hodgkin Huxley model considering chemical synapses (excitatory) among neurons. According to neural spikes synchronisation is expected that a perturbation produce non synchronised regimes. However, in the literature there are works showing that the combination of synaptic plasticity and external perturbation may generate synchronised regime. This article describes the effect of the synaptic plasticity on the synchronisation, where we consider a perturbation with a uniform distribution. This study is relevant to researches of neural disorders control.

  16. Abnormal Cervical Cancer Screening Test Results

    ... AQ FREQUENTLY ASKED QUESTIONS FAQ187 GYNECOLOGIC PROBLEMS Abnormal Cervical Cancer Screening Test Results • What is cervical cancer screening? • What causes abnormal cervical cancer screening test ...

  17. Ribbon Synaptic Plasticity in Gravity Sensors of Rats Flown on Neurolab

    Ross, Muriel D.; Varelas, Joseph

    2003-01-01

    Previous spaceflight experiments (Space Life Sciences-1 and -2 (SLS-1 and SLS-2)) first demonstrated the extraordinary ability of gravity sensor hair cells to change the number, kind, and distribution of connections (synapses) they make to other cells while in weightlessness. The number of synapses in hair cells in one part of the inner ear (the utricle) was markedly elevated on flight day 13 (FD13) of SLS-2. Unanswered questions, however, were whether these increases in synapses occur rapidly and whether they remain stable in weightlessness. The answers have implications for long-duration human space travel. If gravity sensors can adapt quickly, crews may be able to move easily between different gravity levels, since the sensors will adapt rapidly to weightlessness on the spacecraft and then back to Earth's gravity when the mission ends. This ability to adapt is also important for recovery from balance disorders. To further our understanding of this adaptive potential (a property called neuronal synaptic plasticity), the present Neurolab research was undertaken. Our experiment examined whether: (a) increases in synapses would remain stable throughout the flight, (b) changes in the number of synapses were uniform across different portions of the gravity sensors (the utricle and saccule), and (c) synaptic changes were similar for the different types of hair cells (Type I and Type II). Utricular and saccular maculae (the gravity-sensing portions of the inner ear) were collected in flight from rats on FD2 and FD14. Samples were also collected from control rats on the ground. Tissues were prepared for ultrastructural study. Hair cells and their ribbon synapses were examined in a transmission electron microscope. Synapses were counted in all hair cells in 50 consecutive sections that crossed the striolar zone. Results indicate that utricular hair cell synapses initially increased significantly in number in both types of hair cells by FD2. Counts declined by FD14, but

  18. The Molecular Physiology of Activity-Dependent Bulk Endocytosis of Synaptic Vesicles

    Clayton, Emma L.; Cousin, Michael A.

    2010-01-01

    Central nerve terminals release neurotransmitter in response to a wide variety of stimuli. Since maintenance of neurotransmitter release is dependent on the continual supply of synaptic vesicles (SVs), nerve terminals possess an array of endocytosis modes to retrieve and recycle SV membrane and proteins. During mild stimulation conditions single SV retrieval modes such as clathrin-mediated endocytosis (CME) predominate. However during increased neuronal activity additional SV retrieval capacity is required, which is provided by activity-dependent bulk endocytosis (ADBE). ADBE is the dominant SV retrieval mechanism during elevated neuronal activity. It is a high capacity SV retrieval mode that is immediately triggered during such stimulation conditions. This review will summarise the current knowledge regarding the molecular mechanism of ADBE, including molecules required for its triggering and subsequent steps, including SV budding from bulk endosomes. The molecular relationship between ADBE and the SV reserve pool will also be discussed. It is becoming clear that an understanding of the molecular physiology of ADBE will be of critical importance in attempts to modulate both normal and abnormal synaptic function during intense neuronal activity. PMID:19765184

  19. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring.

    Buffington, Shelly A; Di Prisco, Gonzalo Viana; Auchtung, Thomas A; Ajami, Nadim J; Petrosino, Joseph F; Costa-Mattioli, Mauro

    2016-06-16

    Maternal obesity during pregnancy has been associated with increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. Here, we report that maternal high-fat diet (MHFD) induces a shift in microbial ecology that negatively impacts offspring social behavior. Social deficits and gut microbiota dysbiosis in MHFD offspring are prevented by co-housing with offspring of mothers on a regular diet (MRD) and transferable to germ-free mice. In addition, social interaction induces synaptic potentiation (LTP) in the ventral tegmental area (VTA) of MRD, but not MHFD offspring. Moreover, MHFD offspring had fewer oxytocin immunoreactive neurons in the hypothalamus. Using metagenomics and precision microbiota reconstitution, we identified a single commensal strain that corrects oxytocin levels, LTP, and social deficits in MHFD offspring. Our findings causally link maternal diet, gut microbial imbalance, VTA plasticity, and behavior and suggest that probiotic treatment may relieve specific behavioral abnormalities associated with neurodevelopmental disorders. VIDEO ABSTRACT. PMID:27315483

  20. Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex

    Joshua G.A Pinto

    2015-02-01

    Full Text Available Although many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin and found that synaptic development in human primary visual cortex continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the 4 proteins and include a stage during early development (<1 year when only Gephyrin has high inter-individual variability. We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the first year or two of life. A multidimensional analysis (principle component analysis showed that most of the variance was captured by the sum of the 4 synaptic proteins. We used that sum to compare development of human and rat visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.

  1. Neuroimaging abnormalities in Griscelli's disease

    Griscelli's disease is a rare autosomal recessive immunodeficiency syndrome. We report a 7-1/2-month-old white girl who presented with this syndrome, but initially without neurological abnormalities. Initial CT of the brain was normal. Despite haematological remission with chemotherapy, she developed neurological symptoms, progressing to coma. At this time, CT showed areas of coarse calcification in the globi pallidi, left parietal white matter and left brachium pontis. Hypodense areas were present in the genu and posterior limb of the internal capsule on the right side, as well as posterior aspects of both thalami, together with minimal generalised atrophy. MRI revealed areas of increased T2 signal and a focal area of abnormal enhancement in the subcortical white matter. Griscelli's disease should be added to the list of acquired neuroimaging abnormalities in infants. (orig.)

  2. PKA and ERK, but not PKC, in the amygdala contribute to pain-related synaptic plasticity and behavior

    Ramsey Cara

    2008-07-01

    Full Text Available Abstract The laterocapsular division of the central nucleus of the amygdala (CeLC has emerged as an important site of pain-related plasticity and pain modulation. Glutamate and neuropeptide receptors in the CeLC contribute to synaptic and behavioral changes in the arthritis pain model, but the intracellular signaling pathways remain to be determined. This study addressed the role of PKA, PKC, and ERK in the CeLC. Adult male Sprague-Dawley rats were used in all experiments. Whole-cell patch-clamp recordings of CeLC neurons were made in brain slices from normal rats and from rats with a kaolin/carrageenan-induced monoarthritis in the knee (6 h postinduction. Membrane-permeable inhibitors of PKA (KT5720, 1 μM; cAMPS-Rp, 10 μM and ERK (U0126, 1 μM activation inhibited synaptic plasticity in slices from arthritic rats but had no effect on normal transmission in control slices. A PKC inhibitor (GF109203x, 1 μM and an inactive structural analogue of U0126 (U0124, 1 μM had no effect. The NMDA receptor-mediated synaptic component was inhibited by KT5720 or U0126; their combined application had additive effects. U0126 did not inhibit synaptic facilitation by forskolin-induced PKA-activation. Administration of KT5720 (100 μM, concentration in microdialysis probe or U0126 (100 μM into the CeLC, but not striatum (placement control, inhibited audible and ultrasonic vocalizations and spinal reflexes of arthritic rats but had no effect in normal animals. GF109203x (100 μM and U0124 (100 μM did not affect pain behavior. The data suggest that in the amygdala PKA and ERK, but not PKC, contribute to pain-related synaptic facilitation and behavior by increasing NMDA receptor function through independent signaling pathways.

  3. Receptor actions of synaptically released glutamate: the role of transporters on the scale from nanometers to microns.

    Zheng, Kaiyu; Scimemi, Annalisa; Rusakov, Dmitri A

    2008-11-15

    Actions of the excitatory neurotransmitter glutamate inside and outside the synaptic cleft determine the activity of neural circuits in the brain. However, to what degree local glutamate transporters affect these actions on a submicron scale remains poorly understood. Here we focus on hippocampal area CA1, a common subject of synaptic physiology studies. First, we use a two-photon excitation technique to obtain an estimate of the apparent (macroscopic) extracellular diffusion coefficient for glutamate, approximately 0.32 mum(2)/ms. Second, we incorporate this measurement into a Monte Carlo model of the typical excitatory synapse and examine the influence of distributed glutamate transporter molecules on signal transmission. Combined with the results of whole-cell recordings, such simulations argue that, although glutamate transporters have little effect on the activation of synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, this does not rule out the occurrence of up to several dozens of transporters inside the cleft. We further evaluate how the expression pattern of transporter molecules (on the 10-100 nm scale) affects the activation of N-methyl-D-aspartic acid or metabotropic glutamate receptors in the synaptic vicinity. Finally, we extend our simulations to the macroscopic scale, estimating that synaptic activity sufficient to excite principal neurons could intermittently raise extracellular glutamate to approximately 1 muM only at sparse (microns apart) hotspots. Greater rises of glutamate occur only when astrocyte fails). The results provide a quantitative framework for a better understanding of the relationship between glutamate transporters and glutamate receptor signaling. PMID:18689452

  4. The interactive role of CB(1) and GABA(B) receptors in hippocampal synaptic plasticity in rats.

    Nazari, Masoumeh; Komaki, Alireza; Karamian, Ruhollah; Shahidi, Siamak; Sarihi, Abdolrahman; Asadbegi, Masoumeh

    2016-01-01

    Long-term potentiation (LTP) of synaptic transmission is a cellular process underlying learning and memory. Cannabinoids are known to be powerful modulators of this kind of synaptic plasticity. Changes in GABAergic inhibition have also been shown to affect synaptic plasticity in the hippocampus. GABA receptor type B (GABAB) and cannabinoid receptor type 1 (CB1) exhibit overlapping anatomical localization in some brain areas including the hippocampus. CB1 and GABAB are also localized to the same cells and share a common signaling pathway in some brain areas. In this study, we examined the hippocampal effects of co-administrating AM251 and CGP55845, which are CB1 and GABAB antagonists, respectively, on LTP induction in the dentate gyrus (DG) of rats. LTP in the hippocampal area was induced by high-frequency stimulation (HFS) of the perforant path. Our results showed that HFS coupled with administration of the CB1 antagonist increased both the population spike (PS) amplitude and field excitatory post-synaptic potential (fEPSP). Conversely, the GABAB antagonist decreased these parameters along with decreased LTP induction. We also demonstrated that the co-administration of CB1 and GABAB antagonists had different effects on the PS amplitude and fEPSP slope. It is likely that GABAB receptor antagonists modulate cannabinoid outputs that cause a decrease in synaptic plastisity, while in the simultaneous consumption of two antagonists, CB1 antagonists can alter the release of GABA which in turn results in enhancement of LTP induction. These findings suggest that there are functional interactions between the CB1 and GABAB receptor in the hippocampus. PMID:26611204

  5. Knee loading for abnormal gait

    Hutchison, J.; Madsen, D.; Norman, T. L.; -Blaha, J. D.

    2014-01-01

    The purpose of the study was to develop a mathematical model for determining knee loads for abnormal gait. Abnormal gait was defined as a person with varus, i.e. “bowleggedness”, or a person who had an external rotation of the femur (or the inability to internally rotate the femur) which caused an indirect varus in the forward positions of gait. Conditions such as these have been observed clinically to result in increased wear on the medial condyle of total knee replacements. This problem was...

  6. Enhanced susceptibility to spontaneous seizures of noda epileptic rats by loss of synaptic zn(2+.

    Atsushi Takeda

    Full Text Available Zinc homeostasis in the brain is associated with the etiology and manifestation of epileptic seizures. Adult Noda epileptic rats (NER, >12-week-old exhibit spontaneously generalized tonic-clonic convulsion about once a day. To pursue the involvement of synaptic Zn(2+ signal in susceptibility to spontaneous seizures, in the present study, the effect of zinc chelators on epileptogenesis was examined using adult NER. Clioquinol (CQ and TPEN are lipophilic zinc chelotors, transported into the brain and reduce the levels of synaptic Zn(2+. The incidence of tonic-clonic convulsion was markedly increased after i.p. injection of CQ (30-100 mg/kg and TPEN (1 mg/kg. The basal levels of extracellular Zn(2+ measured by ZnAF-2 were decreased before tonic-clonic convulsion was induced with zinc chelators. The hippocampal electroencephalograms during CQ (30 mg/kg-induced convulsions were similar to those during sound-induced convulsions in NER reported previously. Exocytosis of hippocampal mossy fibers, which was measured with FM4-64, was significantly increased in hippocampal slices from CQ-injected NER that did not show tonic-clonic convulsion yet. These results indicate that the abnormal excitability of mossy fibers is induced prior to epileptic seizures by injection of zinc chelators into NER. The incidence of tonic-clonic convulsion induced with CQ (30 mg/kg was significantly reduced by co-injection with aminooxyacetic acid (5-10 mg/kg, an anticonvulsant drug enhancing GABAergic activity, which did not affect locomotor activity. The present paper demonstrates that the abnormal excitability in the brain, especially in mossy fibers, which is potentially associated with the insufficient GABAergic neuron activity, may be a factor to reduce the threshold for epileptogenesis in NER.

  7. Enhanced susceptibility to spontaneous seizures of noda epileptic rats by loss of synaptic zn(2+).

    Takeda, Atsushi; Iida, Masashi; Ando, Masaki; Nakamura, Masatoshi; Tamano, Haruna; Oku, Naoto

    2013-01-01

    Zinc homeostasis in the brain is associated with the etiology and manifestation of epileptic seizures. Adult Noda epileptic rats (NER, >12-week-old) exhibit spontaneously generalized tonic-clonic convulsion about once a day. To pursue the involvement of synaptic Zn(2+) signal in susceptibility to spontaneous seizures, in the present study, the effect of zinc chelators on epileptogenesis was examined using adult NER. Clioquinol (CQ) and TPEN are lipophilic zinc chelotors, transported into the brain and reduce the levels of synaptic Zn(2+). The incidence of tonic-clonic convulsion was markedly increased after i.p. injection of CQ (30-100 mg/kg) and TPEN (1 mg/kg). The basal levels of extracellular Zn(2+) measured by ZnAF-2 were decreased before tonic-clonic convulsion was induced with zinc chelators. The hippocampal electroencephalograms during CQ (30 mg/kg)-induced convulsions were similar to those during sound-induced convulsions in NER reported previously. Exocytosis of hippocampal mossy fibers, which was measured with FM4-64, was significantly increased in hippocampal slices from CQ-injected NER that did not show tonic-clonic convulsion yet. These results indicate that the abnormal excitability of mossy fibers is induced prior to epileptic seizures by injection of zinc chelators into NER. The incidence of tonic-clonic convulsion induced with CQ (30 mg/kg) was significantly reduced by co-injection with aminooxyacetic acid (5-10 mg/kg), an anticonvulsant drug enhancing GABAergic activity, which did not affect locomotor activity. The present paper demonstrates that the abnormal excitability in the brain, especially in mossy fibers, which is potentially associated with the insufficient GABAergic neuron activity, may be a factor to reduce the threshold for epileptogenesis in NER. PMID:23951148

  8. Mice lacking the synaptic adhesion molecule Neph2/Kirrel3 display moderate hyperactivity and defective novel object preference

    Su Yeon eChoi

    2015-07-01

    Full Text Available Synaptic adhesion molecules regulate diverse aspects of neuronal synapse development, including synapse specificity, formation, and maturation. Neph2, also known as Kirrel3, is an immunoglobulin superfamily adhesion molecule implicated in intellectual disability, neurocognitive delay associated with Jacobsen syndrome, and autism spectrum disorders. We here report mice lacking Neph2 (Neph2–/– mice display moderate hyperactivity in a familiar but not novel environment and novel object recognition deficit with normal performances in Morris water maze spatial learning and memory, contextual fear conditioning and extinction, and pattern separation tests. These mice show normal levels of anxiety-like behaviors, social interaction, and repetitive behaviors. At the synapse level, Neph2–/– dentate gyrus granule cells exhibit unaltered dendritic spine density and spontaneous excitatory synaptic transmission. These results suggest that Neph2 is important for normal locomotor activity and object recognition memory.

  9. Proteomic Analysis of Unbounded Cellular Compartments: Synaptic Clefts.

    Loh, Ken H; Stawski, Philipp S; Draycott, Austin S; Udeshi, Namrata D; Lehrman, Emily K; Wilton, Daniel K; Svinkina, Tanya; Deerinck, Thomas J; Ellisman, Mark H; Stevens, Beth; Carr, Steven A; Ting, Alice Y

    2016-08-25

    Cellular compartments that cannot be biochemically isolated are challenging to characterize. Here we demonstrate the proteomic characterization of the synaptic clefts that exist at both excitatory and inhibitory synapses. Normal brain function relies on the careful balance of these opposing neural connections, and understanding how this balance is achieved relies on knowledge of their protein compositions. Using a spatially restricted enzymatic tagging strategy, we mapped the proteomes of two of the most common excitatory and inhibitory synaptic clefts in living neurons. These proteomes reveal dozens of synaptic candidates and assign numerous known synaptic proteins to a specific cleft type. The molecular differentiation of each cleft allowed us to identify Mdga2 as a potential specificity factor influencing Neuroligin-2's recruitment of presynaptic neurotransmitters at inhibitory synapses. PMID:27565350

  10. Compatibility between itinerant synaptic receptors and stable postsynaptic structure

    Sekimoto, Ken

    2009-01-01

    The density of synaptic receptors in front of presynaptic release sites is stabilized in the presence of scaffold proteins, but the receptors and scaffold molecules have local exchanges with characteristic times shorter than that of the receptor-scaffold assembly. We propose a mesoscopic model to account for the regulation of the local density of receptors as quasiequilibrium. It is based on two zones (synaptic and extrasynaptic) and multi-layer (membrane, sub-membrane and cytoplasmic) topological organization. The model includes the balance of chemical potentials associated with the receptor and scaffold protein concentrations in the various compartments. The model shows highly cooperative behavior including a "phase change" resulting in the formation of well-defined post-synaptic domains. This study provides theoretical tools to approach the complex issue of synaptic stability at the synapse, where receptors are transiently trapped yet rapidly diffuse laterally on the plasma membrane.

  11. SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth.

    Corradi, Anna; Fadda, Manuela; Piton, Amélie; Patry, Lysanne; Marte, Antonella; Rossi, Pia; Cadieux-Dion, Maxime; Gauthier, Julie; Lapointe, Line; Mottron, Laurent; Valtorta, Flavia; Rouleau, Guy A; Fassio, Anna; Benfenati, Fabio; Cossette, Patrick

    2014-01-01

    An increasing number of genes predisposing to autism spectrum disorders (ASDs) has been identified, many of which are implicated in synaptic function. This 'synaptic autism pathway' notably includes disruption of SYN1 that is associated with epilepsy, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins (SYN1-3) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in SYN2 are associated with ASD in humans. The phenotype is apparent in males. Female carriers of SYN2 mutations are unaffected, suggesting that SYN2 is another example of autosomal sex-limited expression in ASD. When expressed in SYN2  knockout neurons, wild-type human Syn II fully rescues the SYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify the SYN2 knockout phenotype. These results identify for the first time SYN2  as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD. PMID:23956174

  12. Corticosteroid Regulation of Synaptic Plasticity in the Hippocampus

    Nicola Maggio; Menahem Segal

    2010-01-01

    Stress, via release of steroid hormones, has been shown to affect several cellular functions in the brain, including synaptic receptors and ion channels. As such, corticosteroids were reported to modulate plasticity, expressed as long-term changes in reactivity to afferent stimulation. The classical view of the effects of stress on synaptic plasticity and cognitive functions assumes an inverted U-shape curve, such that a low stress level facilitates and a high stress level (i.e., corticostero...

  13. Activity-dependent modulation of neural circuit synaptic connectivity

    Tessier, Charles R.; Kendal Broadie

    2009-01-01

    In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; 1) early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and 2) subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circ...

  14. Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation

    Sara Calafate; Arjan Buist; Katarzyna Miskiewicz; Vinoy Vijayan; Guy Daneels; Bart de Strooper; Joris de Wit; Patrik Verstreken; Diederik Moechars

    2015-01-01

    Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer’s disease (AD). Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close dista...

  15. Synaptic plasticity in sleep: learning, homeostasis, and disease

    Wang, Gordon; Grone, Brian; Colas, Damien; Appelbaum, Lior; Mourrain, Philippe

    2011-01-01

    Sleep is a fundamental and evolutionarily conserved aspect of animal life. Recent studies have shed light on the role of sleep in synaptic plasticity. Demonstrations of memory replay and synapse homeostasis suggest that one essential role of sleep is in the consolidation and optimization of synaptic circuits to retain salient memory traces despite the noise of daily experience. Here, we review this recent evidence, and suggest that sleep creates a heightened state of plasticity, which may be ...

  16. CAPS1 stabilizes the state of readily releasable synaptic vesicles to fusion competence at CA3–CA1 synapses in adult hippocampus

    Shinoda, Yo; Ishii, Chiaki; Fukazawa, Yugo; Sadakata, Tetsushi; Ishii, Yuki; Sano, Yoshitake; Iwasato, Takuji; Itohara, Shigeyoshi; Furuichi, Teiichi

    2016-01-01

    Calcium-dependent activator protein for secretion 1 (CAPS1) regulates exocytosis of dense-core vesicles in neuroendocrine cells and of synaptic vesicles in neurons. However, the synaptic function of CAPS1 in the mature brain is unclear because Caps1 knockout (KO) results in neonatal death. Here, using forebrain-specific Caps1 conditional KO (cKO) mice, we demonstrate, for the first time, a critical role of CAPS1 in adult synapses. The amplitude of synaptic transmission at CA3–CA1 synapses was strongly reduced, and paired-pulse facilitation was significantly increased, in acute hippocampal slices from cKO mice compared with control mice, suggesting a perturbation in presynaptic function. Morphological analysis revealed an accumulation of synaptic vesicles in the presynapse without any overall morphological change. Interestingly, however, the percentage of docked vesicles was markedly decreased in the Caps1 cKO. Taken together, our findings suggest that CAPS1 stabilizes the state of readily releasable synaptic vesicles, thereby enhancing neurotransmitter release at hippocampal synapses. PMID:27545744

  17. Lead Exposure Impairs Hippocampus Related Learning and Memory by Altering Synaptic Plasticity and Morphology During Juvenile Period.

    Wang, Tao; Guan, Rui-Li; Liu, Ming-Chao; Shen, Xue-Feng; Chen, Jing Yuan; Zhao, Ming-Gao; Luo, Wen-Jing

    2016-08-01

    Lead (Pb) is an environmental neurotoxic metal. Pb exposure may cause neurobehavioral changes, such as learning and memory impairment, and adolescence violence among children. Previous animal models have largely focused on the effects of Pb exposure during early development (from gestation to lactation period) on neurobehavior. In this study, we exposed Sprague-Dawley rats during the juvenile stage (from juvenile period to adult period). We investigated the synaptic function and structural changes and the relationship of these changes to neurobehavioral deficits in adult rats. Our results showed that juvenile Pb exposure caused fear-conditioned memory impairment and anxiety-like behavior, but locomotion and pain behavior were indistinguishable from the controls. Electrophysiological studies showed that long-term potentiation induction was affected in Pb-exposed rats, and this was probably due to excitatory synaptic transmission impairment in Pb-exposed rats. We found that NMDA and AMPA receptor-mediated current was inhibited, whereas the GABA synaptic transmission was normal in Pb-exposed rats. NR2A and phosphorylated GluR1 expression decreased. Moreover, morphological studies showed that density of dendritic spines declined by about 20 % in the Pb-treated group. The spine showed an immature form in Pb-exposed rats, as indicated by spine size measurements. However, the length and arborization of dendrites were unchanged. Our results suggested that juvenile Pb exposure in rats is associated with alterations in the glutamate receptor, which caused synaptic functional and morphological changes in hippocampal CA1 pyramidal neurons, thereby leading to behavioral changes. PMID:26141123

  18. Imaging synaptic density in the living human brain.

    Finnema, Sjoerd J; Nabulsi, Nabeel B; Eid, Tore; Detyniecki, Kamil; Lin, Shu-Fei; Chen, Ming-Kai; Dhaher, Roni; Matuskey, David; Baum, Evan; Holden, Daniel; Spencer, Dennis D; Mercier, Joël; Hannestad, Jonas; Huang, Yiyun; Carson, Richard E

    2016-07-20

    Chemical synapses are the predominant neuron-to-neuron contact in the central nervous system. Presynaptic boutons of neurons contain hundreds of vesicles filled with neurotransmitters, the diffusible signaling chemicals. Changes in the number of synapses are associated with numerous brain disorders, including Alzheimer's disease and epilepsy. However, all current approaches for measuring synaptic density in humans require brain tissue from autopsy or surgical resection. We report the use of the synaptic vesicle glycoprotein 2A (SV2A) radioligand [(11)C]UCB-J combined with positron emission tomography (PET) to quantify synaptic density in the living human brain. Validation studies in a baboon confirmed that SV2A is an alternative synaptic density marker to synaptophysin. First-in-human PET studies demonstrated that [(11)C]UCB-J had excellent imaging properties. Finally, we confirmed that PET imaging of SV2A was sensitive to synaptic loss in patients with temporal lobe epilepsy. Thus, [(11)C]UCB-J PET imaging is a promising approach for in vivo quantification of synaptic density with several potential applications in diagnosis and therapeutic monitoring of neurological and psychiatric disorders. PMID:27440727

  19. Cerebellar Synaptic Plasticity and the Credit Assignment Problem.

    Jörntell, Henrik

    2016-04-01

    The mechanism by which a learnt synaptic weight change can contribute to learning or adaptation of brain function is a type of credit assignment problem, which is a key issue for many parts of the brain. In the cerebellum, detailed knowledge not only of the local circuitry connectivity but also of the topography of different sources of afferent/external information makes this problem particularly tractable. In addition, multiple forms of synaptic plasticity and their general rules of induction have been identified. In this review, we will discuss the possible roles of synaptic and cellular plasticity at specific locations in contributing to behavioral changes. Focus will be on the parts of the cerebellum that are devoted to limb control, which constitute a large proportion of the cortex and where the knowledge of the external connectivity is particularly well known. From this perspective, a number of sites of synaptic plasticity appear to primarily have the function of balancing the overall level of activity in the cerebellar circuitry, whereas the locations at which synaptic plasticity leads to functional changes in terms of limb control are more limited. Specifically, the postsynaptic forms of long-term potentiation (LTP) and long-term depression (LTD) at the parallel fiber synapses made on interneurons and Purkinje cells, respectively, are the types of plasticity that mediate the widest associative capacity and the tightest link between the synaptic change and the external functions that are to be controlled. PMID:25417189

  20. Sperm abnormalities in exposed humans

    Šrám, Radim; Rubeš, J.

    Cambridge : Issue in Toxicology, Royal Society of Chemistry Publ.,, 2007, s. 247-258. ISBN 978-0-85404-847-2 R&D Projects: GA MŽP SL/740/5/03 Institutional research plan: CEZ:AV0Z50390512 Keywords : air pollution exposure * sperm abnormalities * male reproductive health Subject RIV: DN - Health Impact of the Environment Quality

  1. The origin of glutamatergic synaptic inputs controls synaptic plasticity and its modulation by alcohol in mice nucleus accumbens

    Ji, Xincai; Saha, Sucharita; Martin, Gilles E.

    2015-01-01

    It is widely accepted that long-lasting changes of synaptic strength in the nucleus accumbens (NAc), a brain region involved in drug reward, mediate acute and chronic effects of alcohol. However, our understanding of the mechanisms underlying the effects of alcohol on synaptic plasticity is limited by the fact that the NAc receives glutamatergic inputs from distinct brain regions (e.g., the prefrontal cortex (PFCx), the amygdala and the hippocampus), each region providing different informatio...

  2. Coordinated trafficking of synaptic vesicle and active zone proteins prior to synapse formation

    Sabo Shasta L

    2011-05-01

    Full Text Available Abstract Background The proteins required for synaptic transmission are rapidly assembled at nascent synapses, but the mechanisms through which these proteins are delivered to developing presynaptic terminals are not understood. Prior to synapse formation, active zone proteins and synaptic vesicle proteins are transported along axons in distinct organelles referred to as piccolo-bassoon transport vesicles (PTVs and synaptic vesicle protein transport vesicles (STVs, respectively. Although both PTVs and STVs are recruited to the same site in the axon, often within minutes of axo-dendritic contact, it is not known whether or how PTV and STV trafficking is coordinated before synapse formation. Results Here, using time-lapse confocal imaging of the dynamics of PTVs and STVs in the same axon, we show that vesicle trafficking is coordinated through at least two mechanisms. First, a significant proportion of STVs and PTVs are transported together before forming a stable terminal. Second, individual PTVs and STVs share pause sites within the axon. Importantly, for both STVs and PTVs, encountering the other type of vesicle increases their propensity to pause. To determine if PTV-STV interactions are important for pausing, PTV density was reduced in axons by expression of a dominant negative construct corresponding to the syntaxin binding domain of syntabulin, which links PTVs with their KIF5B motor. This reduction in PTVs had a minimal effect on STV pausing and movement, suggesting that an interaction between STVs and PTVs is not responsible for enhancing STV pausing. Conclusions Our results indicate that trafficking of STVs and PTVs is coordinated even prior to synapse development. This novel coordination of transport and pausing might provide mechanisms through which all of the components of a presynaptic terminal can be rapidly accumulated at sites of synapse formation.

  3. EFFECT OF ELECTROACUPUNCTURE ON SYNAPTIC PLASTICITY OF HPPOCAMPAL NEURONS IN CEREBRAL ISCHEMIA RATS

    杨卓欣; 于海波; 王玲; 张家维

    2004-01-01

    Objective:To observe the effect of electroacupuncture (EA) on synaptic structure of hippocampal nerve felts and synaptophysin(SYN)expression in rats with cerebral ischemic injury. Methods: Sixty Wistar rats were randomized into sham-operation group, cerebral ischemia (CI) group and EA group, each of which was further divided into 1week (W) and 5W subgroups. CI injury model was established by occlusion of the bilateral common carotid arteries. "Baihui"(百会 GV 20), "Dazhui" (大椎 GV 14), "Renzhong"(人中 GV 26) and "Guanyuan"(关元 CV 4) were punctured and stimulated electrically. The brain tissue sections containing hippocampus region were stained with immunohistochemical technique and observed under light microscope and transmission electronic microscope. Results: After CI, the ischemic injury as degeneration of the presynapse compositions, decrease of the synaptic numeral density, and low expression of SYN were observed in hippocampal CA1 area. By the 5th week after CI, the neonatal synapses of CI and EA groups appeared, and SYN expression was upregulated. In EA group, the recovery of the numeral density of synapses was especially noticeable, being 93.8% of that of sham-operation group and significantly higher than that in CI group (P<0.01). Compared with sham-operation group, the calibrated optical density (COD) values of SYN increased to 70% in CI group, and 93.3% in EA group, and COD value in EA group was significantly higher than that in CI group (P<0.01). Conclusion: EA can function in promoting synaptic regeneration and enhancing and perfecting the actions of the reconstructed synapses in hippocampal CA1 area in CI rats.

  4. Transcending Transmission

    Schoeneborn, Dennis; Trittin, Hannah

    2013-01-01

    Purpose – Extant research on corporate social responsibility (CSR) communication primarily relies on a transmission model of communication that treats organizations and communication as distinct phenomena. This approach has been criticized for neglecting the formative role of communication in the....... Organizations are stabilized by various non-human entities that “act” on their behalf. Accordingly, CSR communication should also take into account non-human agency and responsibility. Originality/value – This paper links the literature on CSR communication to broader debates in organizational communication...... studies and, in particular, to the CCO perspective. By applying the CCO view, it reconceptualizes CSR communication as a complex process of meaning negotiation....

  5. Abnormal fear conditioning and amygdala processing in an animal model of autism

    Markram, Kamila; Rinaldi, Tania; La Mendola, Deborah;

    2008-01-01

    -treated animals displayed several symptoms common to autism, among them impaired social interactions and increased repetitive behaviors. Furthermore, VPA-treated rats were more anxious and exhibited abnormally high and longer lasting fear memories, which were overgeneralized and harder to extinguish. On the...... cellular level, the amygdala was hyperreactive to electrical stimulation and displayed boosted synaptic plasticity as well as a deficit in inhibition. We show for the first time enhanced, overgeneralized and resistant conditioned fear memories in an animal model of autism. Such hyperfear could be caused by...

  6. Propofol, but not etomidate, increases corticosterone levels and induces long-term alteration in hippocampal synaptic activity in neonatal rats.

    Xu, Changqing; Seubert, Christoph N; Gravenstein, Nikolaus; Martynyuk, Anatoly E

    2016-04-01

    Animal studies provide strong evidence that general anesthetics (GAs), administered during the early postnatal period, induce long-term cognitive and neurological abnormalities. Because the brain growth spurt in rodents is delayed compared to that in humans, a fundamental question is whether the postnatal human brain is similarly vulnerable. Sevoflurane and propofol, GAs that share positive modulation of the gamma-aminobutyric acid type A receptor (GABAAR) function cause marked increase in corticosterone levels and induce long-term developmental alterations in synaptic activity in rodents. If synaptogenesis is affected, investigation of mechanisms of the synaptic effects of GAs is of high interest because synaptogenesis in humans continues for several years after birth. Here, we compared long-term synaptic effects of etomidate with those of propofol. Etomidate and propofol both positively modulate GABAAR activity, but in contrast to propofol, etomidate inhibits the adrenal synthesis of corticosterone. Postnatal day (P) 4, 5, or 6 rats received five injections of etomidate, propofol, or vehicle control during 5h of maternal separation. Endocrine effects of the anesthetics were evaluated by measuring serum levels of corticosterone immediately after anesthesia or maternal separation. The frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal CA1 pyramidal neurons were measured at P24-40 and P≥80. Only propofol caused a significant increase in serum corticosterone levels (F(4.26)=17.739, P<0.001). In contrast to increased frequency of mIPSCs in the propofol group (F(4.23)=8.731, p<0.001), mIPSC activity in the etomidate group was not different from that in the vehicle groups. The results of this study together with previously published data suggest that anesthetic-caused increase in corticosterone levels is required for GABAergic GAs to induce synaptic effects in the form of a long-term increase in the frequency of hippocampal m

  7. Identification of Synaptic Targets of Drosophila Pumilio

    Regulski, Michael; Sinha, Nishi; Barditch, Jody; Tully, Tim; Krainer, Adrian R.; Zhang, Michael Q.; Dubnau, Josh

    2008-01-01

    Drosophila Pumilio (Pum) protein is a translational regulator involved in embryonic patterning and germline development. Recent findings demonstrate that Pum also plays an important role in the nervous system, both at the neuromuscular junction (NMJ) and in long-term memory formation. In neurons, Pum appears to play a role in homeostatic control of excitability via down regulation of para, a voltage gated sodium channel, and may more generally modulate local protein synthesis in neurons via translational repression of eIF-4E. Aside from these, the biologically relevant targets of Pum in the nervous system remain largely unknown. We hypothesized that Pum might play a role in regulating the local translation underlying synapse-specific modifications during memory formation. To identify relevant translational targets, we used an informatics approach to predict Pum targets among mRNAs whose products have synaptic localization. We then used both in vitro binding and two in vivo assays to functionally confirm the fidelity of this informatics screening method. We find that Pum strongly and specifically binds to RNA sequences in the 3′UTR of four of the predicted target genes, demonstrating the validity of our method. We then demonstrate that one of these predicted target sequences, in the 3′UTR of discs large (dlg1), the Drosophila PSD95 ortholog, can functionally substitute for a canonical NRE (Nanos response element) in vivo in a heterologous functional assay. Finally, we show that the endogenous dlg1 mRNA can be regulated by Pumilio in a neuronal context, the adult mushroom bodies (MB), which is an anatomical site of memory storage. PMID:18463699

  8. Echocardiographic abnormalities in hypertensive patients

    A descriptive cross-sectional study was carried out in 120 hypertensive patients with a course of 5 or more years, who went to the emergency room of 'Saturnino Lora' Provincial Teaching Hospital from November 2010 to November 2011 in order to determine the presence or absence of echocardiographic abnormalities typical of hypertension. Of these, 78,3 % was affected, most of whom reported not to continue with regular previous medical treatment, and 21,7 % had not these abnormalities. Age group of 50-60 years, males and blacks prevailed in the case material. The most significant echocardiographic findings were left ventricular hypertrophy and heart failure with ejection fraction of left ventricle preserved

  9. Imaging dopamine transmission in schizophrenia

    Over the last ten years, several positron emission tomography (PET) and single photon computerized tomography (SPECT) studies of the dopamine (DA) system in patients with schizophrenia were performed to test the hypothesis that DA hyperactivity is associated with this illness. In this paper are reviewed the results of fifteen brain imaging studies comparing indices of DA function in drug naive or drug free patients with schizophrenia and healthy controls: thirteen studies included measurements of Da D2 receptor density, two studies compared amphetamine-induced DA release, and two studies measured DOPA decarboxylase activity, an enzyme involved in DA synthesis. It was conducted a meta-analysis of the studies measuring D2 receptor density parameters, under the assumption that all tracers labeled the same population of D2 receptors. This analysis revealed that, compared to healthy controls, patients with schizophrenia present a significant but mild elevation of D2 receptor density parameters and a significant larger variability of these indices. It was found no statistical evidence that studies performed with radiolabeled butyrophenones detected a larger increase in D2 receptor density parameters than studies performed with other radioligands, such as benzamides. Studies of presynaptic activity revealed an increase in DA transmission response to amphetamine challenge, and an increase in DOPA decarboxylase activity. Together, these data are compatible with both pre- and post-synaptic alterations of DA transmission in schizophrenia. Future studies should aim at a better characterization of these alterations, and at defining their role in the pathophysiology of the illness

  10. Priming stimulation modifies synaptic plasticity in the perforant path of hippocampal slice in rat

    Lian ZHANG; Hong-Mei XIAO; Yan-Xia ZHOU; Xiao-Ping LUO

    2006-01-01

    Objective The potential of all central nervous system synapses to exhibit long term potentiation (LTP) or long term depression (LTD) is subject to modulation by prior synaptic activity, a higher-order form of plasticity that has been termed metaplasticity. This study is designed to examine the plasticity and metaplasticity in the lateral perforant path of rat. Methods Field potential was measured with different priming and conditioning stimulation protocols. Results Ten-hertz priming, which does not affect basal synaptic transmission, caused a dramatic reduction in subsequent LTP at lateral perforant path synapses in vitro, and the reduced LTP lasted for at least 2 h. The LTD was unaffected. The reduction of LTP in the lateral perforant path was also readily induced by applying priming antidromically at the mossy fibers. Conclusion Priming with 10 Hz, which is within a frequency range observed during physiological activity, can cause potent,long-lasting inhibition of LTP, but not LTD. This form of metaplasticity adds a layer of complexity to the activity-dependent modification of synapses within the dentate gyrus.

  11. Is Dark Energy Abnormally Weighting?

    Fuzfa, A.; Alimi, J. -M.

    2006-01-01

    We present a new interpretation of dark energy in terms of an \\textit{Abnormally Weighting Energy} (AWE). This means that dark energy does not couple to gravitation in the same way as ordinary matter, yielding a violation of the weak and strong equivalence principles on cosmological scales. The resulting cosmological mechanism accounts for the Hubble diagram of type Ia supernovae in terms of both cosmic acceleration and variation of the gravitational constant while still accounting for the pr...

  12. Computed tomography of thymic abnormalities

    Schnyder, P.; Candardjis, G.

    1987-05-01

    Computed tomographic examinations of 38 patients with surgically and histologically proven diagnosis were reviewed. Twenty subjects (52%) had an invasive thymoma and 16% an hyperplastic thymus. Myasthenia gravis was present in 6 cases (16%) of thymic abnormalities, four (10,5%) with invasive thymoma and two (5%) with thymic hyperplasia. Graves' disease was also present in one case of thymic hyperplasia. We emphasize the contribution of CT to the diagnosis and the prognosis.

  13. Mastoid abnormalities in Down syndrome

    Hearing loss and otitis media are commonly associated with Down syndrome. Hypoplasia of the mastoids is seen in many affected children and sclerosis of mastoid bones is not uncommon in Down syndrome. Awareness and early recognition of mastoid abnormality may lead to appropriate and timely therapy, thereby preserving the child's hearing or compensating for hearing loss; factors which are important for learning and maximum development. (orig.)

  14. Computed tomography abnormalities in hanging

    The CT pattern of bilateral and symmetrical round low density areas in the globi pallidi has been observed in a young man who attempted suicide by hanging. These CT abnormalities are similar to those described in other conditions such as carbon monoxide, hydrogen sulfide, cyanide and methanol poisoning, hypoglycaemia, drowning and acute global central nervous system hypoperfusion.The findings appear to be correlated with acute cerebral hypoxia. (orig.)

  15. Cardiac abnormalities after subarachnoid hemorrhage

    Bilt, I.A.C. van der

    2016-01-01

    Aneurysmal subarachnoid hemorrhage(aSAH) is a devastating neurological disease. During the course of the aSAH several neurological and medical complications may occur. Cardiac abnormalities after aSAH are observed often and resemble stress cardiomyopathy or Tako-tsubo cardiomyopathy(Broken Heart Syndrome) that has been described after acute stress. It is a reversible cardiac dysfunction with distinct imaging features(the echocardiographic or left ventricular angiographic image resembles a Tak...

  16. Synaptic plasticity in area CA1 of rat hippocampal slices following intraventricular application of albumin.

    Salar, Seda; Lapilover, Ezequiel; Müller, Julia; Hollnagel, Jan-Oliver; Lippmann, Kristina; Friedman, Alon; Heinemann, Uwe

    2016-07-01

    Epileptogenesis following insults to the brain may be triggered by a dysfunctional blood-brain barrier (BBB) associated with albumin extravasation and activation of astrocytes. Using ex vivo recordings from the BBB-disrupted hippocampus after neocortical photothrombotic stroke, we previously demonstrated abnormal activity-dependent accumulation of extracellular potassium with facilitated generation of seizure like events and spreading depolarizations. Similar changes could be observed after intracerebroventricular (icv) application of albumin. We hypothesized that alterations in extracellular potassium and glutamate homeostasis might lead to alterations in synaptic interactions. We therefore assessed the effects of icv albumin on homo- and heterosynaptic plasticity in hippocampal CA1, 24h after a single injection or 7days after continuous infusion of icv albumin. We demonstrate alterations in both homo- and heterosynaptic plasticity compared to control conditions in ex vivo slice studies. Albumin-treated tissue reveals (1) reduced long-term depression following low-frequency stimulation; (2) increased long-term potentiation of population spikes in response to 20Hz stimulation; (3) potentiated responses to Schaffer collateral stimulation following high-frequency stimulation of the direct cortical input and low-frequency stimulation of alveus and finally, (4) TGFβ receptor II (TGFβR-II) involvement in albumin-induced homosynaptic plasticity changes. We conclude that albumin-induced network hyperexcitability is associated with abnormal homo- and heterosynaptic plasticity that could partly be reversed by interference with TGFβR-II-mediated signaling and therefore it might be an important factor in the process of epileptogenesis. PMID:26972679

  17. The Abnormal Choroidal Vessels in Aged Patients

    Shizhou Huang; Feng Wen; Dezheng Wu; Guangwei Luo; Caijiao Liu

    2002-01-01

    Background: To show the abnormal choroidal vessels in aged patients with indocyanine-green angiography (ICGA).Methods: ICGA was performed in 350 patients with TOPCON TRC-50IA fundus camera.The images were recorded and retrospectively reviewed.Results: Five aged patients out of 350 cases were found to have abnormal choroidalvessels. The incidence was 1.43%. The abnormal choroidal vessels showed round- shapet,focal enlargement, abnormal shape and entrance, satellite appearance, and vascularloops. These might be due to congenital abnormality of choroid.Conclusion: ICGA could be used to observe the abnormal choroidal vessels.

  18. Spinal motoneuron synaptic plasticity after axotomy in the absence of inducible nitric oxide synthase

    Zanon Renata G

    2010-05-01

    Full Text Available Abstract Background Astrocytes play a major role in preserving and restoring structural and physiological integrity following injury to the nervous system. After peripheral axotomy, reactive gliosis propagates within adjacent spinal segments, influenced by the local synthesis of nitric oxide (NO. The present work investigated the importance of inducible nitric oxide synthase (iNOS activity in acute and late glial responses after injury and in major histocompatibility complex class I (MHC I expression and synaptic plasticity of inputs to lesioned alpha motoneurons. Methods In vivo analyses were carried out using C57BL/6J-iNOS knockout (iNOS-/- and C57BL/6J mice. Glial response after axotomy, glial MHC I expression, and the effects of axotomy on synaptic contacts were measured using immunohistochemistry and transmission electron microscopy. For this purpose, 2-month-old animals were sacrificed and fixed one or two weeks after unilateral sciatic nerve transection, and spinal cord sections were incubated with antibodies against classical MHC I, GFAP (glial fibrillary acidic protein - an astroglial marker, Iba-1 (an ionized calcium binding adaptor protein and a microglial marker or synaptophysin (a presynaptic terminal marker. Western blotting analysis of MHC I and nNOS expression one week after lesion were also performed. The data were analyzed using a two-tailed Student's t test for parametric data or a two-tailed Mann-Whitney U test for nonparametric data. Results A statistical difference was shown with respect to astrogliosis between strains at the different time points studied. Also, MHC I expression by iNOS-/- microglial cells did not increase at one or two weeks after unilateral axotomy. There was a difference in synaptophysin expression reflecting synaptic elimination, in which iNOS-/- mice displayed a decreased number of the inputs to alpha motoneurons, in comparison to that of C57BL/6J. Conclusion The findings herein indicate that i

  19. Short-term synaptic plasticity in the nociceptive thalamic-anterior cingulate pathway

    Vogt Brent A

    2009-09-01

    Full Text Available Abstract Background Although the mechanisms of short- and long-term potentiation of nociceptive-evoked responses are well known in the spinal cord, including central sensitization, there has been a growing body of information on such events in the cerebral cortex. In view of the importance of anterior cingulate cortex (ACC in chronic pain conditions, this review considers neuronal plasticities in the thalamocingulate pathway that may be the earliest changes associated with such syndromes. Results A single nociceptive electrical stimulus to the sciatic nerve induced a prominent sink current in the layer II/III of the ACC in vivo, while high frequency stimulation potentiated the response of this current. Paired-pulse facilitation by electrical stimulation of midline, mediodorsal and intralaminar thalamic nuclei (MITN suggesting that the MITN projection to ACC mediates the nociceptive short-term plasticity. The short-term synaptic plasticities were evaluated for different inputs in vitro where the medial thalamic and contralateral corpus callosum afferents were compared. Stimulation of the mediodorsal afferent evoked a stronger short-term synaptic plasticity and effectively transferred the bursting thalamic activity to cingulate cortex that was not true for contralateral stimulation. This short-term enhancement of synaptic transmission was mediated by polysynaptic pathways and NMDA receptors. Layer II/III neurons of the ACC express a short-term plasticity that involves glutamate and presynaptic calcium influx and is an important mechanism of the short-term plasticity. Conclusion The potentiation of ACC neuronal activity induced by thalamic bursting suggest that short-term synaptic plasticities enable the processing of nociceptive information from the medial thalamus and this temporal response variability is particularly important in pain because temporal maintenance of the response supports cortical integration and memory formation related to

  20. Remodeling of inhibitory synaptic connections in developing ferret visual cortex

    Dalva Matthew B

    2010-02-01

    Full Text Available Abstract Background In the visual cortex, as in many other regions of the developing brain, excitatory synaptic connections undergo substantial remodeling during development. While evidence suggests that local inhibitory synapses may behave similarly, the extent and mechanisms that mediate remodeling of inhibitory connections are not well understood. Results Using scanning laser photostimulation in slices of developing ferret visual cortex, we assessed the overall patterns of developing inhibitory and excitatory synaptic connections converging onto individual neurons. Inhibitory synaptic inputs onto pyramidal neurons in cortical layers 2 and 3 were already present as early as postnatal day 20, well before eye opening, and originated from regions close to the recorded neurons. During the ensuing 2 weeks, the numbers of synaptic inputs increased, with the numbers of inhibitory (and excitatory synaptic inputs peaking near the time of eye opening. The pattern of inhibitory inputs refined rapidly prior to the refinement of excitatory inputs. By uncaging the neurotransmtter GABA in brain slices from animals of different ages, we find that this rapid refinement correlated with a loss of excitatory activity by GABA. Conclusion Inhibitory synapses, like excitatory synapses, undergo significant postnatal remodeling. The time course of the remodeling of inhibitory connections correlates with the emergence of orientation tuning in the visual cortex, implicating these rearrangements in the genesis of adult cortical response properties.

  1. Cell-specific synaptic plasticity induced by network oscillations.

    Zarnadze, Shota; Bäuerle, Peter; Santos-Torres, Julio; Böhm, Claudia; Schmitz, Dietmar; Geiger, Jörg Rp; Dugladze, Tamar; Gloveli, Tengis

    2016-01-01

    Gamma rhythms are known to contribute to the process of memory encoding. However, little is known about the underlying mechanisms at the molecular, cellular and network levels. Using local field potential recording in awake behaving mice and concomitant field potential and whole-cell recordings in slice preparations we found that gamma rhythms lead to activity-dependent modification of hippocampal networks, including alterations in sharp wave-ripple complexes. Network plasticity, expressed as long-lasting increases in sharp wave-associated synaptic currents, exhibits enhanced excitatory synaptic strength in pyramidal cells that is induced postsynaptically and depends on metabotropic glutamate receptor-5 activation. In sharp contrast, alteration of inhibitory synaptic strength is independent of postsynaptic activation and less pronounced. Further, we found a cell type-specific, directionally biased synaptic plasticity of two major types of GABAergic cells, parvalbumin- and cholecystokinin-expressing interneurons. Thus, we propose that gamma frequency oscillations represent a network state that introduces long-lasting synaptic plasticity in a cell-specific manner. PMID:27218453

  2. Synaptic membrane rafts: traffic lights for local neurotrophin signalling?

    Liliana Minichiello

    2013-10-01

    Full Text Available Lipid rafts, cholesterol and lipid rich microdomains, are believed to play important roles as platforms for the partitioning of transmembrane and synaptic proteins involved in synaptic signalling, plasticity and maintenance. There is increasing evidence of a physical interaction between post-synaptic densities and post-synaptic lipid rafts. Localization of proteins within lipid rafts is highly regulated, and therefore lipid rafts may function as traffic lights modulating and fine-tuning neuronal signalling. The tyrosine kinase neurotrophin receptors (Trk and the low-affinity p75 neurotrophin receptor (p75NTR are enriched in neuronal lipid rafts together with the intermediates of downstream signalling pathways, suggesting a possible role of rafts in neurotrophin signalling. Moreover, neurotrophins and their receptors are involved in the regulation of cholesterol metabolism. Cholesterol is an important component of lipid rafts and its depletion leads to gradual loss of synapses, underscoring the importance of lipid rafts for proper neuronal function. Here, we review and discuss the idea that translocation of neurotrophin receptors in synaptic rafts may account for the selectivity of their transduced signals.

  3. Synaptic Mechanisms of Blast-Induced Brain Injury.

    Przekwas, Andrzej; Somayaji, Mahadevabharath R; Gupta, Raj K

    2016-01-01

    Blast wave-induced traumatic brain injury (TBI) is one of the most common injuries to military personnel. Brain tissue compression/tension due to blast-induced cranial deformations and shear waves due to head rotation may generate diffuse micro-damage to neuro-axonal structures and trigger a cascade of neurobiological events culminating in cognitive and neurodegenerative disorders. Although diffuse axonal injury is regarded as a signature wound of mild TBI (mTBI), blast loads may also cause synaptic injury wherein neuronal synapses are stretched and sheared. This synaptic injury may result in temporary disconnect of the neural circuitry and transient loss in neuronal communication. We hypothesize that mTBI symptoms such as loss of consciousness or dizziness, which start immediately after the insult, could be attributed to synaptic injury. Although empirical evidence is beginning to emerge; the detailed mechanisms underlying synaptic injury are still elusive. Coordinated in vitro-in vivo experiments and mathematical modeling studies can shed light into the synaptic injury mechanisms and their role in the potentiation of mTBI symptoms. PMID:26834697

  4. Lrp4 in astrocytes modulates glutamatergic transmission.

    Sun, Xiang-Dong; Li, Lei; Liu, Fang; Huang, Zhi-Hui; Bean, Jonathan C; Jiao, Hui-Feng; Barik, Arnab; Kim, Seon-Myung; Wu, Haitao; Shen, Chengyong; Tian, Yun; Lin, Thiri W; Bates, Ryan; Sathyamurthy, Anupama; Chen, Yong-Jun; Yin, Dong-Min; Xiong, Lei; Lin, Hui-Ping; Hu, Jin-Xia; Li, Bao-Ming; Gao, Tian-Ming; Xiong, Wen-Cheng; Mei, Lin

    2016-08-01

    Neurotransmission requires precise control of neurotransmitter release from axon terminals. This process is regulated by glial cells; however, the underlying mechanisms are not fully understood. We found that glutamate release in the brain was impaired in mice lacking low-density lipoprotein receptor-related protein 4 (Lrp4), a protein that is critical for neuromuscular junction formation. Electrophysiological studies revealed compromised release probability in astrocyte-specific Lrp4 knockout mice. Lrp4 mutant astrocytes suppressed glutamatergic transmission by enhancing the release of ATP, whose level was elevated in the hippocampus of Lrp4 mutant mice. Consequently, the mutant mice were impaired in locomotor activity and spatial memory and were resistant to seizure induction. These impairments could be ameliorated by blocking the adenosine A1 receptor. The results reveal a critical role for Lrp4, in response to agrin, in modulating astrocytic ATP release and synaptic transmission. Our findings provide insight into the interaction between neurons and astrocytes for synaptic homeostasis and/or plasticity. PMID:27294513

  5. A rapid form of activity-dependent recovery from short-term synaptic depression in the intensity pathway of the auditory brainstem

    MacLeod, Katrina M.; Horiuchi, Timothy K.

    2011-01-01

    Short-term synaptic plasticity acts as a time- and firing rate-dependent filter that mediates the transmission of information across synapses. In the avian auditory brainstem, specific forms of plasticity are expressed at different terminals of the same auditory nerve fibers and contribute to the divergence of acoustic timing and intensity information. To identify key differences in the plasticity properties, we made patch-clamp recordings from neurons in the cochlear nucleus responsible for ...

  6. Storage capacity diverges with synaptic efficiency in an associative memory model with synaptic delay and pruning.

    Miyoshi, Seiji; Okada, Masato

    2004-09-01

    It is known that storage capacity per synapse increases by synaptic pruning in the case of a correlation-type associative memory model. However, the storage capacity of the entire network then decreases. To overcome this difficulty, we propose decreasing the connectivity while keeping the total number of synapses constant by introducing delayed synapses. In this paper, a discrete synchronous-type model with both delayed synapses and their prunings is discussed as a concrete example of the proposal. First, we explain the Yanai-Kim theory by employing statistical neurodynamics. This theory involves macrodynamical equations for the dynamics of a network with serial delay elements. Next, considering the translational symmetry of the explained equations, we rederive macroscopic steady-state equations of the model by using the discrete Fourier transformation. The storage capacities are analyzed quantitatively. Furthermore, two types of synaptic prunings are treated analytically: random pruning and systematic pruning. As a result, it becomes clear that in both prunings, the storage capacity increases as the length of delay increases and the connectivity of the synapses decreases when the total number of synapses is constant. Moreover, an interesting fact becomes clear: the storage capacity asymptotically approaches 2/pi due to random pruning. In contrast, the storage capacity diverges in proportion to the logarithm of the length of delay by systematic pruning and the proportion constant is 4/pi. These results theoretically support the significance of pruning following an overgrowth of synapses in the brain and may suggest that the brain prefers to store dynamic attractors such as sequences and limit cycles rather than equilibrium states. PMID:15484896

  7. Long-tailed distribution of synaptic strength reveals origin and functional roles of ongoing fluctuation in cortical circuit

    Teramae, Jun-nosuke

    2016-06-01

    Neurons in the cortical circuit continuous to generate irregular spike firing with extremely low firing rate (about 1-2 Hz) even when animals neither receive any external stimuli nor they do not show any significant motor movement. The ongoing activity is often called neuronal noise because measured spike trains are often highly irregular and also spike timings are highly asynchronous among neurons. Many experiments imply that neural networks themselves must generate the noisy activity as an intrinsic property of cortical circuit. However, how a network of neurons sustains the irregular spike firings with low firing rate remains unclear. Recently, by focusing on long-tailed distribution of amplitude of synaptic connections or EPSP (Excitatory Post-Synaptic Potential), we successfully revealed that due to coexistence of a few extremely strong synaptic connections and majority of weak synapses, nonlinear dynamics of population of spiking neurons can have a nontrivial stable state that corresponding to the intrinsic ongoing fluctuation of the cortical circuit. We also found that due to the fluctuation fidelity of spike transmission between neurons are optimized. Here, we report our recent findings of the ongoing fluctuation from viewpoints of mathematical and computational side.

  8. Phosphatidylinositol turnover (PI) during synaptic activation results from the release of a stimulatory and in inhibitory agonist

    PI has been implicated in the process of synaptic transmission and is increased by agonists. It has been suggested that PI is involved in cellular Ca++ mobilization and the process represents a series of hydrolytic reactions with inositol as the final product. Hence, the rate of release of 3H-inositol (3H-Ins) from prelabelled inositol phospholipids can be used as an index of PI. In the 3H-inositol prelabelled frog sympathetic ganglia, they studied the effect of synaptic activity on PI. PI did not change during orthodromic stimulation (20 Hz, 5 min). However, upon cessation of the stimulation, PI increased rapidly and remained elevated for at least 30 min. This increase in PI was reduced by suffusing the ganglia with either acetylcholine or adenosine. In the presence of atropine (5 μM), orthodromic stimulation increased PI. They hypothesized that synaptic activation releases a long-lasting stimulatory agonist and a short-lived inhibitory (Ach/adenosine) agonist(s) affecting PI. To test this idea, 2 sympathetic ganglia were used. One was prelabelled with 3H-inositol and the other was not. The two ganglia were placed together in a 5 μl drop of Ringers solution containing atropine. Orthodromic stimuli were applied to the non-labelled ganglion and elicited release of 3H-Ins from the non-stimulated ganglion

  9. The Impact of Stimulation Induced Short Term Synaptic Plasticity on Firing Patterns in the Globus Pallidus of the Rat

    Jenia eBugaysen

    2011-03-01

    Full Text Available Electrical stimulation in the globus pallidus (GP leads to complex modulations of neuronal activity in the stimulated nucleus. Multiple in-vivo studies have demonstrated the modulation of both firing rates and patterns during and immediately following the GP stimulation. Previous in-vitro studies, together with computational studies, have suggested the involvement of short-term synaptic plasticity (STP during the stimulation. The aim of the current study was to explore in-vitro the effects of STP on neuronal activity of GP neurons during local repetitive stimulation. We recorded synaptic potentials and assessed the modulations of spontaneous firing in a postsynaptic neuron in acute brain slices via a whole-cell pipette. Low-frequency repetitive stimulation locked the firing of the neuron to the stimulus. However, high-frequency repetitive stimulation in the GP generated a biphasic modulation of the firing frequency consisting of inhibitory and excitatory phases. Using blockers of synaptic transmission, we show that GABAergic synapses mediated the inhibitory and glutamatergic synapses the excitatory part of the response. Furthermore, we report that at high stimulation frequencies both types of synapses undergo short-term depression leading to a time dependent modulation of the neuronal firing. These findings indicate that STP modulates the dynamic responses of pallidal activity during electrical stimulation, and may contribute to a better understanding of the mechanism underlying deep brain stimulation (DBS like protocols.

  10. A mathematical model of the tripartite synapse: astrocyte-induced synaptic plasticity

    Tewari, Shivendra G.; Majumdar, Kaushik Kumar

    2012-01-01

    In this paper, we present a biologically detailed mathematical model of tripartite synapses, where astrocytes modulate short-term synaptic plasticity. The model consists of a pre-synaptic bouton, a post-synaptic dendritic spine-head, a synaptic cleft and a peri-synaptic astrocyte controlling Ca2 +  dynamics inside the synaptic bouton. This in turn controls glutamate release dynamics in the cleft. As a consequence of this, glutamate concentration in the cleft has been modeled, in which glutama...

  11. Volume Transmission in Central Dopamine and Noradrenaline Neurons and Its Astroglial Targets.

    Fuxe, Kjell; Agnati, Luigi F; Marcoli, Manuela; Borroto-Escuela, Dasiel O

    2015-12-01

    Already in the 1960s the architecture and pharmacology of the brainstem dopamine (DA) and noradrenaline (NA) neurons with formation of vast numbers of DA and NA terminal plexa of the central nervous system (CNS) indicated that they may not only communicate via synaptic transmission. In the 1980s the theory of volume transmission (VT) was introduced as a major communication together with synaptic transmission in the CNS. VT is an extracellular and cerebrospinal fluid transmission of chemical signals like transmitters, modulators etc. moving along energy gradients making diffusion and flow of VT signals possible. VT interacts with synaptic transmission mainly through direct receptor-receptor interactions in synaptic and extrasynaptic heteroreceptor complexes and their signaling cascades. The DA and NA neurons are specialized for extrasynaptic VT at the soma-dendrtitic and terminal level. The catecholamines released target multiple DA and adrenergic subtypes on nerve cells, astroglia and microglia which are the major cell components of the trophic units building up the neural-glial networks of the CNS. DA and NA VT can modulate not only the strength of synaptic transmission but also the VT signaling of the astroglia and microglia of high relevance for neuron-glia interactions. The catecholamine VT targeting astroglia can modulate the fundamental functions of astroglia observed in neuroenergetics, in the Glymphatic system, in the central renin-angiotensin system and in the production of long-distance calcium waves. Also the astrocytic and microglial DA and adrenergic receptor subtypes mediating DA and NA VT can be significant drug targets in neurological and psychiatric disease. PMID:25894681

  12. Pregnenolone sulfate induces NMDA receptor dependent release of dopamine from synaptic terminals in the striatum.

    Whittaker, Matthew T; Gibbs, Terrell T; Farb, David H

    2008-10-01

    Neuromodulators that alter the balance between lower-frequency glutamate-mediated excitatory and higher-frequency GABA-mediated inhibitory synaptic transmission are likely to participate in core mechanisms for CNS function and may contribute to the pathophysiology of neurological disorders such as schizophrenia and Alzheimer's disease. Pregnenolone sulfate (PS) modulates both ionotropic glutamate and GABA(A) receptor mediated synaptic transmission. The enzymes necessary for PS synthesis and degradation are found in brain tissue of several species including human and rat, and up to 5 nM PS has been detected in extracts of postmortem human brain. Here, we ask whether PS could modulate transmitter release from nerve terminals located in the striatum. Superfusion of a preparation of striatal nerve terminals comprised of mixed synaptosomes and synaptoneurosomes with brief-duration (2 min) pulses of 25 nM PS demonstrates that PS increases the release of newly accumulated [3H]dopamine ([3H]DA), but not [14C]glutamate or [3H]GABA, whereas pregnenolone is without effect. PS does not affect dopamine transporter (DAT) mediated uptake of [3H]DA, demonstrating that it specifically affects the transmitter release mechanism. The PS-induced [3H]DA release occurs via an NMDA receptor (NMDAR) dependent mechanism as it is blocked by D-2-amino-5-phosphonovaleric acid. PS modulates DA release with very high potency, significantly increasing [3H]DA release at PS concentrations as low as 25 pM. This first report of a selective direct enhancement of synaptosomal dopamine release by PS at picomolar concentrations via an NMDAR dependent mechanism raises the possibility that dopaminergic axon terminals may be a site of action for this neurosteroid. PMID:18710414

  13. Synapses, synaptic activity and intraneuronal Aβ in Alzheimer's disease

    Davide Tampellini

    2010-05-01

    Full Text Available β-amyloid peptide accumulation plays a central role in the pathogenesis of Alzheimer’s disease. Aberrant β-amyloid buildup in the brain has been shown to be present both in the extracellular space and within neurons. Synapses are important targets of β-amyloid, and alterations in synapses better correlate with cognitive impairment than amyloid plaques or neurofibrillary tangles. The link between β-amyloid and synapses became even tighter when it was discovered that β-amyloid accumulates within synapses and that synaptic activity modulates β-amyloid secretion. Currently, a central question in Alzheimer’s disease research is what role synaptic activity plays in the disease process, and how specifically β-amyloid is involved in the synaptic dysfunction that characterizes the disease.

  14. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders

    Ryan M Smith

    2011-01-01

    Full Text Available Interactions between presynaptic and postsynaptic cellular adhesion molecules drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of cellular adhesion molecule RNAs, which ultimately determines neurotransmitter phenotype. The diverse assortment of RNAs produced by alternative splicing generates countless protein isoforms necessary for guiding specialized cell-to-cell connectivity. Failure to generate the appropriate synaptic adhesion proteins is associated with disrupted glutamatergic and gamma-aminobutyric acid signaling, resulting in loss of activity-dependent neuronal plasticity, and risk for developmental disorders, including autism. While the majority of genetic mutations currently linked to autism are rare variants that change the protein coding sequence of synaptic candidate genes, regulatory polymorphisms affecting constitutive and alternative splicing have emerged as risk factors in numerous other diseases, accounting for an estimated 40-60% of general disease risk. Here, we review the relationship between aberrant RNA splicing of synapse-related genes and autism spectrum disorders.

  15. Precise Synaptic Efficacy Alignment Suggests Potentiation Dominated Learning.

    Hartmann, Christoph; Miner, Daniel C; Triesch, Jochen

    2015-01-01

    Recent evidence suggests that parallel synapses from the same axonal branch onto the same dendritic branch have almost identical strength. It has been proposed that this alignment is only possible through learning rules that integrate activity over long time spans. However, learning mechanisms such as spike-timing-dependent plasticity (STDP) are commonly assumed to be temporally local. Here, we propose that the combination of temporally local STDP and a multiplicative synaptic normalization mechanism is sufficient to explain the alignment of parallel synapses. To address this issue, we introduce three increasingly complex models: First, we model the idealized interaction of STDP and synaptic normalization in a single neuron as a simple stochastic process and derive analytically that the alignment effect can be described by a so-called Kesten process. From this we can derive that synaptic efficacy alignment requires potentiation-dominated learning regimes. We verify these conditions in a single-neuron model with independent spiking activities but more realistic synapses. As expected, we only observe synaptic efficacy alignment for long-term potentiation-biased STDP. Finally, we explore how well the findings transfer to recurrent neural networks where the learning mechanisms interact with the correlated activity of the network. We find that due to the self-reinforcing correlations in recurrent circuits under STDP, alignment occurs for both long-term potentiation- and depression-biased STDP, because the learning will be potentiation dominated in both cases due to the potentiating events induced by correlated activity. This is in line with recent results demonstrating a dominance of potentiation over depression during waking and normalization during sleep. This leads us to predict that individual spine pairs will be more similar after sleep compared to after sleep deprivation. In conclusion, we show that synaptic normalization in conjunction with coordinated

  16. Depression as a Glial-Based Synaptic Dysfunction.

    Rial, Daniel; Lemos, Cristina; Pinheiro, Helena; Duarte, Joana M; Gonçalves, Francisco Q; Real, Joana I; Prediger, Rui D; Gonçalves, Nélio; Gomes, Catarina A; Canas, Paula M; Agostinho, Paula; Cunha, Rodrigo A

    2015-01-01

    Recent studies combining pharmacological, behavioral, electrophysiological and molecular approaches indicate that depression results from maladaptive neuroplastic processes occurring in defined frontolimbic circuits responsible for emotional processing such as the prefrontal cortex, hippocampus, amygdala and ventral striatum. However, the exact mechanisms controlling synaptic plasticity that are disrupted to trigger depressive conditions have not been elucidated. Since glial cells (astrocytes and microglia) tightly and dynamically interact with synapses, engaging a bi-directional communication critical for the processing of synaptic information, we now revisit the role of glial cells in the etiology of depression focusing on a dysfunction of the "quad-partite" synapse. This interest is supported by the observations that depressive-like conditions are associated with a decreased density and hypofunction of astrocytes and with an increased microglia "activation" in frontolimbic regions, which is expected to contribute for the synaptic dysfunction present in depression. Furthermore, the traditional culprits of depression (glucocorticoids, biogenic amines, brain-derived neurotrophic factor, BDNF) affect glia functioning, whereas antidepressant treatments (serotonin-selective reuptake inhibitors, SSRIs, electroshocks, deep brain stimulation) recover glia functioning. In this context of a quad-partite synapse, systems modulating glia-synapse bidirectional communication-such as the purinergic neuromodulation system operated by adenosine 5'-triphosphate (ATP) and adenosine-emerge as promising candidates to "re-normalize" synaptic function by combining direct synaptic effects with an ability to also control astrocyte and microglia function. This proposed triple action of purines to control aberrant synaptic function illustrates the rationale to consider the interference with glia dysfunction as a mechanism of action driving the design of future pharmacological tools to

  17. Emergence of Functional Specificity in Balanced Networks with Synaptic Plasticity.

    Sadra Sadeh

    2015-06-01

    Full Text Available In rodent visual cortex, synaptic connections between orientation-selective neurons are unspecific at the time of eye opening, and become to some degree functionally specific only later during development. An explanation for this two-stage process was proposed in terms of Hebbian plasticity based on visual experience that would eventually enhance connections between neurons with similar response features. For this to work, however, two conditions must be satisfied: First, orientation selective neuronal responses must exist before specific recurrent synaptic connections can be established. Second, Hebbian learning must be compatible with the recurrent network dynamics contributing to orientation selectivity, and the resulting specific connectivity must remain stable for unspecific background activity. Previous studies have mainly focused on very simple models, where the receptive fields of neurons were essentially determined by feedforward mechanisms, and where the recurrent network was small, lacking the complex recurrent dynamics of large-scale networks of excitatory and inhibitory neurons. Here we studied the emergence of functionally specific connectivity in large-scale recurrent networks with synaptic plasticity. Our results show that balanced random networks, which already exhibit highly selective responses at eye opening, can develop feature-specific connectivity if appropriate rules of synaptic plasticity are invoked within and between excitatory and inhibitory populations. If these conditions are met, the initial orientation selectivity guides the process of Hebbian learning and, as a result, functionally specific and a surplus of bidirectional connections emerge. Our results thus demonstrate the cooperation of synaptic plasticity and recurrent dynamics in large-scale functional networks with realistic receptive fields, highlight the role of inhibition as a critical element in this process, and paves the road for further computational

  18. Depression as a Glial-Based Synaptic Dysfunction

    Daniel eRial

    2016-01-01

    Full Text Available Recent studies combining pharmacological, behavioral, electrophysiological and molecular approaches indicate that depression results from maladaptive neuroplastic processing occurring in defined frontolimbic circuits responsible for emotional processing such as the prefrontal cortex, hippocampus, amygdala and ventral striatum. However, the exact mechanisms controlling synaptic plasticity that are disrupted to trigger depressive conditions have not been elucidated. Since glial cells (astrocytes and microglia tightly and dynamically interact with synapses, engaging a bi-directional communication critical for the processing of synaptic information, we now revisit the role of glial cells in the etiology of depression focusing on a dysfunction of the ‘quad-partite’ synapse. This interest is supported by the observations that depressive-like conditions are associated with a decreased density and hypofunction of astrocytes and with an increase microglia ‘activation’ in frontolimbic regions, which is expected to contribute for the synaptic dysfunction present in depression. Furthermore, the traditional culprits of depression (glucocorticoids, biogenic amines, BDNF affect glia functioning, whereas antidepressant treatments (SSRIs, electroshock, deep brain stimulation recover glia functioning. In this context of a quad-partite synapse, systems modulating glia-synapse bidirectional communication - such as the purinergic neuromodulation system operated by ATP and adenosine - emerge as promising candidates to re-normalize synaptic function by combining direct synaptic effects with an ability to also control astrocyte and microglia function. This proposed triple action of purines to control aberrant synaptic function illustrates the rationale to consider the interference with glia dysfunction as a mechanism of action driving the design of future pharmacological tools to manage depression.

  19. Nicotinic modulation of synaptic transmission and plasticity in cortico-limbic circuits

    2009-01-01

    Nicotine is the principle addictive agent delivered via cigarette smoking. The addictive activity of nicotine is due to potent interactions with nicotinic acetylcholine receptors (nAChRs) on neurons in the reinforcement and reward circuits of the brain. Beyond its addictive actions, nicotine is thought to have positive effects on performance in working memory and short-term attention-related tasks. The brain areas involved in such behaviors are part of an extensive cortico-limbic network that...

  20. Synchronous and asynchronous modes of synaptic transmission utilize different calcium sources

    Wen, Hua; Hubbard, Jeffrey M; Rakela, Benjamin; Linhoff, Michael W.; Mandel, Gail; Brehm, Paul

    2013-01-01

    eLife digest Neurons communicate with one another at junctions called synapses. The arrival of an electrical signal known as an action potential at the first (presynaptic) neuron causes calcium ions to flood into the cell. This in turn causes the neuron to release packages of chemicals called neurotransmitters into the synapse. These activate receptors on the second (postsynaptic) neuron, triggering a new action potential that travels down the axon to the next synapse. The ions that trigger t...

  1. Synaptotagmin-7 is an asynchronous calcium sensor for synaptic transmission in neurons expressing SNAP-23.

    Jens P Weber

    Full Text Available Synchronization of neurotransmitter release with the presynaptic action potential is essential for maintaining fidelity of information transfer in the central nervous system. However, synchronous release is frequently accompanied by an asynchronous release component that builds up during repetitive stimulation, and can even play a dominant role in some synapses. Here, we show that substitution of SNAP-23 for SNAP-25 in mouse autaptic glutamatergic hippocampal neurons results in asynchronous release and a higher frequency of spontaneous release events (mEPSCs. Use of neurons from double-knock-out (SNAP-25, synaptotagmin-7 mice in combination with viral transduction showed that SNAP-23-driven release is triggered by endogenous synaptotagmin-7. In the absence of synaptotagmin-7 release became even more asynchronous, and the spontaneous release rate increased even more, indicating that synaptotagmin-7 acts to synchronize release and suppress spontaneous release. However, compared to synaptotagmin-1, synaptotagmin-7 is a both leaky and asynchronous calcium sensor. In the presence of SNAP-25, consequences of the elimination of synaptotagmin-7 were small or absent, indicating that the protein pairs SNAP-25/synaptotagmin-1 and SNAP-23/synaptotagmin-7 might act as mutually exclusive calcium sensors. Expression of fusion proteins between pHluorin (pH-sensitive GFP and synaptotagmin-1 or -7 showed that vesicles that fuse using the SNAP-23/synaptotagmin-7 combination contained synaptotagmin-1, while synaptotagmin-7 barely displayed activity-dependent trafficking between vesicle and plasma membrane, implying that it acts as a plasma membrane calcium sensor. Overall, these findings support the idea of alternative syt∶SNARE combinations driving release with different kinetics and fidelity.

  2. Synaptotagmin-7 Is an Asynchronous Calcium Sensor for Synaptic Transmission in Neurons Expressing SNAP-23

    Weber, Jens P; Toft-Bertelsen, Trine L; Mohrmann, Ralf;

    2014-01-01

    Synchronization of neurotransmitter release with the presynaptic action potential is essential for maintaining fidelity of information transfer in the central nervous system. However, synchronous release is frequently accompanied by an asynchronous release component that builds up during repetitive......-7 acts to synchronize release and suppress spontaneous release. However, compared to synaptotagmin-1, synaptotagmin-7 is a both leaky and asynchronous calcium sensor. In the presence of SNAP-25, consequences of the elimination of synaptotagmin-7 were small or absent, indicating that the protein...

  3. Learning from Animation: Smooth Pursuits of Synaptic Transmission of an Impulse with Contextual Cues

    Pınar Köseoğlu

    2013-08-01

    Full Text Available Multimedia animations can provide better learning experiences for learners by carrying microscopic science concepts or subjects to macroscopic level. The purpose of this study is to explore how learners with and without prior experience study a multimedia learning material in an only graphically-animated design and in a verbal contextual cue design through eye tracking methodology. A total of 39 undergraduates from the Biology Education Department participated in the study. A three minute animation, describing how the inter-neurons transfer of stimulus happens through synapses, containing two different cue based design (verbal contextual or graphical animated was used to collect data. The animation was transformed to an experiment on an eye tracker to collect eye movements. A repeated measure ANOVA was executed for data analysis. Results showed a significant within subjects’ treatment effect for design types (verbalized cue vs. graphical animation in terms of eye movements while between subjects effects for comparison of prior experience groups were not found being significant. Based on the findings from this study, it is suggested that further studies could be designed with a expert groups as well as expanding the content.

  4. Differential Effect of Neuropeptides on Excitatory Synaptic Transmission in Human Epileptic Hippocampus

    Ledri, Marco; Sorensen, Andreas T.; Madsen, Marita G.; Christiansen, Soren H.; Ledri, Litsa Nikitidou; Cifra, Alessandra; Bengzon, Johan; Lindberg, Eva; Pinborg, Lars H.; Jespersen, Bo; Gotzsche, Casper R.; Woldbye, David P. D.; Andersson, My; Kokaia, Merab

    2015-01-01

    Development of novel disease-modifying treatment strategies for neurological disorders, which at present have no cure, represents a major challenge for today's neurology. Translation of findings from animal models to humans represents an unresolved gap in most of the preclinical studies. Gene...

  5. Circadian rhythmicity in AVP secretion and GABAergic synaptic transmission in the rat suprachiasmatic nucleus

    Kretschmannová, Karla; Svobodová, Irena; Balík, Aleš; Mazna, Petr; Zemková, Hana

    2005-01-01

    Roč. 1048, - (2005), s. 103-115. ISSN 0077-8923 R&D Projects: GA ČR(CZ) GA309/02/1519; GA AV ČR(CZ) IAA5011103; GA AV ČR(CZ) IAA5011408 Institutional research plan: CEZ:AV0Z5011922 Keywords : circadian rhythms * suprachiasmatic nucleus * melatonin Subject RIV: FH - Neurology Impact factor: 1.971, year: 2005

  6. A General Model of Synaptic Transmission and Short-Term Plasticity

    Pan, Bin; Zucker, Robert S.

    2009-01-01

    Some synapses transmit strongly to action potentials (APs), but weaken with repeated activation; others transmit feebly at first, but strengthen with sustained activity. We measured synchronous and asynchronous transmitter release at “phasic” crayfish neuromuscular junctions (NMJs) showing depression and at facilitating “tonic” junctions, and define the kinetics of depression and facilitation. We offer a comprehensive model of presynaptic processes, encompassing mobilization of reserve vesicl...

  7. PROPYLTHIOURACIL (PTU)-INDUCED HYPOTHYROIDISM: EFFECTS ON SYNAPTIC TRANSMISSION AND LONG TERM POTENTIATION IN HIPPOCAMPAL SLICES.

    Concern has been raised over endocrine effects of some classes of environmental chemicals. Severe hypothyroidism during critical periods of brain developmental leads to alterations in hippocampal structure, learning deficits, yet neurophysiological properties of the hippocampus...

  8. External QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1.

    Hofmann, Mackenzie E; Largent-Milnes, Tally M; Fawley, Jessica A; Andresen, Michael C

    2014-12-01

    The cell-impermeant lidocaine derivative QX-314 blocks sodium channels via intracellular mechanisms. In somatosensory nociceptive neurons, open transient receptor potential vanilloid type 1 (TRPV1) receptors provide a transmembrane passageway for QX-314 to produce long-lasting analgesia. Many cranial primary afferents express TRPV1 at synapses on neurons in the nucleus of the solitary tract and caudal trigeminal nucleus (Vc). Here, we investigated whether QX-314 interrupts neurotransmission from primary afferents in rat brain-stem slices. Shocks to the solitary tract (ST) activated highly synchronous evoked excitatory postsynaptic currents (ST-EPSCs). Application of 300 μM QX-314 increased the ST-EPSC latency from TRPV1+ ST afferents, but, surprisingly, it had similar actions at TRPV1- ST afferents. Continued exposure to QX-314 blocked evoked ST-EPSCs at both afferent types. Neither the time to onset of latency changes nor the time to ST-EPSC failure differed between responses for TRPV1+ and TRPV1- inputs. Likewise, the TRPV1 antagonist capsazepine failed to prevent the actions of QX-314. Whereas QX-314 blocked ST-evoked release, the frequency and amplitude of spontaneous EPSCs remained unaltered. In neurons exposed to QX-314, intracellular current injection evoked action potentials suggesting a presynaptic site of action. QX-314 acted similarly at Vc neurons to increase latency and block EPSCs evoked from trigeminal tract afferents. Our results demonstrate that QX-314 blocked nerve conduction in cranial primary afferents without interrupting the glutamate release mechanism or generation of postsynaptic action potentials. The TRPV1 independence suggests that QX-314 either acted extracellularly or more likely entered these axons through an undetermined pathway common to all cranial primary afferents. PMID:25185814

  9. Mechanism of the modulating action of met-enkephalin on glutamatergic synaptic transmission

    The authors show that the inhibiting effect of met-enkephalin on the glutamate-induced responses of the neurons of the neostriatum may be due to the inhibiting influence of the opioid peptide on the binding of glutamate to its postsynaptic receptors. The authors extracted the striatum from the brains of Wistar rats (100-150 g) and homogenized in 20 volumes of 0.32 sucrose. The homogenate was centrifuged at 900g for 10 min. The supernatant was removed and centrifuged at 20,000g for 40 min. The precipitate obtained (P2-fraction) was subjected to hypoosmotic shock in de-ionized water and recentrifuged at 20,000g for 30 min. The precipitate, containing the fraction of plasma membranes, was suspended in 50 ml of Tris-HCl, pH 7.4, to a protein concentration of 1-2 mg/ml, and used in experiments on the binding of [3H]glutamate on the same day. To determine the binding of [3H]glutamate, 20 microliters of [3H]glutamate (specific activity 29 Ci/mmole), 20 microliters of the membrane suspension, 40 microliters of (0.5 x 10-8-10-7 M) met-enkephalin, and 100 microliters of Tris-buffer were introduced into 1.5 ml polyethylene test tubes. The final concentration of [3H]glutamate in solution was 10-8-4 x 10-7 M. Non-specific binding was determined in the presence of 10-3 M glutamate. The membranes were incubated with a solution of [3H]glutamate at 200C for 30 min

  10. Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat.

    The Food Quality Protection Act and Safe Drinking Water Act mandate the EPA to identify potential health risks associated with chemicals that act on the endocrine system. Perchlorate, a contaminant found in food and water supplies throughout the USA, blocks iodine uptake into the...

  11. Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat: in vivo studies.

    Perchlorate, a contaminant found in food and water supplies throughout the USA, blocks iodine uptake into the thyroid gland to reduce circulating levels of thyroid hormone. Neurological function accompanying developmental exposure to perchlorate was evaluated in the present study...

  12. Deoxyschisandrin modulates synchronized Ca2+ oscillations and spontaneous synaptic transmission of cultured hippocampal neurons

    Min FU; Zhao-hui SUN; Min ZONG; Xiang-ping HE; Huan-cong ZUO; Zuo-ping XIE

    2008-01-01

    Aim: Deoxyschisandrin is one of the most effective composites of Schisandra chinensis, a famous Chinese medicine widely used as an antistress, anti-aging, and neurological performance-improving herb. In this study, we examined its spe- cific mechanisms of action on cultured hippocampal neurons. Methods: Hippoc- ampal neurons, primarily cultured for 9-11 d in vitro, were used for this study. DS were dissolved in DMSO and applied to calcium imaging and whole-cell patch clamp. Results: The application of 3 mg/L DS decreased the frequency of sponta- neous and synchronous oscillations of intracellular Ca2+ to 72%±2% (mean±SEM), and the spontaneous inhibitory postsynaptic currents to 60%±3% (mean±SEM). The inhibitory concentraton 50% (IC50) for the effect of DS on calcium oscillations was 3.8 mg/L. DS also depressed the high voltage-gated Ca2+ channel and the voltage-gated Na+ channel currents at the same time point. It had no effect, however, on voltage-gated K+ and spontaneous excitatory postsynaptic currents. Conclusion: DS inhibited the spontaneous and synchronous oscillations of intra- cellular Ca2+ through the depression of influx of extracellular calcium and the initiation of action potential. By repressing the spontaneous neurotransmitter release, DS modulated the neuronal network activities.

  13. Differential Effect of Neuropeptides on Excitatory Synaptic Transmission in Human Epileptic Hippocampus.

    Ledri, Marco; Sørensen, Andreas T; Madsen, Marita G; Christiansen, Søren H; Ledri, Litsa Nikitidou; Cifra, Alessandra; Bengzon, Johan; Lindberg, Eva; Pinborg, Lars H; Jespersen, Bo; Gøtzsche, Casper R; Woldbye, David P D; Andersson, My; Kokaia, Merab

    2015-07-01

    Development of novel disease-modifying treatment strategies for neurological disorders, which at present have no cure, represents a major challenge for today's neurology. Translation of findings from animal models to humans represents an unresolved gap in most of the preclinical studies. Gene therapy is an evolving innovative approach that may prove useful for clinical applications. In animal models of temporal lobe epilepsy (TLE), gene therapy treatments based on viral vectors encoding NPY or galanin have been shown to effectively suppress seizures. However, how this translates to human TLE remains unknown. A unique possibility to validate these animal studies is provided by a surgical therapeutic approach, whereby resected epileptic tissue from temporal lobes of pharmacoresistant patients are available for neurophysiological studies in vitro. To test whether NPY and galanin have antiepileptic actions in human epileptic tissue as well, we applied these neuropeptides directly to human hippocampal slices in vitro. NPY strongly decreased stimulation-induced EPSPs in dentate gyrus and CA1 (up to 30 and 55%, respectively) via Y2 receptors, while galanin had no significant effect. Receptor autoradiographic binding revealed the presence of both NPY and galanin receptors, while functional receptor binding was only detected for NPY, suggesting that galanin receptor signaling may be impaired. These results underline the importance of validating findings from animal studies in human brain tissue, and advocate for NPY as a more appropriate candidate than galanin for future gene therapy trials in pharmacoresistant TLE patients. PMID:26134645

  14. Making chromosome abnormalities treatable conditions.

    Cody, Jannine DeMars; Hale, Daniel Esten

    2015-09-01

    Individuals affected by the classic chromosome deletion syndromes which were first identified at the beginning of the genetic age, are now positioned to benefit from genomic advances. This issue highlights five of these conditions (4p-, 5p-, 11q-, 18p-, and 18q-). It focuses on the increased in understanding of the molecular underpinnings and envisions how these can be transformed into effective treatments. While it is scientifically exciting to see the phenotypic manifestations of hemizygosity being increasingly understood at the molecular and cellular level, it is even more amazing to consider that we are now on the road to making chromosome abnormalities treatable conditions. PMID:26351122

  15. MR imaging of abnormal synovial processes

    MR imaging can directly image abnormal synovium. The authors reviewed over 50 cases with abnormal synovial processes. The abnormalities include Baker cysts, semimembranous bursitis, chronic shoulder bursitis, peroneal tendon ganglion cyst, periarticular abscesses, thickened synovium from rheumatoid and septic arthritis, and synovial hypertrophy secondary to Legg-Calve-Perthes disease. MR imaging has proved invaluable in identifying abnormal synovium, defining the extent and, to a limited degree, characterizing its makeup

  16. CHROMOSOMAL ABNORMALITIES IN PATIENTS WITH SPERM DISORDERS

    L. Y. Pylyp; L. A. Spinenko; V. D. Zukin; N. M. Bilko

    2013-01-01

    Chromosomal abnormalities are among the most common genetic causes of spermatogenic disruptions. Carriers of chromosomal abnormalities are at increased risk of infertility, miscarriage or birth of a child with unbalanced karyotype due to the production of unbalanced gametes. The natural selection against chromosomally abnormal sperm usually prevents fertilization with sperm barring in cases of serious chromosomal abnormalities. However, assisted reproductive technologies in general and intrac...

  17. Detection of spontaneous synaptic events with an optimally scaled template.

    Clements, J. D.; Bekkers, J M

    1997-01-01

    Spontaneous synaptic events can be difficult to detect when their amplitudes are close to the background noise level. Here we report a sensitive new technique for automatic detection of small asynchronous events. A waveform with the time course of a typical synaptic event (a template) is slid along the current or voltage trace and optimally scaled to fit the data at each position. A detection criterion is calculated based on the optimum scaling factor and the quality of the fit. An event is d...

  18. A memristor SPICE model accounting for synaptic activity dependence.

    Qingjiang Li

    Full Text Available In this work, we propose a new memristor SPICE model that accounts for the typical synaptic characteristics that have been previously demonstrated with practical memristive devices. We show that this model could account for both volatile and non-volatile memristance changes under distinct stimuli. We then demonstrate that our model is capable of supporting typical STDP with simple non-overlapping digital pulse pairs. Finally, we investigate the capability of our model to simulate the activity dependence dynamics of synaptic modification and present simulated results that are in excellent agreement with biological results.

  19. Paradoxical effects of VEGF on synaptic activity partially involved in notch1 signaling in the mouse hippocampus.

    Yang, Jiajia; Yang, Chunxiao; Liu, Chunhua; Zhang, Tao; Yang, Zhuo

    2016-05-01

    It is well known that the neuronal effects of vascular endothelial growth factor (VEGF) include modulating learning and memory, plasticity of mature neurons, and synaptic transmission in addition to neurogenesis. However, there is conflicting evidence particularly of its role in the regulation of excitatory synaptic activity. In this study, application of the patch-clamp technique revealed that lower doses (10 and 50 ng/mL) of VEGF enhanced excitatory neurotransmission in hippocampal slices of mice through both presynaptic and postsynaptic mechanisms. However, the effects were reversed by higher doses of VEGF (>100 ng/mL), which inhibited excitatory neurotransmission via a presynaptic mechanism. These competing, concentration-dependent effects of VEGF suggested that different pathways were involved. The involvement of the Notch1 receptor was tested in the modulation of VEGF on synaptic activity by using heterozygous Notch1(+/-) mice. Notch1 knockdown did not influence the inhibitory effect of high VEGF doses (200 ng/mL) but reduced the enhancement effects of low concentration of VEGF (50 ng/mL) at the postsynaptic level, which might be due to the decreased level of VEGF receptor. The results indicate that the Notch1 receptor plays a role in VEGF-induced modulation of synaptic activity, which provides new insights into a complex VEGF/Notch signaling cross-talk. These findings set the groundwork for understanding new mechanisms of Notch signaling and the neurotrophic effects of VEGF, which is beneficial to develop new therapeutic targets to the VEGF/Notch axis and improve current treatments for neural diseases. PMID:26482652

  20. Kinetic constants of abnormal grain growth in nanocrystalline nickel

    Aleshin, A. N.

    2016-02-01

    The grain growth in nanocrystalline nickel with a purity of 99.5 at % during non-isothermal annealing was experimentally investigated using differential scanning calorimetry and transmission electron microscopy. Nanocrystalline nickel was prepared by electrodeposition and had an average grain size of approximately 20 nm. It was shown that, at a temperature corresponding to the calorimetric signal peak, abnormal grain growth occurs with the formation of a bimodal grain microstructure. Calorimeters signals were processed within the Johnson-Mehl-Avrami formalism. This made it possible to determine the exponent of the corresponding equation, the frequency factor, and the activation energy of the grain growth, which was found to be equal to the activation energy of the vacancy migration. The reasons for the abnormal grain growth in nanocrystalline nickel were discussed.