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Sample records for transduction modulates synaptic

  1. Presynaptic signal transduction pathways that modulate synaptic transmission

    NARCIS (Netherlands)

    de Jong, A.P.H.; Verhage, M.

    2009-01-01

    Presynaptic modulation is a crucial factor in the adaptive capacity of the nervous system. The coupling between incoming action potentials and neurotransmitter secretion is modulated by firstly, recent activity of the presynaptic axon that leads to the accumulation of residual calcium in the

  2. Expression of the synaptic exocytosis-regulating molecule complexin 2 in taste buds and its participation in peripheral taste transduction.

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    Kurokawa, Azusa; Narukawa, Masataka; Ohmoto, Makoto; Yoshimoto, Joto; Abe, Keiko; Misaka, Takumi

    2015-06-01

    Taste information from type III taste cells to gustatory neurons is thought to be transmitted via synapses. However, the molecular mechanisms underlying taste transduction through this pathway have not been fully elucidated. In this study, to identify molecules that participate in synaptic taste transduction, we investigated whether complexins (Cplxs), which play roles in regulating membrane fusion in synaptic vesicle exocytosis, were expressed in taste bud cells. Among four Cplx isoforms, strong expression of Cplx2 mRNA was detected in type III taste cells. To investigate the function of CPLX2 in taste transduction, we observed taste responses in CPLX2-knockout mice. When assessed with electrophysiological and behavioral assays, taste responses to some sour stimuli in CPLX2-knockout mice were significantly lower than those in wild-type mice. These results suggested that CPLX2 participated in synaptic taste transduction from type III taste cells to gustatory neurons. A part of taste information is thought to be transmitted via synapses. However, the molecular mechanisms have not been fully elucidated. To identify molecules that participate in synaptic taste transduction, we investigated complexins (Cplxs) expression in taste bud cells. Strong expression of Cplx2 mRNA was detected in taste bud cells. Furthermore, taste responses to some sour stimuli in CPLX2- knockout mice were significantly lower than those in wild-type mice. These suggested that CPLX2 participated in synaptic taste transduction. © 2015 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of The International Society for Neurochemistry.

  3. Synapse geometry and receptor dynamics modulate synaptic strength.

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    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.

  4. Load-induced modulation of signal transduction networks.

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    Jiang, Peng; Ventura, Alejandra C; Sontag, Eduardo D; Merajver, Sofia D; Ninfa, Alexander J; Del Vecchio, Domitilla

    2011-10-11

    Biological signal transduction networks are commonly viewed as circuits that pass along information--in the process amplifying signals, enhancing sensitivity, or performing other signal-processing tasks--to transcriptional and other components. Here, we report on a "reverse-causality" phenomenon, which we call load-induced modulation. Through a combination of analytical and experimental tools, we discovered that signaling was modulated, in a surprising way, by downstream targets that receive the signal and, in doing so, apply what in physics is called a load. Specifically, we found that non-intuitive changes in response dynamics occurred for a covalent modification cycle when load was present. Loading altered the response time of a system, depending on whether the activity of one of the enzymes was maximal and the other was operating at its minimal rate or whether both enzymes were operating at submaximal rates. These two conditions, which we call "limit regime" and "intermediate regime," were associated with increased or decreased response times, respectively. The bandwidth, the range of frequency in which the system can process information, decreased in the presence of load, suggesting that downstream targets participate in establishing a balance between noise-filtering capabilities and a circuit's ability to process high-frequency stimulation. Nodes in a signaling network are not independent relay devices, but rather are modulated by their downstream targets.

  5. Estrogen's Place in the Family of Synaptic Modulators.

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    Kramár, Enikö A; Chen, Lulu Y; Rex, Christopher S; Gall, Christine M; Lynch, Gary

    2009-01-01

    Estrogen, in addition to its genomic effects, triggers rapid synaptic changes in hippocampus and cortex. Here we summarize evidence that the acute actions of the steroid arise from actin signaling cascades centrally involved in long-term potentiation (LTP). A 10-min infusion of E2 reversibly increased fast EPSPs and promoted theta burst-induced LTP within adult hippocampal slices. The latter effect reflected a lowered threshold and an elevated ceiling for the potentiation effect. E2's actions on transmission and plasticity were completely blocked by latrunculin, a toxin that prevents actin polymerization. E2 also caused a reversible increase in spine concentrations of filamentous (F-) actin and markedly enhanced polymerization caused by theta burst stimulation (TBS). Estrogen activated the small GTPase RhoA, but not the related GTPase Rac, and phosphorylated (inactivated) synaptic cofilin, an actin severing protein targeted by RhoA. An inhibitor of RhoA kinase (ROCK) thoroughly suppressed the synaptic effects of E2. Collectively, these results indicate that E2 engages a RhoA >ROCK> cofilin> actin pathway also used by brain-derived neurotrophic factor and adenosine, and therefore belongs to a family of 'synaptic modulators' that regulate plasticity. Finally, we describe evidence that the acute signaling cascade is critical to the depression of LTP produced by ovariectomy.

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

    International Nuclear Information System (INIS)

    Zhu Guoqi; Chen Ying; Huang Yuying; Li Qinglin; Behnisch, Thomas

    2011-01-01

    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

  7. Modulation of synaptic plasticity by stress hormone associates with plastic alteration of synaptic NMDA receptor in the adult hippocampus.

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    Yiu Chung Tse

    Full Text Available Stress exerts a profound impact on learning and memory, in part, through the actions of adrenal corticosterone (CORT on synaptic plasticity, a cellular model of learning and memory. Increasing findings suggest that CORT exerts its impact on synaptic plasticity by altering the functional properties of glutamate receptors, which include changes in the motility and function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR that are responsible for the expression of synaptic plasticity. Here we provide evidence that CORT could also regulate synaptic plasticity by modulating the function of synaptic N-methyl-D-aspartate receptors (NMDARs, which mediate the induction of synaptic plasticity. We found that stress level CORT applied to adult rat hippocampal slices potentiated evoked NMDAR-mediated synaptic responses within 30 min. Surprisingly, following this fast-onset change, we observed a slow-onset (>1 hour after termination of CORT exposure increase in synaptic expression of GluN2A-containing NMDARs. To investigate the consequences of the distinct fast- and slow-onset modulation of NMDARs for synaptic plasticity, we examined the formation of long-term potentiation (LTP and long-term depression (LTD within relevant time windows. Paralleling the increased NMDAR function, both LTP and LTD were facilitated during CORT treatment. However, 1-2 hours after CORT treatment when synaptic expression of GluN2A-containing NMDARs is increased, bidirectional plasticity was no longer facilitated. Our findings reveal the remarkable plasticity of NMDARs in the adult hippocampus in response to CORT. CORT-mediated slow-onset increase in GluN2A in hippocampal synapses could be a homeostatic mechanism to normalize synaptic plasticity following fast-onset stress-induced facilitation.

  8. Cell-specific gain modulation by synaptically released zinc in cortical circuits of audition.

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    Anderson, Charles T; Kumar, Manoj; Xiong, Shanshan; Tzounopoulos, Thanos

    2017-09-09

    In many excitatory synapses, mobile zinc is found within glutamatergic vesicles and is coreleased with glutamate. Ex vivo studies established that synaptically released (synaptic) zinc inhibits excitatory neurotransmission at lower frequencies of synaptic activity but enhances steady state synaptic responses during higher frequencies of activity. However, it remains unknown how synaptic zinc affects neuronal processing in vivo. Here, we imaged the sound-evoked neuronal activity of the primary auditory cortex in awake mice. We discovered that synaptic zinc enhanced the gain of sound-evoked responses in CaMKII-expressing principal neurons, but it reduced the gain of parvalbumin- and somatostatin-expressing interneurons. This modulation was sound intensity-dependent and, in part, NMDA receptor-independent. By establishing a previously unknown link between synaptic zinc and gain control of auditory cortical processing, our findings advance understanding about cortical synaptic mechanisms and create a new framework for approaching and interpreting the role of the auditory cortex in sound processing.

  9. Modulation of signal transduction by tea catechins and related phytochemicals

    International Nuclear Information System (INIS)

    Shimizu, Masahito; Weinstein, I. Bernard

    2005-01-01

    Epidemiologic studies in human populations and experimental studies in rodents provide evidence that green tea and its constituents can inhibit both the development and growth of tumors at a variety of tissue sites. In addition, EGCG, a major biologically active component of green tea, inhibits growth and induces apoptosis in a variety of cancer cell lines. The purpose of this paper is to review evidence that these effects are mediated, at least in part, through inhibition of the activity of specific receptor tyrosine kinases (RTKs) and related downstream pathways of signal transduction. We also review evidence indicating that the antitumor effects of the related polyphenolic phytochemicals resveratrol, genistein, curcumin, and capsaicin are exerted via similar mechanisms. Some of these agents (EGCG, genistein, and curcumin) appear to directly target specific RTKs, and all of these compounds cause inhibition of the activity of the transcription factors AP-1 and NF-κB, thus inhibiting cell proliferation and enhancing apoptosis. Critical areas of future investigation include: (1) identification of the direct molecular target(s) of EGCG and related polyphenolic compounds in cells; (2) the in vivo metabolism and bioavailability of these compounds; (3) the ancillary effects of these compounds on tumor-stromal interactions; (4) the development of synergistic combinations with other antitumor agents to enhance efficacy in cancer prevention and therapy, and also minimize potential toxicities

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

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    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.

  11. Thalamic synaptic transmission of sensory information modulated by synergistic interaction of adenosine and serotonin.

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    Yang, Ya-Chin; Hu, Chun-Chang; Huang, Chen-Syuan; Chou, Pei-Yu

    2014-03-01

    The thalamic synapses relay peripheral sensory information to the cortex, and constitute an important part of the thalamocortical network that generates oscillatory activities responsible for different vigilance (sleep and wakefulness) states. However, the modulation of thalamic synaptic transmission by potential sleep regulators, especially by combination of regulators in physiological scenarios, is not fully characterized. We found that somnogen adenosine itself acts similar to wake-promoting serotonin, both decreasing synaptic strength as well as short-term depression, at the retinothalamic synapse. We then combined the two modulators considering the coexistence of them in the hypnagogic (sleep-onset) state. Adenosine plus serotonin results in robust synergistic inhibition of synaptic strength and dramatic transformation of short-term synaptic depression to facilitation. These synaptic effects are not achievable with a single modulator, and are consistent with a high signal-to-noise ratio but a low level of signal transmission through the thalamus appropriate for slow-wave sleep. This study for the first time demonstrates that the sleep-regulatory modulators may work differently when present in combination than present singly in terms of shaping information flow in the thalamocortical network. The major synaptic characters such as the strength and short-term plasticity can be profoundly altered by combination of modulators based on physiological considerations. © 2013 International Society for Neurochemistry.

  12. Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc.

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    Anderson, Charles T; Radford, Robert J; Zastrow, Melissa L; Zhang, Daniel Y; Apfel, Ulf-Peter; Lippard, Stephen J; Tzounopoulos, Thanos

    2015-05-19

    Many excitatory synapses contain high levels of mobile zinc within glutamatergic vesicles. Although synaptic zinc and glutamate are coreleased, it is controversial whether zinc diffuses away from the release site or whether it remains bound to presynaptic membranes or proteins after its release. To study zinc transmission and quantify zinc levels, we required a high-affinity rapid zinc chelator as well as an extracellular ratiometric fluorescent zinc sensor. We demonstrate that tricine, considered a preferred chelator for studying the role of synaptic zinc, is unable to efficiently prevent zinc from binding low-nanomolar zinc-binding sites, such as the high-affinity zinc-binding site found in NMDA receptors (NMDARs). Here, we used ZX1, which has a 1 nM zinc dissociation constant and second-order rate constant for binding zinc that is 200-fold higher than those for tricine and CaEDTA. We find that synaptic zinc is phasically released during action potentials. In response to short trains of presynaptic stimulation, synaptic zinc diffuses beyond the synaptic cleft where it inhibits extrasynaptic NMDARs. During higher rates of presynaptic stimulation, released glutamate activates additional extrasynaptic NMDARs that are not reached by synaptically released zinc, but which are inhibited by ambient, tonic levels of nonsynaptic zinc. By performing a ratiometric evaluation of extracellular zinc levels in the dorsal cochlear nucleus, we determined the tonic zinc levels to be low nanomolar. These results demonstrate a physiological role for endogenous synaptic as well as tonic zinc in inhibiting extrasynaptic NMDARs and thereby fine tuning neuronal excitability and signaling.

  13. Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc

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    Anderson, Charles T.; Radford, Robert J.; Zastrow, Melissa L.; Zhang, Daniel Y.; Apfel, Ulf-Peter; Lippard, Stephen J.; Tzounopoulos, Thanos

    2015-01-01

    Many excitatory synapses contain high levels of mobile zinc within glutamatergic vesicles. Although synaptic zinc and glutamate are coreleased, it is controversial whether zinc diffuses away from the release site or whether it remains bound to presynaptic membranes or proteins after its release. To study zinc transmission and quantify zinc levels, we required a high-affinity rapid zinc chelator as well as an extracellular ratiometric fluorescent zinc sensor. We demonstrate that tricine, considered a preferred chelator for studying the role of synaptic zinc, is unable to efficiently prevent zinc from binding low-nanomolar zinc-binding sites, such as the high-affinity zinc-binding site found in NMDA receptors (NMDARs). Here, we used ZX1, which has a 1 nM zinc dissociation constant and second-order rate constant for binding zinc that is 200-fold higher than those for tricine and CaEDTA. We find that synaptic zinc is phasically released during action potentials. In response to short trains of presynaptic stimulation, synaptic zinc diffuses beyond the synaptic cleft where it inhibits extrasynaptic NMDARs. During higher rates of presynaptic stimulation, released glutamate activates additional extrasynaptic NMDARs that are not reached by synaptically released zinc, but which are inhibited by ambient, tonic levels of nonsynaptic zinc. By performing a ratiometric evaluation of extracellular zinc levels in the dorsal cochlear nucleus, we determined the tonic zinc levels to be low nanomolar. These results demonstrate a physiological role for endogenous synaptic as well as tonic zinc in inhibiting extrasynaptic NMDARs and thereby fine tuning neuronal excitability and signaling. PMID:25947151

  14. Synaptic transmission modulates while non-synaptic processes govern the transition from pre-ictal to seizure activity in vitro

    OpenAIRE

    Jefferys, John; Fox, John; Jiruska, Premysl; Kronberg, Greg; Miranda, Dolores; Ruiz-Nuño, Ana; Bikson, Marom

    2018-01-01

    It is well established that non-synaptic mechanisms can generate electrographic seizures after blockade of synaptic function. We investigated the interaction of intact synaptic activity with non-synaptic mechanisms in the isolated CA1 region of rat hippocampal slices using the 'elevated-K+' model of epilepsy. Elevated K+ ictal bursts share waveform features with other models of electrographic seizures, including non-synaptic models where chemical synaptic transmission is suppressed, such as t...

  15. Activity-dependent modulation of neural circuit synaptic connectivity

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    Charles R Tessier

    2009-07-01

    Full Text Available 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 circuits are “hard-wired” in a purely activity-independent manner. This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution. These recent studies reveal that activity-dependent mechanisms are indeed required to refine circuit maps in Drosophila during precise, restricted windows of late-phase development. Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function. This review focuses on our current understanding of activity-dependent synaptic connectivity in Drosophila, primarily through analyzing the role of the fragile X mental retardation protein (FMRP in the Drosophila FXS disease model. The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail.

  16. Modulation of Synaptic Plasticity by Exercise Training as a Basis for Ischemic Stroke Rehabilitation.

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    Nie, Jingjing; Yang, Xiaosu

    2017-01-01

    In recent years, rehabilitation of ischemic stroke draws more and more attention in the world, and has been linked to changes of synaptic plasticity. Exercise training improves motor function of ischemia as well as cognition which is associated with formation of learning and memory. The molecular basis of learning and memory might be synaptic plasticity. Research has therefore been conducted in an attempt to relate effects of exercise training to neuroprotection and neurogenesis adjacent to the ischemic injury brain. The present paper reviews the current literature addressing this question and discusses the possible mechanisms involved in modulation of synaptic plasticity by exercise training. This review shows the pathological process of synaptic dysfunction in ischemic roughly and then discusses the effects of exercise training on scaffold proteins and regulatory protein expression. The expression of scaffold proteins generally increased after training, but the effects on regulatory proteins were mixed. Moreover, the compositions of postsynaptic receptors were changed and the strength of synaptic transmission was enhanced after training. Finally, the recovery of cognition is critically associated with synaptic remodeling in an injured brain, and the remodeling occurs through a number of local regulations including mRNA translation, remodeling of cytoskeleton, and receptor trafficking into and out of the synapse. We do provide a comprehensive knowledge of synaptic plasticity enhancement obtained by exercise training in this review.

  17. Adiponectin modulates synaptic plasticity in hippocampal dentate gyrus.

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    Pousti, Farideh; Ahmadi, Ramesh; Mirahmadi, Fatemeh; Hosseinmardi, Narges; Rohampour, Kambiz

    2018-01-01

    Recent studies have suggested the involvement of some metabolic hormones in memory formation and synaptic plasticity. Insulin dysfunction is known as an essential process in the pathogenesis of sporadic Alzheimer's disease (AD). In this study we examined whether adiponectin (ADN), as an insulin-sensitizing adipokine, could affect hippocampal synaptic plasticity. Field potential recordings were performed on intracerebroventricular (icv) cannulated urethane anesthetized rats. After baseline recording from dentate gyrus (DG) and 10min prior to high/low frequency stimulation (HFS/LFS), 10μl icv ADN (600nm) were injected. The slope of field excitatory postsynaptic potentials (fEPSP) and the amplitude of population spikes (PS) were recorded in response to perforanth path (PP) stimulation. Paired pulse stimuli and ADN injection without any stimulation protocols were also evaluated. Application of ADN before HFS increased PS amplitude recorded in DG significantly (P≤0.05) in comparison to HFS only group. ADN suppressed the potency of LFS to induce long-term depression (LTD), causing a significant difference between fEPSP slope (P≤0.05) and PS amplitude (P≤0.01) between ADN+LFS and ADN group. Paired pulse stimuli applied at 20ms intervals showed more paired pulse facilitation (PPF), when applied after ADN (P≤0.05). ADN induced a chemical long-term potentiation (LTP) in which fEPSP slope and PS amplitude increased significantly (P≤0.01 and P≤0.05, respectively). It is concluded that ADN is able to potentiate the HFS-induced LTP and suppress LFS-induced LTD. ADN caused a chemical LTP, when applied without any tetanic protocol. ADN may enhance the presynaptic release probability. Copyright © 2017. Published by Elsevier B.V.

  18. Modulators of Stomatal Lineage Signal Transduction Alter Membrane Contact Sites and Reveal Specialization among ERECTA Kinases.

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    Ho, Chin-Min Kimmy; Paciorek, Tomasz; Abrash, Emily; Bergmann, Dominique C

    2016-08-22

    Signal transduction from a cell's surface to its interior requires dedicated signaling elements and a cellular environment conducive to signal propagation. Plant development, defense, and homeostasis rely on plasma membrane receptor-like kinases to perceive endogenous and environmental signals, but little is known about their immediate downstream targets and signaling modifiers. Using genetics, biochemistry, and live-cell imaging, we show that the VAP-RELATED SUPPRESSOR OF TMM (VST) family is required for ERECTA-mediated signaling in growth and cell-fate determination and reveal a role for ERECTA-LIKE2 in modulating signaling by its sister kinases. We show that VSTs are peripheral plasma membrane proteins that can form complexes with integral ER-membrane proteins, thereby potentially influencing the organization of the membrane milieu to promote efficient and differential signaling from the ERECTA-family members to their downstream intracellular targets. Copyright © 2016 Elsevier Inc. All rights reserved.

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

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    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.

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

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    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.

  1. Dyslipidemia modulates Müller glial sensing and transduction of ambient information

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    Monika Lakk

    2018-01-01

    Full Text Available Unesterified cholesterol controls the fluidity, permeability and electrical properties of eukaryotic cell membranes. Consequently, cholesterol levels in the retina and the brain are tightly regulated whereas depletion or oversupply caused by diet or heredity contribute to neurodegenerative diseases and vision loss. Astroglia play a central role in the biosynthesis, uptake and transport of cholesterol and also drive inflammatory signaling under hypercholesterolemic conditions associated with high-fat diet (diabetes and neurodegenerative disease. A growing body of evidence shows that unesterified membrane cholesterol modulates the ability of glia to sense and transduce ambient information. Cholesterol-dependence of Müller glia - which function as retinal sentinels for metabolic, mechanical, osmotic and inflammatory signals - is mediated in part by transient receptor potential V4 (TRPV4 channels. Cholesterol supplementation facilitates, whereas depletion suppresses, TRPV4-mediated transduction of temperature and lipid agonists in Müller cells. Acute effects of cholesterol supplementation/depletion on plasma membrane ion channels and calcium homeostasis differ markedly from the effects of chronic dyslipidemia, possibly due to differential modulation of modality-dependent energy barriers associated with the functionality of polymodal channels embedded within lipid rafts. Understanding of cholesterol-dependence of TRP channels is thus providing insight into dyslipidemic pathologies associated with diabetic retinopathy, glaucoma and macular degeneration.

  2. Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.

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    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. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Oxytocin as a Modulator of Synaptic Plasticity: Implications for Neurodevelopmental Disorders

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    Keerthi Thirtamara Rajamani

    2018-06-01

    Full Text Available The neuropeptide oxytocin (OXT is a crucial mediator of parturition and milk ejection and a major modulator of various social behaviors, including social recognition, aggression and parenting. In the past decade, there has been significant excitement around the possible use of OXT to treat behavioral deficits in neurodevelopmental disorders, including autism spectrum disorder (ASD. Yet, despite the fast move to clinical trials with OXT, little attention has been paid to the possibility that the OXT system in the brain is perturbed in these disorders and to what extent such perturbations may contribute to social behavior deficits. Large-scale whole-exome sequencing studies in subjects with ASD, along with biochemical and electrophysiological studies in animal models of the disorder, indicate several risk genes that play an essential role in brain synapses, suggesting that deficits in synaptic activity and plasticity underlie the pathophysiology in a considerable portion of these cases. OXT has been repeatedly shown, both in vitro and in vivo, to modify synaptic properties and plasticity and to modulate neural activity in circuits that regulate social behavior. Together, these findings led us to hypothesize that failure of the OXT system during early development, as a direct or indirect consequence of genetic mutations, may impact social behavior by altering synaptic activity and plasticity. In this article, we review the evidence that support our hypothesis.

  4. A cytosolic juxtamembrane interface modulates plexin A3 oligomerization and signal transduction.

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    Rachael Barton

    Full Text Available Plexins (plxns are transmembrane (TM receptors involved in the guidance of vascular, lymphatic vessel, and neuron growth as well as cancer metastasis. Plxn signaling results in cytosolic GTPase-activating protein activity, and previous research implicates dimerization as important for activation of plxn signaling. Purified, soluble plxn extracellular and cytosolic domains exhibit only weak homomeric interactions, suggesting a role for the plxn TM and juxtamembrane regions in homooligomerization. In this study, we consider a heptad repeat in the Danio rerio PlxnA3 cytosolic juxtamembrane domain (JM for its ability to influence PlxnA3 homooligomerization in TM-domain containing constructs. Site-directed mutagenesis in conjunction with the AraTM assay and bioluminescent energy transfer (BRET² suggest an interface involving a JM heptad repeat, in particular residue M1281, regulates PlxnA3 homomeric interactions when examined in constructs containing an ectodomain, TM and JM domain. In the presence of a neuropilin-2a co-receptor and semaphorin 3F ligand, disruption to PlxnA3 homodimerization caused by an M1281F mutation is eliminated, suggesting destabilization of the PlxnA3 homodimer in the JM is not sufficient to disrupt co-receptor complex formation. In contrast, enhanced homodimerization of PlxnA3 caused by mutation M1281L remains even in the presence of ligand semaphorin 3F and co-receptor neuropilin-2a. Consistent with this pattern of PlxnA3 dimerization in the presence of ligand and co-receptor, destabilizing mutations to PlxnA3 homodimerization (M1281F are able to rescue motor patterning defects in sidetracked zebrafish embryos, whereas mutations that enhance PlxnA3 homodimerization (M1281L are not. Collectively, our results indicate the JM heptad repeat, in particular residue M1281, forms a switchable interface that modulates both PlxnA3 homomeric interactions and signal transduction.

  5. Synaptic transistor with a reversible and analog conductance modulation using a Pt/HfOx/n-IGZO memcapacitor

    Science.gov (United States)

    Yang, Paul; Kim, Hyung Jun; Zheng, Hong; Beom, Geon Won; Park, Jong-Sung; Kang, Chi Jung; Yoon, Tae-Sik

    2017-06-01

    A synaptic transistor emulating the biological synaptic motion is demonstrated using the memcapacitance characteristics in a Pt/HfOx/n-indium-gallium-zinc-oxide (IGZO) memcapacitor. First, the metal-oxide-semiconductor (MOS) capacitor with Pt/HfOx/n-IGZO structure exhibits analog, polarity-dependent, and reversible memcapacitance in capacitance-voltage (C-V), capacitance-time (C-t), and voltage-pulse measurements. When a positive voltage is applied repeatedly to the Pt electrode, the accumulation capacitance increases gradually and sequentially. The depletion capacitance also increases consequently. The capacitances are restored by repeatedly applying a negative voltage, confirming the reversible memcapacitance. The analog and reversible memcapacitance emulates the potentiation and depression synaptic motions. The synaptic thin-film transistor (TFT) with this memcapacitor also shows the synaptic motion with gradually increasing drain current by repeatedly applying the positive gate and drain voltages and reversibly decreasing one by applying the negative voltages, representing synaptic weight modulation. The reversible and analog conductance change in the transistor at both the voltage sweep and pulse operations is obtained through the memcapacitance and threshold voltage shift at the same time. These results demonstrate the synaptic transistor operations with a MOS memcapacitor gate stack consisting of Pt/HfOx/n-IGZO.

  6. Primary cilia modulate Ihh signal transduction in response to hydrostatic loading of growth plate chondrocytes.

    Science.gov (United States)

    Shao, Yvonne Y; Wang, Lai; Welter, Jean F; Ballock, R Tracy

    2012-01-01

    Indian hedgehog (Ihh) is a key component of the regulatory apparatus governing chondrocyte proliferation and differentiation in the growth plate. Recent studies have demonstrated that the primary cilium is the site of Ihh signaling within the cell, and that primary cilia are essential for bone and cartilage formation. Primary cilia are also postulated to act as mechanosensory organelles that transduce mechanical forces acting on the cell into biological signals. In this study, we used a hydrostatic compression system to examine Ihh signal transduction under the influence of mechanical load. Our results demonstrate that hydrostatic compression increased both Ihh gene expression and Ihh-responsive Gli-luciferase activity. These increases were aborted by disrupting the primary cilia structure with chloral hydrate. These results suggest that growth plate chondrocytes respond to hydrostatic loading by increasing Ihh signaling, and that the primary cilium is required for this mechano-biological signal transduction to occur. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Primary Cilia Modulate IHH Signal Transduction in Response to Hydrostatic Loading of Growth Plate Chondrocytes

    Science.gov (United States)

    Shao, Y, Yvonne Y.; Wang, Lai; Welter, J, Jean F.; Ballock, R. Tracy

    2011-01-01

    Indian Hedgehog (Ihh) is a key component of the regulatory apparatus governing chondrocyte proliferation and differentiation in the growth plate. Recent studies have demonstrated that the primary cilium is the site of Ihh signaling within the cell, and that primary cilia are essential for bone and cartilage formation. Primary cilia are also postulated to act as mechanosensory organelles that transduce mechanical forces acting on the cell into biological signals. In this study, we used a hydrostatic compression system to examine Ihh signal transduction under the influence of mechanical load. Our results demonstrate that hydrostatic compression increased both Ihh gene expression and Ihh-responsive Gli-luciferase activity. These increases were aborted by disrupting the primary cilia structure with chloral hydrate. These results suggest that growth plate chondrocytes respond to hydrostatic loading by increasing Ihh signaling, and that the primary cilium is required for this mechano-biological signal transduction to occur. PMID:21930256

  8. Dbo/Henji Modulates Synaptic dPAK to Gate Glutamate Receptor Abundance and Postsynaptic Response.

    Directory of Open Access Journals (Sweden)

    Manyu Wang

    2016-10-01

    Full Text Available In response to environmental and physiological changes, the synapse manifests plasticity while simultaneously maintains homeostasis. Here, we analyzed mutant synapses of henji, also known as dbo, at the Drosophila neuromuscular junction (NMJ. In henji mutants, NMJ growth is defective with appearance of satellite boutons. Transmission electron microscopy analysis indicates that the synaptic membrane region is expanded. The postsynaptic density (PSD houses glutamate receptors GluRIIA and GluRIIB, which have distinct transmission properties. In henji mutants, GluRIIA abundance is upregulated but that of GluRIIB is not. Electrophysiological results also support a GluR compositional shift towards a higher IIA/IIB ratio at henji NMJs. Strikingly, dPAK, a positive regulator for GluRIIA synaptic localization, accumulates at the henji PSD. Reducing the dpak gene dosage suppresses satellite boutons and GluRIIA accumulation at henji NMJs. In addition, dPAK associated with Henji through the Kelch repeats which is the domain essential for Henji localization and function at postsynapses. We propose that Henji acts at postsynapses to restrict both presynaptic bouton growth and postsynaptic GluRIIA abundance by modulating dPAK.

  9. Dbo/Henji Modulates Synaptic dPAK to Gate Glutamate Receptor Abundance and Postsynaptic Response.

    Science.gov (United States)

    Wang, Manyu; Chen, Pei-Yi; Wang, Chien-Hsiang; Lai, Tzu-Ting; Tsai, Pei-I; Cheng, Ying-Ju; Kao, Hsiu-Hua; Chien, Cheng-Ting

    2016-10-01

    In response to environmental and physiological changes, the synapse manifests plasticity while simultaneously maintains homeostasis. Here, we analyzed mutant synapses of henji, also known as dbo, at the Drosophila neuromuscular junction (NMJ). In henji mutants, NMJ growth is defective with appearance of satellite boutons. Transmission electron microscopy analysis indicates that the synaptic membrane region is expanded. The postsynaptic density (PSD) houses glutamate receptors GluRIIA and GluRIIB, which have distinct transmission properties. In henji mutants, GluRIIA abundance is upregulated but that of GluRIIB is not. Electrophysiological results also support a GluR compositional shift towards a higher IIA/IIB ratio at henji NMJs. Strikingly, dPAK, a positive regulator for GluRIIA synaptic localization, accumulates at the henji PSD. Reducing the dpak gene dosage suppresses satellite boutons and GluRIIA accumulation at henji NMJs. In addition, dPAK associated with Henji through the Kelch repeats which is the domain essential for Henji localization and function at postsynapses. We propose that Henji acts at postsynapses to restrict both presynaptic bouton growth and postsynaptic GluRIIA abundance by modulating dPAK.

  10. Cerebral CBM1 neuron contributes to synaptic modulation appearing during rejection of seaweed in Aplysia kurodai.

    Science.gov (United States)

    Narusuye, Kenji; Nagahama, Tatsumi

    2002-11-01

    The Japanese species Aplysia kurodai feeds well on Ulva but rejects Gelidium with distinctive rhythmic patterned movements of the jaws and radula. We have previously shown that the patterned jaw movements during the rejection of Gelidium might be caused by long-lasting suppression of the monosynaptic transmission from the multiaction MA neurons to the jaw-closing (JC) motor neurons in the buccal ganglia and that the modulation might be directly produced by some cerebral neurons. In the present paper, we have identified a pair of catecholaminergic neurons (CBM1) in bilateral cerebral M clusters. The CBM1, probably equivalent to CBI-1 in A. californica, simultaneously produced monosynaptic excitatory postsynaptic potentials (EPSPs) in the MA and JC neurons. Firing of the CBM1 reduced the size of the inhibitory postsynaptic currents (IPSCs) in the JC neuron, evoked by the MA spikes, for >100 s. Moreover, the application of dopamine mimicked the CBM1 modulatory effects and pretreatment with a D1 antagonist, SCH23390, blocked the modulatory effects induced by dopamine. It could also largely block the modulatory effects induced by the CBM1 firing. These results suggest that the CBM1 may directly modulate the synaptic transmission by releasing dopamine. Moreover, we explored the CBM1 spike activity induced by taste stimulation of the animal lips with seaweed extracts by the use of calcium imaging. The calcium-sensitive dye, Calcium Green-1, was iontophoretically loaded into a cell body of the CBM1 using a microelectrode. Application of either Ulva or Gelidium extract to the lips increased the fluorescence intensity, but the Gelidium extract always induced a larger change in fluorescence compared with the Ulva extract, although the solution used induced the maximum spike responses of the CBM1 for each of the seaweed extracts. When the firing frequency of the CBM1 activity after taste stimulation was estimated, the Gelidium extract induced a spike activity of ~30 spikes

  11. Platelet activating factor enhances synaptic vesicle exocytosis via PKC, elevated intracellular calcium, and modulation of synapsin 1 dynamics and phosphorylation

    Directory of Open Access Journals (Sweden)

    Jennetta W Hammond

    2016-01-01

    Full Text Available Platelet activating factor (PAF is an inflammatory phospholipid signaling molecule implicated in synaptic plasticity, learning and memory and neurotoxicity during neuroinflammation. However, little is known about the intracellular mechanisms mediating PAF’s physiological or pathological effects on synaptic facilitation. We show here that PAF receptors are localized at the synapse. Using fluorescent reporters of presynaptic activity we show that a non-hydrolysable analogue of PAF (cPAF enhances synaptic vesicle release from individual presynaptic boutons by increasing the size or release of the readily releasable pool and the exocytosis rate of the total recycling pool. cPAF also activates previously silent boutons resulting in vesicle release from a larger number of terminals. The underlying mechanism involves elevated calcium within presynaptic boutons and protein kinase C (PKC activation. Furthermore, cPAF increases synapsin I phosphorylation at sites 1 and 3, and increases dispersion of synapsin I from the presynaptic compartment during stimulation, freeing synaptic vesicles for subsequent release. These findings provide a conceptual framework for how PAF, regardless of its cellular origin, can modulate synapses during normal and pathologic synaptic activity.

  12. Modulation of Network Oscillatory Activity and GABAergic Synaptic Transmission by CB1 Cannabinoid Receptors in the Rat Medial Entorhinal Cortex

    Directory of Open Access Journals (Sweden)

    Nicola H. Morgan

    2008-01-01

    Full Text Available Cannabinoids modulate inhibitory GABAergic neurotransmission in many brain regions. Within the temporal lobe, cannabinoid receptors are highly expressed, and are located presynaptically at inhibitory terminals. Here, we have explored the role of type-1 cannabinoid receptors (CB1Rs at the level of inhibitory synaptic currents and field-recorded network oscillations. We report that arachidonylcyclopropylamide (ACPA; 10 M, an agonist at CB1R, inhibits GABAergic synaptic transmission onto both superficial and deep medial entorhinal (mEC neurones, but this has little effect on network oscillations in beta/gamma frequency bands. By contrast, the CB1R antagonist/inverse agonist LY320135 (500 nM, increased GABAergic synaptic activity and beta/gamma oscillatory activity in superficial mEC, was suppressed, whilst that in deep mEC was enhanced. These data indicate that cannabinoid-mediated effects on inhibitory synaptic activity may be constitutively active in vitro, and that modulation of CB1R activation using inverse agonists unmasks complex effects of CBR function on network activity.

  13. Gap43 transcription modulation in the adult brain depends on sensory activity and synaptic cooperation.

    Directory of Open Access Journals (Sweden)

    Nicole Rosskothen-Kuhl

    Full Text Available Brain development and learning is accompanied by morphological and molecular changes in neurons. The growth associated protein 43 (Gap43, indicator of neurite elongation and synapse formation, is highly expressed during early stages of development. Upon maturation of the brain, Gap43 is down-regulated by most neurons with the exception of subdivisions such as the CA3 region of hippocampus, the lateral superior olive (LSO and the central inferior colliculus (CIC. Little is known about the regulation of this mRNA in adult brains. We found that the expression of Gap43 mRNA in specific neurons can be modulated by changing sensory activity of the adult brain. Using the central auditory system of rats as a model, Gap43 protein and mRNA levels were determined in LSO and CIC of hearing-experienced rats unilaterally or bilaterally deafened or unilaterally stimulated by a cochlear implant (CI. Our data indicate that Gap43 is a marker useful beyond monitoring neuronal growth and synaptogenesis, reflecting also specific patterns of synaptic activities on specific neurons. Thus, unilateral loss of input to an adult auditory system directly causes asymmetrical expression of Gap43 mRNA between LSOs or CICs on both sides of the brainstem. This consequence can be prevented by simple-patterned stimulation of a dysfunctional ear by way of a CI. We suggest that as a function of input balance and activity pattern, Gap43 mRNA expression changes as cells associate converging afferent signals.

  14. Synaptic heterogeneity and stimulus-induced modulation of depression in central synapses.

    Science.gov (United States)

    Hunter, J D; Milton, J G

    2001-08-01

    Short-term plasticity is a pervasive feature of synapses. Synapses exhibit many forms of plasticity operating over a range of time scales. We develop an optimization method that allows rapid characterization of synapses with multiple time scales of facilitation and depression. Investigation of paired neurons that are postsynaptic to the same identified interneuron in the buccal ganglion of Aplysia reveals that the responses of the two neurons differ in the magnitude of synaptic depression. Also, for single neurons, prolonged stimulation of the presynaptic neuron causes stimulus-induced increases in the early phase of synaptic depression. These observations can be described by a model that incorporates two availability factors, e.g., depletable vesicle pools or desensitizing receptor populations, with different time courses of recovery, and a single facilitation component. This model accurately predicts the responses to novel stimuli. The source of synaptic heterogeneity is identified with variations in the relative sizes of the two availability factors, and the stimulus-induced decrement in the early synaptic response is explained by a slowing of the recovery rate of one of the availability factors. The synaptic heterogeneity and stimulus-induced modifications in synaptic depression observed here emphasize that synaptic efficacy depends on both the individual properties of synapses and their past history.

  15. Neurosteroid modulation of neuronal excitability and synaptic transmission in the rat medial vestibular nuclei.

    Science.gov (United States)

    Grassi, Silvarosa; Frondaroli, Adele; Dieni, Cristina; Dutia, Mayank B; Pettorossi, Vito E

    2007-07-01

    In rat brainstem slices, we investigated the influence of the neurosteroids tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone (ALLO) on the synaptically driven and spontaneous activity of vestibular neurons, by analysing their effects on the amplitude of the field potentials evoked in the medial vestibular nuclei (MVN) by vestibular afferent stimulation and on the spontaneous firing rate of MVN neurons. Furthermore, the interaction with gamma-aminobutyric acid (GABA) and glutamate receptors was analysed by using specific antagonists for GABA(A) (bicuculline), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/ kainate [2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulphonamide disodium salt (NBQX)], N-methyl-D-aspartate (NMDA) [D-(-)-2-amino-5-phosphonopentanoic acid (AP-5)] and group I metabotropic glutamate receptors (mGlu-I) [(R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA)] receptors. THDOC and ALLO evoked two opposite long-lasting effects, consisting of either a potentiation or a reduction of field potential and firing rate, which showed early and late components, occurring in conjunction or separately after neurosteroid application. The depressions depended on GABA(A) receptors, as they were abolished by bicuculline, while early potentiation involved glutamate AMPA/kainate receptors, as NBQX markedly reduced the incidence of early firing rate enhancement and, in the case of ALLO, even provoked depression. This suggests that THDOC and ALLO enhance the GABA(A) inhibitory influence on the MVN neurons and facilitate the AMPA/kainate facilitatory one. Conversely, a late potentiation effect, which was still induced after glutamate and GABA(A) receptor blockade, might involve a different mechanism. We conclude that the modulation of neuronal activity in the MVN by THDOC and ALLO, through their actions on GABA(A) and AMPA/kainate receptors, may have a physiological role in regulating the vestibular system function under normal

  16. Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations

    Directory of Open Access Journals (Sweden)

    Yusuke Nakatsu

    2016-09-01

    Full Text Available Prolyl isomerases are divided into three groups, the FKBP family, Cyclophilin and the Parvulin family (Pin1 and Par14. Among these isomerases, Pin1 is a unique prolyl isomerase binding to the motif including pSer/pThr-Pro that is phosphorylated by kinases. Once bound, Pin1 modulates the enzymatic activity, protein stability or subcellular localization of target proteins by changing the cis- and trans-formations of proline. Several studies have examined the roles of Pin1 in the pathogenesis of cancers and Alzheimer’s disease. On the other hand, recent studies have newly demonstrated Pin1 to be involved in regulating glucose and lipid metabolism. Interestingly, while Pin1 expression is markedly increased by high-fat diet feeding, Pin1 KO mice are resistant to diet-induced obesity, non-alcoholic steatohepatitis and diabetic vascular dysfunction. These phenomena result from the binding of Pin1 to several key factors regulating metabolic functions, which include insulin receptor substrate-1, AMPK, Crtc2 and NF-κB p65. In this review, we focus on recent advances in elucidating the physiological roles of Pin1 as well as the pathogenesis of disorders involving this isomerase, from the viewpoint of the relationships between signal transductions and metabolic functions.

  17. Supernatant from bifidobacterium differentially modulates transduction signaling pathways for biological functions of human dendritic cells.

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    Cyrille Hoarau

    Full Text Available BACKGROUND: Probiotic bacteria have been shown to modulate immune responses and could have therapeutic effects in allergic and inflammatory disorders. However, the signaling pathways engaged by probiotics are poorly understood. We have previously reported that a fermentation product from Bifidobacterium breve C50 (BbC50sn could induce maturation, high IL-10 production and prolonged survival of DCs via a TLR2 pathway. We therefore studied the roles of mitogen-activated protein kinases (MAPK, glycogen synthase kinase-3 (GSK3 and phosphatidylinositol 3-kinase (PI3K pathways on biological functions of human monocyte-derived DCs treated with BbC50sn. METHODOLOGY/PRINCIPAL FINDINGS: DCs were differentiated from human monocytes with IL-4 and GM-CSF for 5 days and cultured with BbC50sn, lipopolysaccharide (LPS or Zymosan, with or without specific inhibitors of p38MAPK (SB203580, ERK (PD98059, PI3K (LY294002 and GSK3 (SB216763. We found that 1 the PI3K pathway was positively involved in the prolonged DC survival induced by BbC50sn, LPS and Zymosan in contrast to p38MAPK and GSK3 which negatively regulated DC survival; 2 p38MAPK and PI3K were positively involved in DC maturation, in contrast to ERK and GSK3 which negatively regulated DC maturation; 3 ERK and PI3K were positively involved in DC-IL-10 production, in contrast to GSK3 that was positively involved in DC-IL-12 production whereas p38MAPK was positively involved in both; 4 BbC50sn induced a PI3K/Akt phosphorylation similar to Zymosan and a p38MAPK phosphorylation similar to LPS. CONCLUSION/SIGNIFICANCE: We report for the first time that a fermentation product of a bifidobacteria can differentially activate MAPK, GSK3 and PI3K in order to modulate DC biological functions. These results give new insights on the fine-tuned balance between the maintenance of normal mucosal homeostasis to commensal and probiotic bacteria and the specific inflammatory immune responses to pathogen bacteria.

  18. Raf kinase inhibitory protein: a signal transduction modulator and metastasis suppressor.

    Science.gov (United States)

    Granovsky, Alexey E; Rosner, Marsha Rich

    2008-04-01

    Cells have a multitude of controls to maintain their integrity and prevent random switching from one biological state to another. Raf Kinase Inhibitory Protein (RKIP), a member of the phosphatidylethanolamine binding protein (PEBP) family, is representative of a new class of modulators of signaling cascades that function to maintain the "yin yang" or balance of biological systems. RKIP inhibits MAP kinase (Raf-MEK-ERK), G protein-coupled receptor (GPCR) kinase and NFkappaB signaling cascades. Because RKIP targets different kinases dependent upon its state of phosphorylation, RKIP also acts to integrate crosstalk initiated by multiple environmental stimuli. Loss or depletion of RKIP results in disruption of the normal cellular stasis and can lead to chromosomal abnormalities and disease states such as cancer. Since RKIP and the PEBP family have been reviewed previously, the goal of this analysis is to provide an update and highlight some of the unique features of RKIP that make it a critical player in the regulation of cellular signaling processes.

  19. DEG/ENaC ion channels involved in sensory transduction are modulated by cold temperature

    Science.gov (United States)

    Askwith, Candice C.; Benson, Christopher J.; Welsh, Michael J.; Snyder, Peter M.

    2001-01-01

    Several DEG/ENaC cation channel subunits are expressed in the tongue and in cutaneous sensory neurons, where they are postulated to function as receptors for salt and sour taste and for touch. Because these tissues are exposed to large temperature variations, we examined how temperature affects DEG/ENaC channel function. We found that cold temperature markedly increased the constitutively active Na+ currents generated by epithelial Na+ channels (ENaC). Half-maximal stimulation occurred at 25°C. Cold temperature did not induce current from other DEG/ENaC family members (BNC1, ASIC, and DRASIC). However, when these channels were activated by acid, cold temperature potentiated the currents by slowing the rate of desensitization. Potentiation was abolished by a “Deg” mutation that alters channel gating. Temperature changes in the physiologic range had prominent effects on current in cells heterologously expressing acid-gated DEG/ENaC channels, as well as in dorsal root ganglion sensory neurons. The finding that cold temperature modulates DEG/ENaC channel function may provide a molecular explanation for the widely recognized ability of temperature to modify taste sensation and mechanosensation. PMID:11353858

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

    Czech Academy of Sciences Publication Activity Database

    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

  1. Short- and long-term modulation of synaptic inputs to brain reward areas by nicotine

    NARCIS (Netherlands)

    Fagen, Z.M.; Mansvelder, H.D.; Keath, R.; McGehee, D.S.

    2003-01-01

    Dopamine signaling in brain reward areas is a key element in the development of drug abuse and dependence. Recent anatomical and electrophysiological research has begun to elucidate both complexity and specificity In synaptic connections between ventral tegmental neurons and their inputs.

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

    Directory of Open Access Journals (Sweden)

    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.

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

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    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.

  4. pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract

    Science.gov (United States)

    McCrimmon, Donald R.; Martina, Marco

    2013-01-01

    The nucleus of the solitary tract (NTS) is the major site for termination of visceral sensory afferents contributing to homeostatic regulation of, for example, arterial pressure, gastric motility, and breathing. Whereas much is known about how different neuronal populations influence these functions, information about the role of glia remains scant. In this article, we propose that glia may contribute to NTS functions by modulating excitatory neurotransmission. We found that acidification (pH 7.0) depolarizes NTS glia by inhibiting K+-selective membrane currents. NTS glia also showed functional expression of voltage-sensitive glutamate transporters, suggesting that extracellular acidification regulates synaptic transmission by compromising glial glutamate uptake. To test this hypothesis, we evoked glutamatergic slow excitatory potentials (SEPs) in NTS neurons with repetitive stimulation (20 pulses at 10 Hz) of the solitary tract. This SEP depends on accumulation of glutamate following repetitive stimulation, since it was potentiated by blocking glutamate uptake with dl-threo-β-benzyloxyaspartic acid (TBOA) or a glia-specific glutamate transport blocker, dihydrokainate (DHK). Importantly, extracellular acidification (pH 7.0) also potentiated the SEP. This effect appeared to be mediated through a depolarization-induced inhibition of glial transporter activity, because it was occluded by TBOA and DHK. In agreement, pH 7.0 did not directly alter d-aspartate-induced responses in NTS glia or properties of presynaptic glutamate release. Thus acidification-dependent regulation of glial function affects synaptic transmission within the NTS. These results suggest that glia play a modulatory role in the NTS by integrating local tissue signals (such as pH) with synaptic inputs from peripheral afferents. PMID:23615553

  5. Agonist-dependent modulation of G-protein coupling and transduction of 5-HT1A receptors in rat dorsal raphe nucleus.

    Science.gov (United States)

    Valdizán, Elsa Maria; Castro, Elena; Pazos, Angel

    2010-08-01

    5-HT1A receptors couple to different Go/Gi proteins in order to mediate a wide range of physiological actions. While activation of post-synaptic 5-HT1A receptors is mainly related to inhibition of adenylyl cyclase activity, functionality of autoreceptors located in raphe nuclei has been classically ascribed to modifications of the activity of potassium and calcium channels. In order to evaluate the possible existence of agonist-directed trafficking for 5-HT1A autoreceptors in the rat dorsal raphe nucleus, we studied their activation by two agonists with a different profile of efficacy [(+)8-OH-DPAT and buspirone], addressing simultaneously the identification of the specific Galpha subtypes ([35S]GTPgammaS labelling and immunoprecipitation) involved and the subsequent changes in cAMP formation. A significant increase (32%, plabelling of immunoprecipitates was obtained with anti-Galphai3 antibodies but not with anti-Galphao, anti-Galphai1, anti-Galphai2, anti-Galphaz or anti-Galphas antibodies. In contrast, in the presence of buspirone, significant [35S]GTPgammaS labelling of immunoprecipitates was obtained with anti-Galphai3 (50%, plabelling with anti-Galphai1, anti-Galphaz or anti-Galphas. The selective 5-HT1A antagonist WAY 100635 blocked the labelling induced by both agonists. Furthermore, (+)8-OH-DPAT failed to modify forskolin-stimulated cAMP accumulation, while buspirone induced a dose-dependent, WAY 100635-sensitive, inhibition of this response (Imax 30.8+/-4.9, pIC50 5.95+/-0.46). These results demonstrate the existence of an agonist-dependency pattern of G-protein coupling and transduction for 5-HT1A autoreceptors in native brain tissue. These data also open new perspectives for the understanding of the differential profiles of agonist efficacy in pre- vs. post-synaptic 5-HT1A receptor-associated responses.

  6. Neurotrophin-3 Regulates Synapse Development by Modulating TrkC-PTPσ Synaptic Adhesion and Intracellular Signaling Pathways.

    Science.gov (United States)

    Han, Kyung Ah; Woo, Doyeon; Kim, Seungjoon; Choii, Gayoung; Jeon, Sangmin; Won, Seoung Youn; Kim, Ho Min; Heo, Won Do; Um, Ji Won; Ko, Jaewon

    2016-04-27

    neurotrophin-3 (NT-3) modulates the synaptic adhesion pathway involving neurotrophin receptor tyrosine kinase C (TrkC) and presynaptic protein tyrosine phosphatase σ (PTPσ) in a bidirectional manner at excitatory synapses. NT-3 acts in concentration-independent manner to facilitate TrkC-mediated presynaptic differentiation, whereas it acts in a concentration-dependent manner to exert differential effects on TrkC-mediated organization of postsynaptic development. We further investigated TrkC extracellular ligand binding, intracellular signaling pathways, and kinase activity in NT-3-induced synapse development. Last, we found that interneuronal differences in TrkC levels regulate the synapse number. Overall, these results suggest that NT-3 functions as a positive modulator of synaptogenesis involving TrkC and PTPσ. Copyright © 2016 the authors 0270-6474/16/364817-16$15.00/0.

  7. High pressure and [Ca2+] produce an inverse modulation of synaptic input strength, network excitability and frequency response in the rat dentate gyrus

    Directory of Open Access Journals (Sweden)

    Thomas I Talpalar

    2016-09-01

    Full Text Available Hyperbaric environments induce the high pressure neurological syndrome (HPNS characterized by hyperexcitability of the central nervous system and memory impairment. Human divers and other animals experience the HPNS at pressures beyond 1.1 MPa. High pressure depresses synaptic transmission and alters its dynamics in various animal models. Medial perforant path (MPP synapses connecting the medial entorhinal cortex with the hippocampal formation are suppressed by 50% at 10.1MPa. Reduction of synaptic inputs is paradoxically associated with enhanced ability of dentate gyrus’ granule cells to generate spikes at high pressure. This mechanism allows MPP inputs to elicit standard granule cell outputs at 0.1 -25 Hz frequencies under hyperbaric conditions. An increased postsynaptic gain of MPP inputs probably allows diving animals to perform in hyperbaric environments, but makes them vulnerable to high intensity/frequency stimuli producing hyperexcitability. Increasing extracellular Ca2+ (Ca2+o partially reverted pressure-mediated depression of MPP inputs and increased MPP’s low-pass filter properties. We postulated that raising Ca2+o in addition to increase synaptic inputs may reduce network excitability in the dentate gyrus potentially improving its function and reducing sensitivity to high intensity and pathologic stimuli. For this matter, we activated the MPP with single and 50 Hz frequency stimuli that simulated physiologic and deleterious conditions, while assessing the granule cell’s output under various conditions of pressure and Ca2+o. Our results reveal that pressure and Ca2+o produce an inverse modulation on synaptic input strength and network excitability. These coincident phenomena suggest a potential general mechanism of networks that adjusts gain as an inverse function of synaptic inputs’ strength. Such mechanism may serve for adaptation to variable pressure and other physiological and pathological conditions and may explain the

  8. Dopamine modulates persistent synaptic activity and enhances the signal-to-noise ratio in the prefrontal cortex.

    Directory of Open Access Journals (Sweden)

    Sven Kroener

    2009-08-01

    Full Text Available The importance of dopamine (DA for prefrontal cortical (PFC cognitive functions is widely recognized, but its mechanisms of action remain controversial. DA is thought to increase signal gain in active networks according to an inverted U dose-response curve, and these effects may depend on both tonic and phasic release of DA from midbrain ventral tegmental area (VTA neurons.We used patch-clamp recordings in organotypic co-cultures of the PFC, hippocampus and VTA to study DA modulation of spontaneous network activity in the form of Up-states and signals in the form of synchronous EPSP trains. These cultures possessed a tonic DA level and stimulation of the VTA evoked DA transients within the PFC. The addition of high (> or = 1 microM concentrations of exogenous DA to the cultures reduced Up-states and diminished excitatory synaptic inputs (EPSPs evoked during the Down-state. Increasing endogenous DA via bath application of cocaine also reduced Up-states. Lower concentrations of exogenous DA (0.1 microM had no effect on the up-state itself, but they selectively increased the efficiency of a train of EPSPs to evoke spikes during the Up-state. When the background DA was eliminated by depleting DA with reserpine and alpha-methyl-p-tyrosine, or by preparing corticolimbic co-cultures without the VTA slice, Up-states could be enhanced by low concentrations (0.1-1 microM of DA that had no effect in the VTA containing cultures. Finally, in spite of the concentration-dependent effects on Up-states, exogenous DA at all but the lowest concentrations increased intracellular current-pulse evoked firing in all cultures underlining the complexity of DA's effects in an active network.Taken together, these data show concentration-dependent effects of DA on global PFC network activity and they demonstrate a mechanism through which optimal levels of DA can modulate signal gain to support cognitive functioning.

  9. Tumor necrosis factor-alpha activates signal transduction in hypothalamus and modulates the expression of pro-inflammatory proteins and orexigenic/anorexigenic neurotransmitters.

    Science.gov (United States)

    Amaral, Maria E; Barbuio, Raquel; Milanski, Marciane; Romanatto, Talita; Barbosa, Helena C; Nadruz, Wilson; Bertolo, Manoel B; Boschero, Antonio C; Saad, Mario J A; Franchini, Kleber G; Velloso, Licio A

    2006-07-01

    Tumor necrosis factor-alpha (TNF-alpha) is known to participate in the wastage syndrome that accompanies cancer and severe infectious diseases. More recently, a role for TNF-alpha in the pathogenesis of type 2 diabetes mellitus and obesity has been shown. Much of the regulatory action exerted by TNF-alpha upon the control of energy stores depends on its action on the hypothalamus. In this study, we show that TNF-alpha activates canonical pro-inflammatory signal transduction pathways in the hypothalamus of rats. These signaling events lead to the transcriptional activation of an early responsive gene and to the induction of expression of cytokines and a cytokine responsive protein such as interleukin-1beta, interleukin-6, interleukin-10 and suppressor of cytokine signalling-3, respectively. In addition, TNF-alpha induces the expression of neurotransmitters involved in the control of feeding and thermogenesis. Thus, TNF-alpha may act directly in the hypothalamus inducing a pro-inflammatory response and the modulation of expression of neurotransmitters involved in energy homeostasis.

  10. Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

    Science.gov (United States)

    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.

  11. Modulation of NMDA Receptor Properties and Synaptic Transmission by the NR3A Subunit in Mouse Hippocampal and Cerebrocortical Neurons

    Science.gov (United States)

    Tong, Gary; Takahashi, Hiroto; Tu, Shichun; Shin, Yeonsook; Talantova, Maria; Zago, Wagner; Xia, Peng; Nie, Zhiguo; Goetz, Thomas; Zhang, Dongxian; Lipton, Stuart A.; Nakanishi, Nobuki

    2015-01-01

    Expression of the NR3A subunit with NR1/NR2 in Xenopus oocytes or mammalian cell lines leads to a reduction in N-methyl-D-aspartate (NMDA)-induced currents and decreased Mg2+ sensitivity and Ca2+ permeability compared with NR1/NR2 receptors. Consistent with these findings, neurons from NR3A knockout (KO) mice exhibit enhanced NMDA-induced currents. Recombinant NR3A can also form excitatory glycine receptors with NR1 in the absence of NR2. However, the effects of NR3A on channel properties in neurons and synaptic transmission have not been fully elucidated. To study physiological roles of NR3A subunits, we generated NR3A transgenic (Tg) mice. Cultured NR3A Tg neurons exhibited two populations of NMDA receptor (NMDAR) channels, reduced Mg2+ sensitivity, and decreased Ca2+ permeability in response to NMDA/glycine, but glycine alone did not elicit excitatory currents. In addition, NMDAR-mediated excitatory postsynaptic currents (EPSCs) in NR3A Tg hippocampal slices showed reduced Mg2+ sensitivity, consistent with the notion that NR3A subunits incorporated into synaptic NMDARs. To study the function of endogenous NR3A subunits, we compared NMDAR-mediated EPSCs in NR3A KO and WT control mice. In NR3A KO mice, the ratio of the amplitudes of the NMDAR-mediated component to α-amino-3-hydroxy-5-methyl-4-isox-azolepropionic acid receptor-mediated component of the EPSC was significantly larger than that seen in WT littermates. This result suggests that NR3A subunits contributed to the NMDAR-mediated component of the EPSC in WT mice. Taken together, these results show that NR3A subunits contribute to NMDAR responses from both synaptic and extra-synaptic receptors, likely composed of NR1, NR2, and NR3 subunits. PMID:18003876

  12. Adenosine A2A receptors modulate the dopamine D2 receptor-mediated inhibition of synaptic transmission in the mouse prefrontal cortex.

    Science.gov (United States)

    Real, Joana I; Simões, Ana Patrícia; Cunha, Rodrigo A; Ferreira, Samira G; Rial, Daniel

    2018-05-01

    Prefrontal cortex (PFC) circuits are modulated by dopamine acting on D 1 - and D 2 -like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A 2A receptors (A 2 A R) also control PFC-related responses and A 2 A R antagonists are potential anti-psychotic drugs. As tight antagonistic A 2 A R-D 2 R and synergistic A 2 A R-D 1 R interactions occur in other brain regions, we now investigated the crosstalk between A 2 A R and D 1 /D 2 R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired-pulse responses. Dopamine inhibition was prevented by the D 2 R-like antagonist sulpiride but not by the D 1 R antagonist SCH23390 and was mimicked by the D 2 R agonist sumanirole, but not by the agonists of either D 4 R (A-412997) or D 3 R (PD128907). Dopamine inhibition was prevented by the A 2 A R antagonist, SCH58261, and attenuated in A 2 A R knockout mice. Accordingly, triple-labelling immunocytochemistry experiments revealed the co-localization of A 2 A R and D 2 R immunoreactivity in glutamatergic (vGluT1-positive) nerve terminals of the PFC. This reported positive A 2 A R-D 2 R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti-psychotic potential of A 2 A R antagonists. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  13. Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease.

    Science.gov (United States)

    Dunn, Amy R; Stout, Kristen A; Ozawa, Minagi; Lohr, Kelly M; Hoffman, Carlie A; Bernstein, Alison I; Li, Yingjie; Wang, Minzheng; Sgobio, Carmelo; Sastry, Namratha; Cai, Huaibin; Caudle, W Michael; Miller, Gary W

    2017-03-14

    Members of the synaptic vesicle glycoprotein 2 (SV2) family of proteins are involved in synaptic function throughout the brain. The ubiquitously expressed SV2A has been widely implicated in epilepsy, although SV2C with its restricted basal ganglia distribution is poorly characterized. SV2C is emerging as a potentially relevant protein in Parkinson disease (PD), because it is a genetic modifier of sensitivity to l-DOPA and of nicotine neuroprotection in PD. Here we identify SV2C as a mediator of dopamine homeostasis and report that disrupted expression of SV2C within the basal ganglia is a pathological feature of PD. Genetic deletion of SV2C leads to reduced dopamine release in the dorsal striatum as measured by fast-scan cyclic voltammetry, reduced striatal dopamine content, disrupted α-synuclein expression, deficits in motor function, and alterations in neurochemical effects of nicotine. Furthermore, SV2C expression is dramatically altered in postmortem brain tissue from PD cases but not in Alzheimer disease, progressive supranuclear palsy, or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated α-synuclein. These data establish SV2C as a mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction.

  14. Modulation of firing and synaptic transmission of serotonergic neurons by intrinsic G protein-coupled receptors and ion channels

    Directory of Open Access Journals (Sweden)

    Takashi eMaejima

    2013-05-01

    Full Text Available Serotonergic neurons project to virtually all regions of the CNS and are consequently involved in many critical physiological functions such as mood, sexual behavior, feeding, sleep/wake cycle, memory, cognition, blood pressure regulation, breathing and reproductive success. Therefore serotonin release and serotonergic neuronal activity have to be precisely controlled and modulated by interacting brain circuits to adapt to specific emotional and environmental states. We will review the current knowledge about G protein-coupled receptors and ion channels involved in the regulation of serotonergic system, how their regulation is modulating the intrinsic activity of serotonergic neurons and its transmitter release and will discuss the latest methods for controlling the modulation of serotonin release and intracellular signaling in serotonergic neurons in vitro and in vivo.

  15. Synaptic Cell Adhesion

    OpenAIRE

    Missler, Markus; Südhof, Thomas C.; Biederer, Thomas

    2012-01-01

    Chemical synapses are asymmetric intercellular junctions that mediate synaptic transmission. Synaptic junctions are organized by trans-synaptic cell adhesion molecules bridging the synaptic cleft. Synaptic cell adhesion molecules not only connect pre- and postsynaptic compartments, but also mediate trans-synaptic recognition and signaling processes that are essential for the establishment, specification, and plasticity of synapses. A growing number of synaptic cell adhesion molecules that inc...

  16. Glutamatergic modulation of synaptic-like vesicle recycling in mechanosensory lanceolate nerve terminals of mammalian hair follicles.

    Science.gov (United States)

    Banks, Robert W; Cahusac, Peter M B; Graca, Anna; Kain, Nakul; Shenton, Fiona; Singh, Paramjeet; Njå, Arild; Simon, Anna; Watson, Sonia; Slater, Clarke R; Bewick, Guy S

    2013-05-15

    Our aim in the present study was to determine whether a glutamatergic modulatory system involving synaptic-like vesicles (SLVs) is present in the lanceolate ending of the mouse and rat hair follicle and, if so, to assess its similarity to that of the rat muscle spindle annulospiral ending we have described previously. Both types of endings are formed by the peripheral sensory terminals of primary mechanosensory dorsal root ganglion cells, so the presence of such a system in the lanceolate ending would provide support for our hypothesis that it is a general property of fundamental importance to the regulation of the responsiveness of the broad class of primary mechanosensory endings. We show not only that an SLV-based system is present in lanceolate endings, but also that there are clear parallels between its operation in the two types of mechanosensory endings. In particular, we demonstrate that, as in the muscle spindle: (i) FM1-43 labels the sensory terminals of the lanceolate ending, rather than the closely associated accessory (glial) cells; (ii) the dye enters and leaves the terminals primarily by SLV recycling; (iii) the dye does not block the electrical response to mechanical stimulation, in contrast to its effect on the hair cell and dorsal root ganglion cells in culture; (iv) SLV recycling is Ca(2+) sensitive; and (v) the sensory terminals are enriched in glutamate. Thus, in the lanceolate sensory ending SLV recycling is itself regulated, at least in part, by glutamate acting through a phospholipase D-coupled metabotropic glutamate receptor.

  17. Cerebellar Norepinephrine Modulates Learning of Delay Classical Eyeblink Conditioning: Evidence for Post-Synaptic Signaling via PKA

    Science.gov (United States)

    Fister, Mathew; Bickford, Paula C.; Cartford, M. Claire; Samec, Amy

    2004-01-01

    The neurotransmitter norepinephrine (NE) has been shown to modulate cerebellar-dependent learning and memory. Lesions of the nucleus locus coeruleus or systemic blockade of noradrenergic receptors has been shown to delay the acquisition of several cerebellar-dependent learning tasks. To date, no studies have shown a direct involvement of…

  18. Muscle Contraction Regulates BDNF/TrkB Signaling to Modulate Synaptic Function through Presynaptic cPKCα and cPKCβI.

    Science.gov (United States)

    Hurtado, Erica; Cilleros, Víctor; Nadal, Laura; Simó, Anna; Obis, Teresa; Garcia, Neus; Santafé, Manel M; Tomàs, Marta; Halievski, Katherine; Jordan, Cynthia L; Lanuza, Maria A; Tomàs, Josep

    2017-01-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) acts via tropomyosin-related kinase B receptor (TrkB) to regulate synapse maintenance and function in the neuromuscular system. The potentiation of acetylcholine (ACh) release by BDNF requires TrkB phosphorylation and Protein Kinase C (PKC) activation. BDNF is secreted in an activity-dependent manner but it is not known if pre- and/or postsynaptic activities enhance BDNF expression in vivo at the neuromuscular junction (NMJ). Here, we investigated whether nerve and muscle cell activities regulate presynaptic conventional PKC (cPKCα and βI) via BDNF/TrkB signaling to modulate synaptic strength at the NMJ. To differentiate the effects of presynaptic activity from that of muscle contraction, we stimulated the phrenic nerve of rat diaphragms (1 Hz, 30 min) with or without contraction (abolished by μ-conotoxin GIIIB). Then, we performed ELISA, Western blotting, qRT-PCR, immunofluorescence and electrophysiological techniques. We found that nerve-induced muscle contraction: (1) increases the levels of mature BDNF protein without affecting pro-BDNF protein or BDNF mRNA levels; (2) downregulates TrkB.T1 without affecting TrkB.FL or p75 neurotrophin receptor (p75) levels; (3) increases presynaptic cPKCα and cPKCβI protein level through TrkB signaling; and (4) enhances phosphorylation of cPKCα and cPKCβI. Furthermore, we demonstrate that cPKCβI, which is exclusively located in the motor nerve terminals, increases activity-induced acetylcholine release. Together, these results show that nerve-induced muscle contraction is a key regulator of BDNF/TrkB signaling pathway, retrogradely activating presynaptic cPKC isoforms (in particular cPKCβI) to modulate synaptic function. These results indicate that a decrease in neuromuscular activity, as occurs in several neuromuscular disorders, could affect the BDNF/TrkB/PKC pathway that links pre- and postsynaptic activity to maintain neuromuscular function.

  19. Muscle Contraction Regulates BDNF/TrkB Signaling to Modulate Synaptic Function through Presynaptic cPKCα and cPKCβI

    Directory of Open Access Journals (Sweden)

    Erica Hurtado

    2017-05-01

    Full Text Available The neurotrophin brain-derived neurotrophic factor (BDNF acts via tropomyosin-related kinase B receptor (TrkB to regulate synapse maintenance and function in the neuromuscular system. The potentiation of acetylcholine (ACh release by BDNF requires TrkB phosphorylation and Protein Kinase C (PKC activation. BDNF is secreted in an activity-dependent manner but it is not known if pre- and/or postsynaptic activities enhance BDNF expression in vivo at the neuromuscular junction (NMJ. Here, we investigated whether nerve and muscle cell activities regulate presynaptic conventional PKC (cPKCα and βI via BDNF/TrkB signaling to modulate synaptic strength at the NMJ. To differentiate the effects of presynaptic activity from that of muscle contraction, we stimulated the phrenic nerve of rat diaphragms (1 Hz, 30 min with or without contraction (abolished by μ-conotoxin GIIIB. Then, we performed ELISA, Western blotting, qRT-PCR, immunofluorescence and electrophysiological techniques. We found that nerve-induced muscle contraction: (1 increases the levels of mature BDNF protein without affecting pro-BDNF protein or BDNF mRNA levels; (2 downregulates TrkB.T1 without affecting TrkB.FL or p75 neurotrophin receptor (p75 levels; (3 increases presynaptic cPKCα and cPKCβI protein level through TrkB signaling; and (4 enhances phosphorylation of cPKCα and cPKCβI. Furthermore, we demonstrate that cPKCβI, which is exclusively located in the motor nerve terminals, increases activity-induced acetylcholine release. Together, these results show that nerve-induced muscle contraction is a key regulator of BDNF/TrkB signaling pathway, retrogradely activating presynaptic cPKC isoforms (in particular cPKCβI to modulate synaptic function. These results indicate that a decrease in neuromuscular activity, as occurs in several neuromuscular disorders, could affect the BDNF/TrkB/PKC pathway that links pre- and postsynaptic activity to maintain neuromuscular function.

  20. EDITORIAL: Synaptic electronics Synaptic electronics

    Science.gov (United States)

    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

  1. Agonist-dependent modulation of G-protein coupling and transduction of 5-HT1A receptors in rat dorsal raphe nucleus

    OpenAIRE

    Valdizán, Elsa M.; Castro, Elena; Pazos, Ángel

    2009-01-01

    5-HT1A receptors couple to different Go/Gi proteins in order to mediate a wide range of physiological actions. While activation of post-synaptic 5-HT1A receptors is mainly related to inhibition of adenylyl cyclase activity, functionality of autoreceptors located in raphe nuclei has been classically ascribed to modifications of the activity of potassium and calcium channels. In order to evaluate the possible existence of agonist-directed trafficking for 5-HT1A autoreceptors in the rat dorsal r...

  2. Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice.

    Science.gov (United States)

    Wang, Ying; Tang, Xi Can; Zhang, Hai Yan

    2012-02-01

    Huperzine A (HupA) is a potent acetylcholinesterase inhibitor (AChEI) used in the treatment of Alzheimer's disease (AD). Recently, HupA was shown to be active in modulating the nonamyloidogenic metabolism of β-amyloid precursor protein (APP) in APP-transfected human embryonic kidney cell line (HEK293swe). However, in vivo research concerning the mechanism of HupA in APP transgenic mice has not yet been fully elucidated. The present study indicates that the loss of dendritic spine density and synaptotagmin levels in the brain of APPswe/presenilin-1 (PS1) transgenic mice was significantly ameliorated by chronic HupA treatment and provides evidence that this neuroprotection was associated with reduced amyloid plaque burden and oligomeric β-amyloid (Aβ) levels in the cortex and hippocampus of APPswe/PS1dE9 transgenic mice. Our findings further demonstrate that the amelioration effect of HupA on Aβ deposits may be mediated, at least in part, by regulation of the compromised expression of a disintegrin and metalloprotease 10 (ADAM10) and excessive membrane trafficking of β-site APP cleavage enzyme 1 (BACE1) in these transgenic mice. In addition, extracellular signal-regulated kinases 1/2 (Erk1/2) phosphorylation may also be partially involved in the effect of HupA on APP processing. In conclusion, our work for the first time demonstrates the neuroprotective effect of HupA on synaptic deficits in APPswe/PS1dE9 transgenic mice and further clarifies the potential pharmacological targets for this protective effect, in which modulation of nonamyloidogenic and amyloidogenic APP processing pathways may be both involved. These findings may provide adequate evidence for the clinical and experimental benefits gained from HupA treatment. Copyright © 2011 Wiley Periodicals, Inc.

  3. Synaptic Effects of Electric Fields

    Science.gov (United States)

    Rahman, Asif

    Learning and sensory processing in the brain relies on the effective transmission of information across synapses. The strength and efficacy of synaptic transmission is modifiable through training and can be modulated with noninvasive electrical brain stimulation. Transcranial electrical stimulation (TES), specifically, induces weak intensity and spatially diffuse electric fields in the brain. Despite being weak, electric fields modulate spiking probability and the efficacy of synaptic transmission. These effects critically depend on the direction of the electric field relative to the orientation of the neuron and on the level of endogenous synaptic activity. TES has been used to modulate a wide range of neuropsychiatric indications, for various rehabilitation applications, and cognitive performance in diverse tasks. How can a weak and diffuse electric field, which simultaneously polarizes neurons across the brain, have precise changes in brain function? Designing therapies to maximize desired outcomes and minimize undesired effects presents a challenging problem. A series of experiments and computational models are used to define the anatomical and functional factors leading to specificity of TES. Anatomical specificity derives from guiding current to targeted brain structures and taking advantage of the direction-sensitivity of neurons with respect to the electric field. Functional specificity originates from preferential modulation of neuronal networks that are already active. Diffuse electric fields may recruit connected brain networks involved in a training task and promote plasticity along active synaptic pathways. In vitro, electric fields boost endogenous synaptic plasticity and raise the ceiling for synaptic learning with repeated stimulation sessions. Synapses undergoing strong plasticity are preferentially modulated over weak synapses. Therefore, active circuits that are involved in a task could be more susceptible to stimulation than inactive circuits

  4. Investigating the molecular pathway through which L-Lactate interacts with synaptic NMDAR to modulate neuronal plasticity

    KAUST Repository

    Ibrahim, Engy

    2016-12-01

    In the brain, glycogen, the storage form of glucose, is exclusively localized in astrocytes (Magistretti and Allaman, 2015). Glycogenolysis leads to the production of L-lactate, which is shuttled to neurons for ATP production. Interestingly, L-lactate was recently shown to be not only a source of energy, but also a signaling molecule to neurons. This was demonstrated through the inhibition of L-lactate production or transport in an inhibitory avoidance paradigm, where the rodents developed amnesia. This inhibition of memory consolidation was rescued by L-lactate and not by equicaloric glucose emphasizing that L-lactate acts as a signaling molecule as well (Suzuki et al., 2011). A recent study in our laboratory suggests that the action of L-lactate takes place through a cascade of molecular events via the modulation of N-methyl-D-aspartate receptor (NMDAR) activity (Yang et al., 2014). Since NADH produced similar results to those seen with L-lactate, it was hypothesized that the action of the latter is based on altering the redox state of the cell, in particular in view of the fact that redox-sensitive sites are present on the NMDAR. However, the precise molecular mechanism underlying the apparent change in the NMDAR activity is not fully elucidated. The objective of this study is to explore those mechanisms.

  5. Azadirachtin blocks the calcium channel and modulates the cholinergic miniature synaptic current in the central nervous system of Drosophila.

    Science.gov (United States)

    Qiao, Jingda; Zou, Xiaolu; Lai, Duo; Yan, Ying; Wang, Qi; Li, Weicong; Deng, Shengwen; Xu, Hanhong; Gu, Huaiyu

    2014-07-01

    Azadirachtin is a botanical pesticide, which possesses conspicuous biological actions such as insecticidal, anthelmintic, antifeedancy, antimalarial effects as well as insect growth regulation. Deterrent for chemoreceptor functions appears to be the main mechanism involved in the potent biological actions of Azadirachtin, although the cytotoxicity and subtle changes to skeletal muscle physiology may also contribute to its insecticide responses. In order to discover the effects of Azadirachtin on the central nervous system (CNS), patch-clamp recording was applied to Drosophila melanogaster, which has been widely used in neurological research. Here, we describe the electrophysiological properties of a local neuron located in the suboesophageal ganglion region of D. melanogaster using the whole brain. The patch-clamp recordings suggested that Azadirachtin modulates the properties of cholinergic miniature excitatory postsynaptic current (mEPSC) and calcium currents, which play important roles in neural activity of the CNS. The frequency of mEPSC and the peak amplitude of the calcium currents significantly decreased after application of Azadirachtin. Our study indicates that Azadirachtin can interfere with the insect's CNS via inhibition of excitatory cholinergic transmission and partly blocking the calcium channel. © 2013 Society of Chemical Industry.

  6. Synaptic function is modulated by LRRK2 and glutamate release is increased in cortical neurons of G2019S LRRK2 knock-in mice.

    Science.gov (United States)

    Beccano-Kelly, Dayne A; Kuhlmann, Naila; Tatarnikov, Igor; Volta, Mattia; Munsie, Lise N; Chou, Patrick; Cao, Li-Ping; Han, Heather; Tapia, Lucia; Farrer, Matthew J; Milnerwood, Austen J

    2014-01-01

    Mutations in Leucine-Rich Repeat Kinase-2 (LRRK2) result in familial Parkinson's disease and the G2019S mutation alone accounts for up to 30% in some ethnicities. Despite this, the function of LRRK2 is largely undetermined although evidence suggests roles in phosphorylation, protein interactions, autophagy and endocytosis. Emerging reports link loss of LRRK2 to altered synaptic transmission, but the effects of the G2019S mutation upon synaptic release in mammalian neurons are unknown. To assess wild type and mutant LRRK2 in established neuronal networks, we conducted immunocytochemical, electrophysiological and biochemical characterization of >3 week old cortical cultures of LRRK2 knock-out, wild-type overexpressing and G2019S knock-in mice. Synaptic release and synapse numbers were grossly normal in LRRK2 knock-out cells, but discretely reduced glutamatergic activity and reduced synaptic protein levels were observed. Conversely, synapse density was modestly but significantly increased in wild-type LRRK2 overexpressing cultures although event frequency was not. In knock-in cultures, glutamate release was markedly elevated, in the absence of any change to synapse density, indicating that physiological levels of G2019S LRRK2 elevate probability of release. Several pre-synaptic regulatory proteins shown by others to interact with LRRK2 were expressed at normal levels in knock-in cultures; however, synapsin 1 phosphorylation was significantly reduced. Thus, perturbations to the pre-synaptic release machinery and elevated synaptic transmission are early neuronal effects of LRRK2 G2019S. Furthermore, the comparison of knock-in and overexpressing cultures suggests that one copy of the G2019S mutation has a more pronounced effect than an ~3-fold increase in LRRK2 protein. Mutant-induced increases in transmission may convey additional stressors to neuronal physiology that may eventually contribute to the pathogenesis of Parkinson's disease.

  7. Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Harsh Sancheti

    Full Text Available Alzheimer's disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits and synaptic plasticity have been shown to be affected in the early stages of Alzheimer's disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer's disease (3xTg-AD that shows progression of pathology as a function of age; two age groups: 6 months (young and 12 months (old were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O and long term potentiation (LTP (measured by electrophysiology. Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice.

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

    Science.gov (United States)

    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.

  9. Saccharomyces boulardii Preserves the Barrier Function and Modulates the Signal Transduction Pathway Induced in Enteropathogenic Escherichia coli-Infected T84 Cells

    Science.gov (United States)

    Czerucka, Dorota; Dahan, Stephanie; Mograbi, Baharia; Rossi, Bernard; Rampal, Patrick

    2000-01-01

    Use of the nonpathogenic yeast Saccharomyces boulardii in the treatment of infectious diarrhea has attracted growing interest. The present study designed to investigate the effect of this yeast on enteropathogenic Escherichia coli (EPEC)-associated disease demonstrates that S. boulardii abrogated the alterations induced by an EPEC strain on transepithelial resistance, [3H]inulin flux, and ZO-1 distribution in T84 cells. Moreover, EPEC-mediated apoptosis of epithelial cells was delayed in the presence of S. boulardii. The yeast did not modify the number of adherent bacteria but lowered by 50% the number of intracellular bacteria. Infection by EPEC induced tyrosine phosphorylation of several proteins in T84 cells, including p46 and p52 SHC isoforms, that was attenuated in the presence of S. boulardii. Similarly, EPEC-induced activation of the ERK1/2 mitogen-activated protein (MAP) kinase pathway was diminished in the presence of the yeast. Interestingly, inhibition of the ERK1/2 pathway with the specific inhibitor PD 98059 decreased EPEC internalization, suggesting that modulation of the ERK1/2 MAP pathway might account for the lowering of the number of intracellular bacteria observed in the presence of S. boulardii. Altogether, this study demonstrated that S. boulardii exerts a protective effect on epithelial cells after EPEC adhesion by modulating the signaling pathway induced by bacterial infection. PMID:10992512

  10. Falsification of the ionic channel theory of hair cell transduction.

    Science.gov (United States)

    Rossetto, Michelangelo

    2013-11-01

    The hair cell provides the transduction of mechanical vibrations in the balance and acoustic sense of all vertebrates that swim, walk, or fly. The current theory places hair cell transduction in a mechanically controlled ion channel. Although the theory of a mechanical input modulating the flow of ions through an ion pore has been a useful tool, it is falsified by experimental data in the literature and can be definitively falsified by a proposed experiment.

  11. Organophosphorous pesticide metabolite (DEDTP) induces changes in the activation status of human lymphocytes by modulating the interleukin 2 receptor signal transduction pathway

    International Nuclear Information System (INIS)

    Esquivel-Senties, M.S.; Barrera, I.; Ortega, A.; Vega, L.

    2010-01-01

    Diethyldithiophosphate (DEDTP) is a metabolite formed by biotransformation of organophosphorous (OP) compounds that has a longer half-life than its parental compound. Here we evaluate the effects of DEDTP on human CD4+ T lymphocytes. In vitro exposure to DEDTP (1-50 μM) decreased [ 3 H]thymidine incorporation in resting cells and increased CD25 surface expression without altering cell viability. DEDTP treatment inhibited anti-CD3/anti-CD28 stimulation-induced CD4+ and CD8+ T cell proliferation determined by CFSE dilution. Decreased CD25 expression and intracellular IL-2 levels were correlated with this defect in cell proliferation. IL-2, IFN-γ and IL-10 secretion were also reduced while IL-4 secretion was not altered. Increased phosphorylation of SOCS3 and dephosphorylation of STAT5 were induced by DEDTP after as little as 5 min of exposure. In addition, DEDTP induced phosphorylation of ERK, JNK and p38 and NFAT nuclear translocation. These results suggest that DEDTP can modulate phosphorylation of intracellular proteins such as SOCS3, which functions as a negative regulator of cytokine signalling, and that DEDTP exposure may thus cause T cells to fail to respond to further antigen challenges.

  12. BDNF-TrkB Signaling Coupled to nPKCε and cPKCβI Modulate the Phosphorylation of the Exocytotic Protein Munc18-1 During Synaptic Activity at the Neuromuscular Junction

    Directory of Open Access Journals (Sweden)

    Anna Simó

    2018-06-01

    Full Text Available Munc18-1, a neuron-specific member of the Sec1/Munc18 family, is involved in neurotransmitter release by binding tightly to syntaxin. Munc18-1 is phosphorylated by PKC on Ser-306 and Ser-313 in vitro which reduces the amount of Munc18-1 able to bind syntaxin. We have previously identified that PKC is involved in neurotransmitter release when continuous electrical stimulation imposes a moderate activity on the NMJ and that muscle contraction through TrkB has an important impact on presynaptic PKC isoforms levels, specifically cPKCβI and nPKCε. Therefore, the present study was designed to understand how Munc18-1 phosphorylation is affected by (1 synaptic activity at the neuromuscular junction, (2 nPKCε and cPKCβI isoforms activity, (3 muscle contraction per se, and (4 the BDNF/TrkB signaling in a neuromuscular activity-dependent manner. We performed immunohistochemistry and confocal techniques to evidence the presynaptic location of Munc18-1 in the rat diaphragm muscle. To study synaptic activity, we stimulated the phrenic nerve (1 Hz, 30 min with or without contraction (abolished by μ-conotoxin GIIIB. Specific inhibitory reagents were used to block nPKCε and cPKCβI activity and to modulate the tropomyosin receptor kinase B (TrkB. Main results obtained from Western blot experiments showed that phosphorylation of Munc18-1 at Ser-313 increases in response to a signaling mechanism initiated by synaptic activity and directly mediated by nPKCε. Otherwise, cPKCβI and TrkB activities work together to prevent this synaptic activity–induced Munc18-1 phosphorylation by a negative regulation of cPKCβI over nPKCε. Therefore, a balance between the activities of these PKC isoforms could be a relevant cue in the regulation of the exocytotic apparatus. The results also demonstrate that muscle contraction prevents the synaptic activity–induced Munc18-1 phosphorylation through a mechanism that opposes the TrkB/cPKCβI/nPKCε signaling.

  13. BDNF-TrkB Signaling Coupled to nPKCε and cPKCβI Modulate the Phosphorylation of the Exocytotic Protein Munc18-1 During Synaptic Activity at the Neuromuscular Junction.

    Science.gov (United States)

    Simó, Anna; Just-Borràs, Laia; Cilleros-Mañé, Víctor; Hurtado, Erica; Nadal, Laura; Tomàs, Marta; Garcia, Neus; Lanuza, Maria A; Tomàs, Josep

    2018-01-01

    Munc18-1, a neuron-specific member of the Sec1/Munc18 family, is involved in neurotransmitter release by binding tightly to syntaxin. Munc18-1 is phosphorylated by PKC on Ser-306 and Ser-313 in vitro which reduces the amount of Munc18-1 able to bind syntaxin. We have previously identified that PKC is involved in neurotransmitter release when continuous electrical stimulation imposes a moderate activity on the NMJ and that muscle contraction through TrkB has an important impact on presynaptic PKC isoforms levels, specifically cPKCβI and nPKCε. Therefore, the present study was designed to understand how Munc18-1 phosphorylation is affected by (1) synaptic activity at the neuromuscular junction, (2) nPKCε and cPKCβI isoforms activity, (3) muscle contraction per se , and (4) the BDNF/TrkB signaling in a neuromuscular activity-dependent manner. We performed immunohistochemistry and confocal techniques to evidence the presynaptic location of Munc18-1 in the rat diaphragm muscle. To study synaptic activity, we stimulated the phrenic nerve (1 Hz, 30 min) with or without contraction (abolished by μ-conotoxin GIIIB). Specific inhibitory reagents were used to block nPKCε and cPKCβI activity and to modulate the tropomyosin receptor kinase B (TrkB). Main results obtained from Western blot experiments showed that phosphorylation of Munc18-1 at Ser-313 increases in response to a signaling mechanism initiated by synaptic activity and directly mediated by nPKCε. Otherwise, cPKCβI and TrkB activities work together to prevent this synaptic activity-induced Munc18-1 phosphorylation by a negative regulation of cPKCβI over nPKCε. Therefore, a balance between the activities of these PKC isoforms could be a relevant cue in the regulation of the exocytotic apparatus. The results also demonstrate that muscle contraction prevents the synaptic activity-induced Munc18-1 phosphorylation through a mechanism that opposes the TrkB/cPKCβI/nPKCε signaling.

  14. Neuromodulation, development and synaptic plasticity.

    Science.gov (United States)

    Foehring, R C; Lorenzon, N M

    1999-03-01

    We discuss parallels in the mechanisms underlying use-dependent synaptic plasticity during development and long-term potentiation (LTP) and long-term depression (LTD) in neocortical synapses. Neuromodulators, such as norepinephrine, serotonin, and acetylcholine have also been implicated in regulating both developmental plasticity and LTP/LTD. There are many potential levels of interaction between neuromodulators and plasticity. Ion channels are substrates for modulation in many cell types. We discuss examples of modulation of voltage-gated Ca2+ channels and Ca(2+)-dependent K+ channels and the consequences for neocortical pyramidal cell firing behaviour. At the time when developmental plasticity is most evident in rat cortex, the substrate for modulation is changing as the densities and relative proportions of various ion channels types are altered during ontogeny. We discuss examples of changes in K+ and Ca2+ channels and the consequence for modulation of neuronal activity.

  15. Modulation of Long-term Potentiation of Cortico-amygdala Synaptic Responses and Auditory Fear Memory by Dietary Polyunsaturated Fatty Acid

    Directory of Open Access Journals (Sweden)

    Daisuke Yamada

    2016-08-01

    Full Text Available Converging evidence suggests that an imbalance of ω3 to ω6 polyunsaturated fatty acid (PUFA in the brain is involved in mental illnesses such as anxiety disorders. However, the underlying mechanism is unknown. We previously reported that the dietary ratio of ω3 to ω6 PUFA alters this ratio in the brain, and influences contextual fear memory. In addition to behavioral change, enhancement of cannabinoid CB1 receptor-mediated short-term synaptic plasticity and facilitation of the agonist sensitivity of CB1 receptors have been observed in excitatory synaptic responses in the basolateral nucleus of the amygdala. However, it is not known whether long-term synaptic plasticity in the amygdala is influenced by the dietary ratio of ω3 to ω6 PUFA. In the present study, we examined long-term potentiation (LTP of optogenetically–evoked excitatory synaptic responses in synapses between the terminal of the projection from the auditory cortex and the pyramidal cells in the lateral nucleus of the amygdala. We found that LTP in this pathway was attenuated in mice fed a diet with a high ω3 to ω6 PUFA ratio (0.97, compared with mice fed a diet with a low ω3 to ω6 PUFA ratio (0.14. Furthermore, mice in the former condition showed reduced fear responses in an auditory fear conditioning test, compared with mice in the latter condition. In both electrophysiological and behavioral experiments, the effect of a diet with a high ω3 to ω6 PUFA ratio was completely blocked by treatment with a CB1 receptor antagonist. Furthermore, a significant reduction was observed in cholesterol content, but not in the level of an endogenous CB1 receptor agonist, 2-arachidonoylglycerol, in brain samples containing the amygdala. These results suggest that the balance of ω3 to ω6 PUFA has an impact on fear memory and cortico-amygdala synaptic plasticity, both in a CB1 receptor–dependent manner.

  16. Synaptic control of motoneuronal excitability

    DEFF Research Database (Denmark)

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

    2000-01-01

    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......, and membrane properties, both passive and active. We then describe the general anatomical organization of synaptic input to motoneurons, followed by a description of the major transmitter systems that affect motoneuronal excitability, including ligands, receptor distribution, pre- and postsynaptic actions...... and norepinephrine, and neuropeptides, as well as the glutamate and GABA acting at metabotropic receptors, modulate motoneuronal excitability through pre- and postsynaptic actions. Acting principally via second messenger systems, their actions converge on common effectors, e.g., leak K(+) current, cationic inward...

  17. Molecular mechanisms of synaptic remodeling in alcoholism.

    Science.gov (United States)

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-05

    Alcohol use and alcohol addiction represent dysfunctional brain circuits resulting from neuroadaptive changes during protracted alcohol exposure and its withdrawal. Alcohol exerts a potent effect on synaptic plasticity and dendritic spine formation in specific brain regions, providing a neuroanatomical substrate for the pathophysiology of alcoholism. Epigenetics has recently emerged as a critical regulator of gene expression and synaptic plasticity-related events in the brain. Alcohol exposure and withdrawal induce changes in crucial epigenetic processes in the emotional brain circuitry (amygdala) that may be relevant to the negative affective state defined as the "dark side" of addiction. Here, we review the literature concerning synaptic plasticity and epigenetics, with a particular focus on molecular events related to dendritic remodeling during alcohol abuse and alcoholism. Targeting epigenetic processes that modulate synaptic plasticity may yield novel treatments for alcoholism. Published by Elsevier Ireland Ltd.

  18. Lateral regulation of synaptic transmission by astrocytes.

    Science.gov (United States)

    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. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Caffeine and modafinil given during 48 h sleep deprivation modulate object recognition memory and synaptic proteins in the hippocampus of the rat.

    Science.gov (United States)

    Wadhwa, M; Sahu, S; Kumari, P; Kauser, H; Ray, K; Panjwani, U

    2015-11-01

    We aimed to evaluate the effect of caffeine/modafinil on sleep deprivation (SD) induced alterations in recognition memory and synaptic proteins. The data revealed a beneficial effect of caffeine/modafinil against deficit in the familiar object retrieval performance and object exploration ratio after 48 h SD. Caffeine treatment prevented the SD induced down-regulation of synaptophysin and synapsin I proteins with no change in PSD-95 protein in hippocampus. However, modafinil administration improved the down-regulation of synaptophysin, synapsin I and PSD-95 proteins in hippocampus. Hence, caffeine/modafinil can serve as counter measures in amelioration of SD induced consequences at behavioural and protein levels. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Synaptic transmission block by presynaptic injection of oligomeric amyloid beta

    Science.gov (United States)

    Moreno, Herman; Yu, Eunah; Pigino, Gustavo; Hernandez, Alejandro I.; Kim, Natalia; Moreira, Jorge E.; Sugimori, Mutsuyuki; Llinás, Rodolfo R.

    2009-01-01

    Early Alzheimer's disease (AD) pathophysiology is characterized by synaptic changes induced by degradation products of amyloid precursor protein (APP). The exact mechanisms of such modulation are unknown. Here, we report that nanomolar concentrations of intraaxonal oligomeric (o)Aβ42, but not oAβ40 or extracellular oAβ42, acutely inhibited synaptic transmission at the squid giant synapse. Further characterization of this phenotype demonstrated that presynaptic calcium currents were unaffected. However, electron microscopy experiments revealed diminished docked synaptic vesicles in oAβ42-microinjected terminals, without affecting clathrin-coated vesicles. The molecular events of this modulation involved casein kinase 2 and the synaptic vesicle rapid endocytosis pathway. These findings open the possibility of a new therapeutic target aimed at ameliorating synaptic dysfunction in AD. PMID:19304802

  1. Synaptic Plasticity and Nociception

    Institute of Scientific and Technical Information of China (English)

    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.

  2. Banach Synaptic Algebras

    Science.gov (United States)

    Foulis, David J.; Pulmannov, Sylvia

    2018-04-01

    Using a representation theorem of Erik Alfsen, Frederic Schultz, and Erling Størmer for special JB-algebras, we prove that a synaptic algebra is norm complete (i.e., Banach) if and only if it is isomorphic to the self-adjoint part of a Rickart C∗-algebra. Also, we give conditions on a Banach synaptic algebra that are equivalent to the condition that it is isomorphic to the self-adjoint part of an AW∗-algebra. Moreover, we study some relationships between synaptic algebras and so-called generalized Hermitian algebras.

  3. Folate and S-adenosylmethionine modulate synaptic activity in cultured cortical neurons: acute differential impact on normal and apolipoprotein-deficient mice

    International Nuclear Information System (INIS)

    Serra, Michael; Chan, Amy; Dubey, Maya; Shea, Thomas B; Gilman, Vladimir

    2008-01-01

    Folate deficiency is accompanied by a decline in the cognitive neurotransmitter acetylcholine and a decline in cognitive performance in mice lacking apolipoprotein E (ApoE−/− mice), a low-density lipoprotein that regulates aspects of lipid metabolism. One direct consequence of folate deficiency is a decline in S-adenosylmethionine (SAM). Since dietary SAM supplementation maintains acetylcholine levels and cognitive performance in the absence of folate, we examined herein the impact of folate and SAM on neuronal synaptic activity. Embryonic cortical neurons from mice expressing or lacking ApoE (ApoE+/+ or −/−, respectively) were cultured for 1 month on multi-electrode arrays, and signaling was recorded. ApoE+/+ cultures displayed significantly more frequent spontaneous signals than ApoE−/− cultures. Supplementation with 166 µm SAM (not normally present in culture medium) increased signal frequency and decreased signal amplitude in ApoE+/+ cultures. SAM also increased the frequency of tightly clustered signal bursts. Folate deprivation reversibly reduced signal frequency in ApoE+/+ cultures; SAM supplementation maintained signal frequency despite folate deprivation. These findings support the importance of dietary supplementation with folate and SAM on neuronal health. Supplementation with 166 µm SAM did not alter signaling in ApoE−/− cultures, which may be a reflection of the reduced SAM levels in ApoE−/− mice. The differential impact of SAM on ApoE+/+ and −/− neurons underscores the combined impact of nutritional and genetic deficiencies on neuronal homeostasis. (communication)

  4. Neuroplasticity pathways and protein-interaction networks are modulated by vortioxetine in rodents

    DEFF Research Database (Denmark)

    Waller, Jessica A.; Nygaard, Sara Holm; Li, Yan

    2017-01-01

    species and sexes, different brain regions, and in response to distinct routes of administration and regimens. Conclusions: A recurring theme, based on the present study as well as previous findings, is that networks related to synaptic plasticity, synaptic transmission, signal transduction...... and rat in response to distinct treatment regimens and in different brain regions. Furthermore, analysis of complexes of physically-interacting proteins reveal that biomarkers involved in transcriptional regulation, neurodevelopment, neuroplasticity, and endocytosis are modulated by vortioxetine....... A subsequent qPCR study examining the expression of targets in the protein-protein interactome space in response to chronic vortioxetine treatment over a range of doses provides further biological validation that vortioxetine engages neuroplasticity networks. Thus, the same biology is regulated in different...

  5. Tuning piezoresistive transduction in nanomechanical resonators by geometrical asymmetries

    Energy Technology Data Exchange (ETDEWEB)

    Llobet, J.; Sansa, M.; Lorenzoni, M.; Pérez-Murano, F., E-mail: francesc.perez@csic.es [Institut de Microelectrònica de Barcelona (IMB-CNM CSIC), Campus UAB, 08193 Bellaterra (Spain); Borrisé, X. [Institut Català de Nanociència i Nanotecnologia (ICN2), Campus UAB, 08193 Bellaterra Spain (Spain); San Paulo, A. [Instituto de Microelectrónica de Madrid (IMM-CSIC), 28760 Tres Cantos, Madrid (Spain)

    2015-08-17

    The effect of geometrical asymmetries on the piezoresistive transduction in suspended double clamped beam nanomechanical resonators is investigated. Tapered silicon nano-beams, fabricated using a fast and flexible prototyping method, are employed to determine how the asymmetry affects the transduced piezoresistive signal for different mechanical resonant modes. This effect is attributed to the modulation of the strain in pre-strained double clamped beams, and it is confirmed by means of finite element simulations.

  6. Deconvolution of Voltage Sensor Time Series and Electro-diffusion Modeling Reveal the Role of Spine Geometry in Controlling Synaptic Strength.

    Science.gov (United States)

    Cartailler, Jerome; Kwon, Taekyung; Yuste, Rafael; Holcman, David

    2018-03-07

    Most synaptic excitatory connections are made on dendritic spines. But how the voltage in spines is modulated by its geometry remains unclear. To investigate the electrical properties of spines, we combine voltage imaging data with electro-diffusion modeling. We first present a temporal deconvolution procedure for the genetically encoded voltage sensor expressed in hippocampal cultured neurons and then use electro-diffusion theory to compute the electric field and the current-voltage conversion. We extract a range for the neck resistances of 〈R〉=100±35MΩ. When a significant current is injected in a spine, the neck resistance can be inversely proportional to its radius, but not to the radius square, as predicted by Ohm's law. We conclude that the postsynaptic voltage cannot only be modulated by changing the number of receptors, but also by the spine geometry. Thus, spine morphology could be a key component in determining synaptic transduction and plasticity. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. proBDNF Negatively Regulates Neuronal Remodeling, Synaptic Transmission, and Synaptic Plasticity in Hippocampus

    Directory of Open Access Journals (Sweden)

    Jianmin Yang

    2014-05-01

    Full Text Available Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP via TrkB activation. BDNF is initially translated as proBDNF, which binds p75NTR. In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75NTR. Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission, and plasticity, effects that are distinct from those of mature BDNF.

  8. Synaptic Plasticity, Dementia and Alzheimer Disease.

    Science.gov (United States)

    Skaper, Stephen D; Facci, Laura; Zusso, Morena; Giusti, Pietro

    2017-01-01

    Neuroplasticity is not only shaped by learning and memory but is also a mediator of responses to neuron attrition and injury (compensatory plasticity). As an ongoing process it reacts to neuronal cell activity and injury, death, and genesis, which encompasses the modulation of structural and functional processes of axons, dendrites, and synapses. The range of structural elements that comprise plasticity includes long-term potentiation (a cellular correlate of learning and memory), synaptic efficacy and remodelling, synaptogenesis, axonal sprouting and dendritic remodelling, and neurogenesis and recruitment. Degenerative diseases of the human brain continue to pose one of biomedicine's most intractable problems. Research on human neurodegeneration is now moving from descriptive to mechanistic analyses. At the same time, it is increasing apparently that morphological lesions traditionally used by neuropathologists to confirm post-mortem clinical diagnosis might furnish us with an experimentally tractable handle to understand causative pathways. Consider the aging-dependent neurodegenerative disorder Alzheimer's disease (AD) which is characterised at the neuropathological level by deposits of insoluble amyloid β-peptide (Aβ) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. We now appreciate that mild cognitive impairment in early AD may be due to synaptic dysfunction caused by accumulation of non-fibrillar, oligomeric Aβ, occurring well in advance of evident widespread synaptic loss and neurodegeneration. Soluble Aβ oligomers can adversely affect synaptic structure and plasticity at extremely low concentrations, although the molecular substrates by which synaptic memory mechanisms are disrupted remain to be fully elucidated. The dendritic spine constitutes a primary locus of excitatory synaptic transmission in the mammalian central nervous system. These structures protruding from dendritic

  9. Ultrafast Synaptic Events in a Chalcogenide Memristor

    Science.gov (United States)

    Li, Yi; Zhong, Yingpeng; Xu, Lei; Zhang, Jinjian; Xu, Xiaohua; Sun, Huajun; Miao, Xiangshui

    2013-04-01

    Compact and power-efficient plastic electronic synapses are of fundamental importance to overcoming the bottlenecks of developing a neuromorphic chip. Memristor is a strong contender among the various electronic synapses in existence today. However, the speeds of synaptic events are relatively slow in most attempts at emulating synapses due to the material-related mechanism. Here we revealed the intrinsic memristance of stoichiometric crystalline Ge2Sb2Te5 that originates from the charge trapping and releasing by the defects. The device resistance states, representing synaptic weights, were precisely modulated by 30 ns potentiating/depressing electrical pulses. We demonstrated four spike-timing-dependent plasticity (STDP) forms by applying programmed pre- and postsynaptic spiking pulse pairs in different time windows ranging from 50 ms down to 500 ns, the latter of which is 105 times faster than the speed of STDP in human brain. This study provides new opportunities for building ultrafast neuromorphic computing systems and surpassing Von Neumann architecture.

  10. MAGUKs: multifaceted synaptic organizers.

    Science.gov (United States)

    Won, Sehoon; Levy, Jon M; Nicoll, Roger A; Roche, Katherine W

    2017-04-01

    The PSD-95 family of proteins, known as MAGUKs, have long been recognized to be central building blocks of the PSD. They are categorized as scaffolding proteins, which link surface-expressed receptors to the intracellular signaling molecules. Although the four members of the PSD-95 family (PSD-95, PSD-93, SAP102, and SAP97) have many shared roles in regulating synaptic function, recent studies have begun to delineate specific binding partners and roles in plasticity. In the current review, we will highlight the conserved and unique roles of these proteins. Published by Elsevier Ltd.

  11. Quantum Transduction with Adaptive Control

    Science.gov (United States)

    Zhang, Mengzhen; Zou, Chang-Ling; Jiang, Liang

    2018-01-01

    Quantum transducers play a crucial role in hybrid quantum networks. A good quantum transducer can faithfully convert quantum signals from one mode to another with minimum decoherence. Most investigations of quantum transduction are based on the protocol of direct mode conversion. However, the direct protocol requires the matching condition, which in practice is not always feasible. Here we propose an adaptive protocol for quantum transducers, which can convert quantum signals without requiring the matching condition. The adaptive protocol only consists of Gaussian operations, feasible in various physical platforms. Moreover, we show that the adaptive protocol can be robust against imperfections associated with finite squeezing, thermal noise, and homodyne detection, and it can be implemented to realize quantum state transfer between microwave and optical modes.

  12. Cellular semiotics and signal transduction

    DEFF Research Database (Denmark)

    Bruni, Luis Emilio

    2007-01-01

    Semiosis, the processes of production, communication and interpretation of signs - coding and de-coding - takes place within and between organisms. The term "endosemiosis" refers to the processes of interpretation and sign transmission inside an organism (as opposed to "exosemiosis", which refers...... to the processes of sign interpretation and transmission between organisms of the same or different species). In Biosemiotics it is customary to recognise the cell as the most elementary integration unit for semiosis. Therefore intra and intercellular communication constitute the departure point for the study...... considering semiotic logic in order to construct our understanding of living phenomena. Given the central integrating role of signal transduction in physiological and ecological studies, this chapter outlines its semiotic implications. The multi-modality and modularity of signal molecules and relative...

  13. Quantum Transduction with Adaptive Control.

    Science.gov (United States)

    Zhang, Mengzhen; Zou, Chang-Ling; Jiang, Liang

    2018-01-12

    Quantum transducers play a crucial role in hybrid quantum networks. A good quantum transducer can faithfully convert quantum signals from one mode to another with minimum decoherence. Most investigations of quantum transduction are based on the protocol of direct mode conversion. However, the direct protocol requires the matching condition, which in practice is not always feasible. Here we propose an adaptive protocol for quantum transducers, which can convert quantum signals without requiring the matching condition. The adaptive protocol only consists of Gaussian operations, feasible in various physical platforms. Moreover, we show that the adaptive protocol can be robust against imperfections associated with finite squeezing, thermal noise, and homodyne detection, and it can be implemented to realize quantum state transfer between microwave and optical modes.

  14. Endothelial cell oxidative stress and signal transduction

    Directory of Open Access Journals (Sweden)

    ROCIO FONCEA

    2000-01-01

    Full Text Available Endothelial dysfunction (ED is an early event in atherosclerotic disease, preceding clinical manifestations and complications. Increased reactive oxygen species (ROS have been implicated as important mechanisms that contribute to ED, and ROS’s may function as intracellular messengers that modulate signaling pathways. Several intracellular signal events stimulated by ROS have been defined, including the identification of two members of the mitogen activated protein kinase family (ERK1/2 and big MAP kinase, BMK1, tyrosine kinases (Src and Syk and different isoenzymes of PKC as redox-sensitive kinases. ROS regulation of signal transduction components include the modification in the activity of transcriptional factors such as NFkB and others that result in changes in gene expression and modifications in cellular responses. In order to understand the intracellular mechanisms induced by ROS in endothelial cells (EC, we are studying the response of human umbilical cord vein endothelial cells to increased ROS generation by different pro-atherogenic stimuli. Our results show that Homocysteine (Hcy and oxidized LDL (oxLDL enhance the activity and expression of oxidative stress markers, such as NFkB and heme oxygenase 1. These results suggest that these pro-atherogenic stimuli increase oxidative stress in EC, and thus explain the loss of endothelial function associated with the atherogenic process

  15. Architectures and representations for string transduction

    NARCIS (Netherlands)

    Chrupala, Grzegorz

    2015-01-01

    String transduction problems are ubiquitous in natural language processing: they include transliteration, grapheme-to-phoneme conversion, text normalization and translation. String transduction can be reduced to the simpler problems of sequence labeling by expressing the target string as a sequence

  16. Human hematopoietic cell culture, transduction, and analyses

    DEFF Research Database (Denmark)

    Bonde, Jesper; Wirthlin, Louisa; Kohn, Donald B

    2008-01-01

    This unit provides methods for introducing genes into human hematopoietic progenitor cells. The Basic Protocol describes isolation of CD34(+) cells, transduction of these cells with a retroviral vector on fibronectin-coated plates, assaying the efficiency of transduction, and establishing long-te...

  17. Synaptic electronics: materials, devices and applications.

    Science.gov (United States)

    Kuzum, Duygu; Yu, Shimeng; Wong, H-S Philip

    2013-09-27

    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.

  18. Synaptic electronics: materials, devices and applications

    International Nuclear Information System (INIS)

    Kuzum, Duygu; Yu, Shimeng; Philip Wong, H-S

    2013-01-01

    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)

  19. BDNF-induced local protein synthesis and synaptic plasticity.

    Science.gov (United States)

    Leal, Graciano; Comprido, Diogo; Duarte, Carlos B

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and long-term potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-γ (PLC-γ) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre- and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short- and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Self-organised criticality via retro-synaptic signals

    Science.gov (United States)

    Hernandez-Urbina, Victor; Herrmann, J. Michael

    2016-12-01

    The brain is a complex system par excellence. In the last decade the observation of neuronal avalanches in neocortical circuits suggested the presence of self-organised criticality in brain networks. The occurrence of this type of dynamics implies several benefits to neural computation. However, the mechanisms that give rise to critical behaviour in these systems, and how they interact with other neuronal processes such as synaptic plasticity are not fully understood. In this paper, we present a long-term plasticity rule based on retro-synaptic signals that allows the system to reach a critical state in which clusters of activity are distributed as a power-law, among other observables. Our synaptic plasticity rule coexists with other synaptic mechanisms such as spike-timing-dependent plasticity, which implies that the resulting synaptic modulation captures not only the temporal correlations between spiking times of pre- and post-synaptic units, which has been suggested as requirement for learning and memory in neural systems, but also drives the system to a state of optimal neural information processing.

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

    Science.gov (United States)

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

    2011-01-01

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

  2. Isolation of Synaptosomes, Synaptic Plasma Membranes, and Synaptic Junctional Complexes.

    Science.gov (United States)

    Michaelis, Mary L; Jiang, Lei; Michaelis, Elias K

    2017-01-01

    Isolation of synaptic nerve terminals or synaptosomes provides an opportunity to study the process of neurotransmission at many levels and with a variety of approaches. For example, structural features of the synaptic terminals and the organelles within them, such as synaptic vesicles and mitochondria, have been elucidated with electron microscopy. The postsynaptic membranes are joined to the presynaptic "active zone" of transmitter release through cell adhesion molecules and remain attached throughout the isolation of synaptosomes. These "post synaptic densities" or "PSDs" contain the receptors for the transmitters released from the nerve terminals and can easily be seen with electron microscopy. Biochemical and cell biological studies with synaptosomes have revealed which proteins and lipids are most actively involved in synaptic release of neurotransmitters. The functional properties of the nerve terminals, such as responses to depolarization and the uptake or release of signaling molecules, have also been characterized through the use of fluorescent dyes, tagged transmitters, and transporter substrates. In addition, isolated synaptosomes can serve as the starting material for the isolation of relatively pure synaptic plasma membranes (SPMs) that are devoid of organelles from the internal environment of the nerve terminal, such as mitochondria and synaptic vesicles. The isolated SPMs can reseal and form vesicular structures in which transport of ions such as sodium and calcium, as well as solutes such as neurotransmitters can be studied. The PSDs also remain associated with the presynaptic membranes during isolation of SPM fractions, making it possible to isolate the synaptic junctional complexes (SJCs) devoid of the rest of the plasma membranes of the nerve terminals and postsynaptic membrane components. Isolated SJCs can be used to identify the proteins that constitute this highly specialized region of neurons. In this chapter, we describe the steps involved

  3. Protein Transduction Based Therapies for Breast Cancer

    National Research Council Canada - National Science Library

    Robbins, Paul D

    2004-01-01

    We have demonstrated that certain transduction peptides such as 12 lysines and 12 arginines can facilitate internalization into breast tumor lines with higher efficiency than smaller polymers of cationic amino acids...

  4. Protein Transduction Based Therapies for Breast Cancer

    National Research Council Canada - National Science Library

    Robbins, Paul D

    2005-01-01

    We have demonstrated that certain transduction peptides such as 12 lysines and 12 arginines can facilitate internalization into breast tumor lines with higher efficiency than smaller polymers of cationic amino acids...

  5. Secreted factors as synaptic organizers.

    Science.gov (United States)

    Johnson-Venkatesh, Erin M; Umemori, Hisashi

    2010-07-01

    A critical step in synaptic development is the differentiation of presynaptic and postsynaptic compartments. This complex process is regulated by a variety of secreted factors that serve as synaptic organizers. Specifically, fibroblast growth factors, Wnts, neurotrophic factors and various other intercellular signaling molecules are proposed to regulate presynaptic and/or postsynaptic differentiation. Many of these factors appear to function at both the neuromuscular junction and in the central nervous system, although the specific function of the molecules differs between the two. Here we review secreted molecules that organize the synaptic compartments and discuss how these molecules shape synaptic development, focusing on mammalian in vivo systems. Their critical role in shaping a functional neural circuit is underscored by their possible link to a wide range of neurological and psychiatric disorders both in animal models and by mutations identified in human patients. © The Authors (2010). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  6. Methamphetamine reduces LTP and increases baseline synaptic transmission in the CA1 region of mouse hippocampus.

    Directory of Open Access Journals (Sweden)

    Jarod Swant

    2010-06-01

    Full Text Available Methamphetamine (METH is an addictive psychostimulant whose societal impact is on the rise. Emerging evidence suggests that psychostimulants alter synaptic plasticity in the brain--which may partly account for their adverse effects. While it is known that METH increases the extracellular concentration of monoamines dopamine, serotonin, and norepinephrine, it is not clear how METH alters glutamatergic transmission. Within this context, the aim of the present study was to investigate the effects of acute and systemic METH on basal synaptic transmission and long-term potentiation (LTP; an activity-induced increase in synaptic efficacy in CA1 sub-field in the hippocampus. Both the acute ex vivo application of METH to hippocampal slices and systemic administration of METH decreased LTP. Interestingly, the acute ex vivo application of METH at a concentration of 30 or 60 microM increased baseline synaptic transmission as well as decreased LTP. Pretreatment with eticlopride (D2-like receptor antagonist did not alter the effects of METH on synaptic transmission or LTP. In contrast, pretreatment with D1/D5 dopamine receptor antagonist SCH23390 or 5-HT1A receptor antagonist NAN-190 abrogated the effect of METH on synaptic transmission. Furthermore, METH did not increase baseline synaptic transmission in D1 dopamine receptor haploinsufficient mice. Our findings suggest that METH affects excitatory synaptic transmission via activation of dopamine and serotonin receptor systems in the hippocampus. This modulation may contribute to synaptic maladaption induced by METH addiction and/or METH-mediated cognitive dysfunction.

  7. Synaptic consolidation across multiple timescales

    Directory of Open Access Journals (Sweden)

    Lorric Ziegler

    2014-03-01

    Full Text Available The brain is bombarded with a continuous stream of sensory events, but retains only a small subset in memory. The selectivity of memory formation prevents our memory from being overloaded with irrelevant items that would rapidly bring the brain to its storage limit; moreover, selectivity also prevents overwriting previously formed memories with new ones. Memory formation in the hippocampus, as well as in other brain regions, is thought to be linked to changes in the synaptic connections between neurons. In this view, sensory events imprint traces at the level of synapses that reflect potential memory items. The question of memory selectivity can therefore be reformulated as follows: what are the reasons and conditions that some synaptic traces fade away whereas others are consolidated and persist? Experimentally, changes in synaptic strength induced by 'Hebbian' protocols fade away over a few hours (early long-term potentiation or e-LTP, unless these changes are consolidated. The experiments and conceptual theory of synaptic tagging and capture (STC provide a mechanistic explanation for the processes involved in consolidation. This theory suggests that the initial trace of synaptic plasticity sets a tag at the synapse, which then serves as a marker for potential consolidation of the changes in synaptic efficacy. The actual consolidation processes, transforming e-LTP into late LTP (l-LTP, require the capture of plasticity-related proteins (PRP. We translate the above conceptual model into a compact computational model that accounts for a wealth of in vitro data including experiments on cross-tagging, tag-resetting and depotentiation. A central ingredient is that synaptic traces are described with several variables that evolve on different time scales. Consolidation requires the transmission of information from a 'fast' synaptic trace to a 'slow' one through a 'write' process, including the formation of tags and the production of PRP for the

  8. Synaptic membrane rafts: traffic lights for local neurotrophin signaling?

    Science.gov (United States)

    Zonta, Barbara; Minichiello, Liliana

    2013-10-18

    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 signaling, 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 signaling. The tyrosine kinase neurotrophin receptors (Trk) and the low-affinity p75 neurotrophin receptor (p75(NTR)) are enriched in neuronal lipid rafts together with the intermediates of downstream signaling pathways, suggesting a possible role of rafts in neurotrophin signaling. 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.

  9. Synaptic membrane rafts: traffic lights for local neurotrophin signalling?

    Directory of Open Access Journals (Sweden)

    Barbara eZonta

    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.

  10. Sensory cilia and integration of signal transduction in human health and disease

    DEFF Research Database (Denmark)

    Christensen, Søren T; Pedersen, Lotte B; Schneider, Linda

    2007-01-01

    The primary cilium is a hallmark of mammalian tissue cells. Recent research has shown that these organelles display unique sets of selected signal transduction modules including receptors, ion channels, effector proteins and transcription factors that relay chemical and physical stimuli from the ...

  11. Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells.

    Science.gov (United States)

    Liu, Xunxian; Allen, Jeffrey D; Arnold, Julia T; Blackman, Marc R

    2008-04-01

    Prostate stromal and epithelial cell communication is important in prostate functioning and cancer development. Primary human stromal cells from normal prostate stromal cells (PRSC) maintain a smooth muscle phenotype, whereas those from prostate cancer (6S) display reactive and fibroblastic characteristics. Dihydrotestosterone (DHT) stimulates insulin-like growth factor-I (IGF-I) production by 6S but not PSRC cells. Effects of reactive versus normal stroma on normal human prostate epithelial (NPE or PREC) cells are poorly understood. We co-cultured NPE plus 6S or PRSC cells to compare influences of different stromal cells on normal epithelium. Because NPE and PREC cells lose androgen receptor (AR) expression in culture, DHT effects must be modulated by associated stromal cells. When treated with camptothecin (CM), NPE cells, alone and in stromal co-cultures, displayed a dose-dependent increase in DNA fragmentation. NPE/6S co-cultures exhibited reduced CM-induced cell death with exposure to DHT, whereas NPE/PRSC co-cultures exhibited CM-induced cell death regardless of DHT treatment. DHT blocked CM-induced, IGF-I-mediated, NPE death in co-cultured NPE/6S cells without, but not with, added anti-IGF-I and anti-IGF-R antibodies. Lycopene consumption is inversely related to human prostate cancer risk and inhibits IGF-I and androgen signaling in rat prostate cancer. In this study, lycopene, in dietary concentrations, reversed DHT effects of 6S cells on NPE cell death, decreased 6S cell IGF-I production by reducing AR and beta-catenin nuclear localization and inhibited IGF-I-stimulated NPE and PREC growth, perhaps by attenuating IGF-I's effects on serine phosphorylation of Akt and GSK3beta and tyrosine phosphorylation of GSK3. This study expands the understanding of the preventive mechanisms of lycopene in prostate cancer.

  12. Signal Transduction Mechanisms Underlying Group I mGluR-mediated Increase in Frequency and Amplitude of Spontaneous EPSCs in the Spinal Trigeminal Subnucleus Oralis of the Rat

    Directory of Open Access Journals (Sweden)

    Ahn Dong-Kuk

    2009-09-01

    Full Text Available Abstract Group I mGluRs (mGluR1 and 5 pre- and/or postsynaptically regulate synaptic transmission at glutamatergic synapses. By recording spontaneous EPSCs (sEPSCs in the spinal trigeminal subnucleus oralis (Vo, we here investigated the regulation of glutamatergic transmission through the activation of group I mGluRs. Bath-applied DHPG (10 μM/5 min, activating the group I mGluRs, increased sEPSCs both in frequency and amplitude; particularly, the increased amplitude was long-lasting. The DHPG-induced increases of sEPSC frequency and amplitude were not NMDA receptor-dependent. The DHPG-induced increase in the frequency of sEPSCs, the presynaptic effect being further confirmed by the DHPG effect on paired-pulse ratio of trigeminal tract-evoked EPSCs, an index of presynaptic modulation, was significantly but partially reduced by blockades of voltage-dependent sodium channel, mGluR1 or mGluR5. Interestingly, PKC inhibition markedly enhanced the DHPG-induced increase of sEPSC frequency, which was mainly accomplished through mGluR1, indicating an inhibitory role of PKC. In contrast, the DHPG-induced increase of sEPSC amplitude was not affected by mGluR1 or mGluR5 antagonists although the long-lasting property of the increase was disappeared; however, the increase was completely inhibited by blocking both mGluR1 and mGluR5. Further study of signal transduction mechanisms revealed that PLC and CaMKII mediated the increases of sEPSC in both frequency and amplitude by DHPG, while IP3 receptor, NO and ERK only that of amplitude during DHPG application. Altogether, these results indicate that the activation of group I mGluRs and their signal transduction pathways differentially regulate glutamate release and synaptic responses in Vo, thereby contributing to the processing of somatosensory signals from orofacial region.

  13. Purinergic mechanosensory transduction and visceral pain

    Directory of Open Access Journals (Sweden)

    Burnstock Geoffrey

    2009-11-01

    Full Text Available Abstract In this review, evidence is presented to support the hypothesis that mechanosensory transduction occurs in tubes and sacs and can initiate visceral pain. Experimental evidence for this mechanism in urinary bladder, ureter, gut, lung, uterus, tooth-pulp and tongue is reviewed. Potential therapeutic strategies are considered for the treatment of visceral pain in such conditions as renal colic, interstitial cystitis and inflammatory bowel disease by agents that interfere with mechanosensory transduction in the organs considered, including P2X3 and P2X2/3 receptor antagonists that are orally bioavailable and stable in vivo and agents that inhibit or enhance ATP release and breakdown.

  14. Ankyrins: Roles in synaptic biology and pathology.

    Science.gov (United States)

    Smith, Katharine R; Penzes, Peter

    2018-05-03

    Ankyrins are broadly expressed adaptors that organize diverse membrane proteins into specialized domains and link them to the sub-membranous cytoskeleton. In neurons, ankyrins are known to have essential roles in organizing the axon initial segment and nodes of Ranvier. However, recent studies have revealed novel functions for ankyrins at synapses, where they organize and stabilize neurotransmitter receptors, modulate dendritic spine morphology and control adhesion to the presynaptic site. Ankyrin genes have also been highly associated with a range of neurodevelopmental and psychiatric diseases, including bipolar disorder, schizophrenia and autism, which all demonstrate overlap in their genetics, mechanisms and phenotypes. This review discusses the novel synaptic functions of ankyrin proteins in neurons, and places these exciting findings in the context of ANK genes as key neuropsychiatric disorder risk-factors. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Reduced modeling of signal transduction – a modular approach

    Directory of Open Access Journals (Sweden)

    Ederer Michael

    2007-09-01

    Full Text Available Abstract Background Combinatorial complexity is a challenging problem in detailed and mechanistic mathematical modeling of signal transduction. This subject has been discussed intensively and a lot of progress has been made within the last few years. A software tool (BioNetGen was developed which allows an automatic rule-based set-up of mechanistic model equations. In many cases these models can be reduced by an exact domain-oriented lumping technique. However, the resulting models can still consist of a very large number of differential equations. Results We introduce a new reduction technique, which allows building modularized and highly reduced models. Compared to existing approaches further reduction of signal transduction networks is possible. The method also provides a new modularization criterion, which allows to dissect the model into smaller modules that are called layers and can be modeled independently. Hallmarks of the approach are conservation relations within each layer and connection of layers by signal flows instead of mass flows. The reduced model can be formulated directly without previous generation of detailed model equations. It can be understood and interpreted intuitively, as model variables are macroscopic quantities that are converted by rates following simple kinetics. The proposed technique is applicable without using complex mathematical tools and even without detailed knowledge of the mathematical background. However, we provide a detailed mathematical analysis to show performance and limitations of the method. For physiologically relevant parameter domains the transient as well as the stationary errors caused by the reduction are negligible. Conclusion The new layer based reduced modeling method allows building modularized and strongly reduced models of signal transduction networks. Reduced model equations can be directly formulated and are intuitively interpretable. Additionally, the method provides very good

  16. Depression as a Glial-Based Synaptic Dysfunction

    Directory of Open Access Journals (Sweden)

    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.

  17. Organic/inorganic hybrid synaptic transistors gated by proton conducting methylcellulose films

    Energy Technology Data Exchange (ETDEWEB)

    Wan, Chang Jin; Wan, Qing, E-mail: wanqing@nju.edu.cn, E-mail: yshi@nju.edu.cn [School of Electronic Science & Engineering, and Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093 (China); Ningbo Institute of Material Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201 (China); Zhu, Li Qiang [Ningbo Institute of Material Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201 (China); Wan, Xiang; Shi, Yi, E-mail: wanqing@nju.edu.cn, E-mail: yshi@nju.edu.cn [School of Electronic Science & Engineering, and Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing 210093 (China)

    2016-01-25

    The idea of building a brain-inspired cognitive system has been around for several decades. Recently, electric-double-layer transistors gated by ion conducting electrolytes were reported as the promising candidates for synaptic electronics and neuromorphic system. In this letter, indium-zinc-oxide transistors gated by proton conducting methylcellulose electrolyte films were experimentally demonstrated with synaptic plasticity including paired-pulse facilitation and spatiotemporal-correlated dynamic logic. More importantly, a model based on proton-related electric-double-layer modulation and stretched-exponential decay function was proposed, and the theoretical results are in good agreement with the experimentally measured synaptic behaviors.

  18. Organic/inorganic hybrid synaptic transistors gated by proton conducting methylcellulose films

    International Nuclear Information System (INIS)

    Wan, Chang Jin; Wan, Qing; Zhu, Li Qiang; Wan, Xiang; Shi, Yi

    2016-01-01

    The idea of building a brain-inspired cognitive system has been around for several decades. Recently, electric-double-layer transistors gated by ion conducting electrolytes were reported as the promising candidates for synaptic electronics and neuromorphic system. In this letter, indium-zinc-oxide transistors gated by proton conducting methylcellulose electrolyte films were experimentally demonstrated with synaptic plasticity including paired-pulse facilitation and spatiotemporal-correlated dynamic logic. More importantly, a model based on proton-related electric-double-layer modulation and stretched-exponential decay function was proposed, and the theoretical results are in good agreement with the experimentally measured synaptic behaviors

  19. Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration.

    Science.gov (United States)

    Du, Heng; Guo, Lan; Wu, Xiaoping; Sosunov, Alexander A; McKhann, Guy M; Chen, John Xi; Yan, Shirley ShiDu

    2014-12-01

    The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cyclophilin D (CypD), an integral part of mitochondrial permeability transition pore (mPTP), is involved in amyloid beta (Aβ)-instigated mitochondrial dysfunction. Blockade of CypD prevents Aβ-induced mitochondrial malfunction and the consequent cognitive impairments. Here, we showed the elimination of reactive oxygen species (ROS) by antioxidants probucol or superoxide dismutase (SOD)/catalase blocks Aβ-mediated inactivation of protein kinase A (PKA)/cAMP regulatory-element-binding (CREB) signal transduction pathway and loss of synapse, suggesting the detrimental effects of oxidative stress on neuronal PKA/CREB activity. Notably, neurons lacking CypD significantly attenuate Aβ-induced ROS. Consequently, CypD-deficient neurons are resistant to Aβ-disrupted PKA/CREB signaling by increased PKA activity, phosphorylation of PKA catalytic subunit (PKA C), and CREB. In parallel, lack of CypD protects neurons from Aβ-induced loss of synapses and synaptic dysfunction. Furthermore, compared to the mAPP mice, CypD-deficient mAPP mice reveal less inactivation of PKA-CREB activity and increased synaptic density, attenuate abnormalities in dendritic spine maturation, and improve spontaneous synaptic activity. These findings provide new insights into a mechanism in the crosstalk between the CypD-dependent mitochondrial oxidative stress and signaling cascade, leading to synaptic injury, functioning through the PKA/CREB signal transduction pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Mechanical transduction via a single soft polymer

    Science.gov (United States)

    Hou, Ruizheng; Wang, Nan; Bao, Weizhu; Wang, Zhisong

    2018-04-01

    Molecular machines from biology and nanotechnology often depend on soft structures to perform mechanical functions, but the underlying mechanisms and advantages or disadvantages over rigid structures are not fully understood. We report here a rigorous study of mechanical transduction along a single soft polymer based on exact solutions to the realistic three-dimensional wormlike-chain model and augmented with analytical relations derived from simpler polymer models. The results reveal surprisingly that a soft polymer with vanishingly small persistence length below a single chemical bond still transduces biased displacement and mechanical work up to practically significant amounts. This "soft" approach possesses unique advantages over the conventional wisdom of rigidity-based transduction, and potentially leads to a unified mechanism for effective allosterylike transduction and relay of mechanical actions, information, control, and molecules from one position to another in molecular devices and motors. This study also identifies an entropy limit unique to the soft transduction, and thereby suggests a possibility of detecting higher efficiency for kinesin motor and mutants in future experiments.

  1. Motor unit recruitment strategies and muscle properties determine the influence of synaptic noise on force steadiness

    Science.gov (United States)

    Dideriksen, Jakob L.; Negro, Francesco; Enoka, Roger M.

    2012-01-01

    Motoneurons receive synaptic inputs from tens of thousands of connections that cause membrane potential to fluctuate continuously (synaptic noise), which introduces variability in discharge times of action potentials. We hypothesized that the influence of synaptic noise on force steadiness during voluntary contractions is limited to low muscle forces. The hypothesis was examined with an analytical description of transduction of motor unit spike trains into muscle force, a computational model of motor unit recruitment and rate coding, and experimental analysis of interspike interval variability during steady contractions with the abductor digiti minimi muscle. Simulations varied contraction force, level of synaptic noise, size of motor unit population, recruitment range, twitch contraction times, and level of motor unit short-term synchronization. Consistent with the analytical derivations, simulations and experimental data showed that force variability at target forces above a threshold was primarily due to low-frequency oscillations in neural drive, whereas the influence of synaptic noise was almost completely attenuated by two low-pass filters, one related to convolution of motoneuron spike trains with motor unit twitches (temporal summation) and the other attributable to summation of single motor unit forces (spatial summation). The threshold force above which synaptic noise ceased to influence force steadiness depended on recruitment range, size of motor unit population, and muscle contractile properties. This threshold was low (motor unit recruitment and muscle properties of a typical muscle are tuned to limit the influence of synaptic noise on force steadiness to low forces and that the inability to produce a constant force during stronger contractions is mainly attributable to the common low-frequency oscillations in motoneuron discharge rates. PMID:22423000

  2. Genetic Analysis of Gravity Signal Transduction in Arabidopsis Roots

    Science.gov (United States)

    Masson, Patrick; Strohm, Allison; Barker, Richard; Su, Shih-Heng

    Like most other plant organs, roots use gravity as a directional guide for growth. Specialized cells within the columella region of the root cap (the statocytes) sense the direction of gravity through the sedimentation of starch-filled plastids (amyloplasts). Amyloplast movement and/or pressure on sensitive membranes triggers a gravity signal transduction pathway within these cells, which leads to a fast transcytotic relocalization of plasma-membrane associated auxin-efflux carrier proteins of the PIN family (PIN3 and PIN7) toward the bottom membrane. This leads to a polar transport of auxin toward the bottom flank of the cap. The resulting lateral auxin gradient is then transmitted toward the elongation zones where it triggers a curvature that ultimately leads to a restoration of vertical downward growth. Our laboratory is using strategies derived from genetics and systems biology to elucidate the molecular mechanisms that modulate gravity sensing and signal transduction in the columella cells of the root cap. Our previous research uncovered two J-domain-containing proteins, ARG1 and ARL2, as contributing to this process. Mutations in the corresponding paralogous genes led to alterations of root and hypocotyl gravitropism accompanied by an inability for the statocytes to develop a cytoplasmic alkalinization, relocalize PIN3, and transport auxin laterally, in response to gravistimulation. Both proteins are associated peripherally to membranes belonging to various compartments of the vesicular trafficking pathway, potentially modulating the trafficking of defined proteins between plasma membrane and endosomes. MAR1 and MAR2, on the other end, are distinct proteins of the plastidic outer envelope protein import TOC complex (the transmembrane channel TOC75 and the receptor TOC132, respectively). Mutations in the corresponding genes enhance the gravitropic defects of arg1. Using transformation-rescue experiments with truncated versions of TOC132 (MAR2), we have shown

  3. Signal transduction and chemotaxis in mast cells

    Czech Academy of Sciences Publication Activity Database

    Dráber, Petr; Hálová, Ivana; Polakovičová, Iva; Kawakami, T.

    2016-01-01

    Roč. 778, jaro (2016), s. 11-23 ISSN 0014-2999 R&D Projects: GA ČR(CZ) GA14-09807S; GA ČR(CZ) GBP302/12/G101; GA ČR(CZ) GA14-00703S Institutional support: RVO:68378050 Keywords : Mast cell * IgE receptor * KIT receptor * Signal transduction * Chemotaxis * Plasma membrane Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.896, year: 2016

  4. Macro-Fiber Composite Based Transduction

    Science.gov (United States)

    2016-03-01

    substrate Material properties of single crystal macro fiber composite actuators for active twist rotor blades Park, Jae-Sang (Seoul National...Passive Smart Structures and Integrated Systems 2007 Material properties of single crystal macro fiber composite actuators for active twist rotor ...19b. TELEPHONE NUMBER (Include area code) 10-03-20 16 Final Report 01 Jan 2013 - 31 Dec 2015 Macro-Fiber Composite Based Transduction N000-14-13-1-0212

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

    Directory of Open Access Journals (Sweden)

    Bardia F Behabadi

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

  6. Synaptic activity-related classical protein kinase C isoform localization in the adult rat neuromuscular synapse.

    Science.gov (United States)

    Besalduch, Núria; Tomàs, Marta; Santafé, Manel M; Garcia, Neus; Tomàs, Josep; Lanuza, Maria Angel

    2010-01-10

    Protein kinase C (PKC) is essential for signal transduction in a variety of cells, including neurons and myocytes, and is involved in both acetylcholine release and muscle fiber contraction. Here, we demonstrate that the increases in synaptic activity by nerve stimulation couple PKC to transmitter release in the rat neuromuscular junction and increase the level of alpha, betaI, and betaII isoforms in the membrane when muscle contraction follows the stimulation. The phosphorylation activity of these classical PKCs also increases. It seems that the muscle has to contract in order to maintain or increase classical PKCs in the membrane. We use immunohistochemistry to show that PKCalpha and PKCbetaI were located in the nerve terminals, whereas PKCalpha and PKCbetaII were located in the postsynaptic and the Schwann cells. Stimulation and contraction do not change these cellular distributions, but our results show that the localization of classical PKC isoforms in the membrane is affected by synaptic activity.

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

    Directory of Open Access Journals (Sweden)

    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.

  8. The C1q complement family of synaptic organizers: not just complementary.

    Science.gov (United States)

    Yuzaki, Michisuke

    2017-08-01

    Molecules that regulate formation, differentiation, and maintenance of synapses are called synaptic organizers. Recently, various 'C1q family' proteins have been shown to be released from neurons, and serve as a new class of synaptic organizers. Cbln1 and C1ql1 proteins regulate the formation and maintenance of parallel fiber-Purkinje cell and climbing fiber-Purkinje cell synapses, respectively, in the cerebellum. Cbln1 also modulates the function of postsynaptic delta2 glutamate receptors to regulate synaptic plasticity. C1ql2 and C1ql3, released from mossy fibers, determine the synaptic localization of postsynaptic kainate receptors in the hippocampus. C1ql3 also regulates the formation of synapses between the basolateral amygdala and the prefrontal cortex. These findings indicate the diverse functions of C1q family proteins in various brain regions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Synaptic Conversion of Chloride-Dependent Synapses in Spinal Nociceptive Circuits: Roles in Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Mark S. Cooper

    2011-01-01

    Full Text Available Electrophysiological conversion of chloride-dependent synapses from inhibitory to excitatory function, as a result of aberrant neuronal chloride homeostasis, is a known mechanism for the genesis of neuropathic pain. This paper examines theoretically how this type of synaptic conversion can disrupt circuit logic in spinal nociceptive circuits. First, a mathematical scaling factor is developed to represent local aberration in chloride electrochemical driving potential. Using this mathematical scaling factor, electrophysiological symbols are developed to represent the magnitude of synaptic conversion within nociceptive circuits. When inserted into a nociceptive circuit diagram, these symbols assist in understanding the generation of neuropathic pain associated with the collapse of transmembrane chloride gradients. A more generalized scaling factor is also derived to represent the interplay of chloride and bicarbonate driving potentials on the function of GABAergic and glycinergic synapses. These mathematical and symbolic representations of synaptic conversion help illustrate the critical role that anion driving potentials play in the transduction of pain. Using these representations, we discuss ramifications of glial-mediated synaptic conversion in the genesis, and treatment, of neuropathic pain.

  10. Short-Term Synaptic Plasticity Regulation in Solution-Gated Indium-Gallium-Zinc-Oxide Electric-Double-Layer Transistors.

    Science.gov (United States)

    Wan, Chang Jin; Liu, Yang Hui; Zhu, Li Qiang; Feng, Ping; Shi, Yi; Wan, Qing

    2016-04-20

    In the biological nervous system, synaptic plasticity regulation is based on the modulation of ionic fluxes, and such regulation was regarded as the fundamental mechanism underlying memory and learning. Inspired by such biological strategies, indium-gallium-zinc-oxide (IGZO) electric-double-layer (EDL) transistors gated by aqueous solutions were proposed for synaptic behavior emulations. Short-term synaptic plasticity, such as paired-pulse facilitation, high-pass filtering, and orientation tuning, was experimentally emulated in these EDL transistors. Most importantly, we found that such short-term synaptic plasticity can be effectively regulated by alcohol (ethyl alcohol) and salt (potassium chloride) additives. Our results suggest that solution gated oxide-based EDL transistors could act as the platforms for short-term synaptic plasticity emulation.

  11. Design principles of electrical synaptic plasticity.

    Science.gov (United States)

    O'Brien, John

    2017-09-08

    Essentially all animals with nervous systems utilize electrical synapses as a core element of communication. Electrical synapses, formed by gap junctions between neurons, provide rapid, bidirectional communication that accomplishes tasks distinct from and complementary to chemical synapses. These include coordination of neuron activity, suppression of voltage noise, establishment of electrical pathways that define circuits, and modulation of high order network behavior. In keeping with the omnipresent demand to alter neural network function in order to respond to environmental cues and perform tasks, electrical synapses exhibit extensive plasticity. In some networks, this plasticity can have dramatic effects that completely remodel circuits or remove the influence of certain cell types from networks. Electrical synaptic plasticity occurs on three distinct time scales, ranging from milliseconds to days, with different mechanisms accounting for each. This essay highlights principles that dictate the properties of electrical coupling within networks and the plasticity of the electrical synapses, drawing examples extensively from retinal networks. Copyright © 2017 The Author. Published by Elsevier B.V. All rights reserved.

  12. Epigenetic Basis of Neuronal and Synaptic Plasticity.

    Science.gov (United States)

    Karpova, Nina N; Sales, Amanda J; Joca, Samia R

    2017-01-01

    Neuronal network and plasticity change as a function of experience. Altered neural connectivity leads to distinct transcriptional programs of neuronal plasticity-related genes. The environmental challenges throughout life may promote long-lasting reprogramming of gene expression and the development of brain disorders. The modifications in neuronal epigenome mediate gene-environmental interactions and are required for activity-dependent regulation of neuronal differentiation, maturation and plasticity. Here, we highlight the latest advances in understanding the role of the main players of epigenetic machinery (DNA methylation and demethylation, histone modifications, chromatin-remodeling enzymes, transposons, and non-coding RNAs) in activity-dependent and long- term neural and synaptic plasticity. The review focuses on both the transcriptional and post-transcriptional regulation of gene expression levels, including the processes of promoter activation, alternative splicing, regulation of stability of gene transcripts by natural antisense RNAs, and alternative polyadenylation. Further, we discuss the epigenetic aspects of impaired neuronal plasticity and the pathogenesis of neurodevelopmental (Rett syndrome, Fragile X Syndrome, genomic imprinting disorders, schizophrenia, and others), stressrelated (mood disorders) and neurodegenerative Alzheimer's, Parkinson's and Huntington's disorders. The review also highlights the pharmacological compounds that modulate epigenetic programming of gene expression, the potential treatment strategies of discussed brain disorders, and the questions that should be addressed during the development of effective and safe approaches for the treatment of brain disorders.

  13. The computational power of astrocyte mediated synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Rogier eMin

    2012-11-01

    Full Text Available Research in the last two decades has made clear that astrocytes play a crucial role in the brain beyond their functions in energy metabolism and homeostasis. Many studies have shown that astrocytes can dynamically modulate neuronal excitability and synaptic plasticity, and might participate in higher brain functions like learning and memory. With the plethora of astrocyte-mediated signaling processes described in the literature today, the current challenge is to identify which of these processes happen under what physiological condition, and how this shapes information processing and, ultimately, behavior. To answer these questions will require a combination of advanced physiological, genetical and behavioral experiments. Additionally, mathematical modeling will prove crucial for testing predictions on the possible functions of astrocytes in neuronal networks, and to generate novel ideas as to how astrocytes can contribute to the complexity of the brain. Here, we aim to provide an outline of how astrocytes can interact with neurons. We do this by reviewing recent experimental literature on astrocyte-neuron interactions, discussing the dynamic effects of astrocytes on neuronal excitability and short- and long-term synaptic plasticity. Finally, we will outline the potential computational functions that astrocyte-neuron interactions can serve in the brain. We will discuss how astrocytes could govern metaplasticity in the brain, how they might organize the clustering of synaptic inputs, and how they could function as memory elements for neuronal activity. We conclude that astrocytes can enhance the computational power of neuronal networks in previously unexpected ways.

  14. A versatile optical tool for studying synaptic GABAA receptor trafficking.

    Science.gov (United States)

    Lorenz-Guertin, Joshua M; Wilcox, Madeleine R; Zhang, Ming; Larsen, Mads B; Pilli, Jyotsna; Schmidt, Brigitte F; Bruchez, Marcel P; Johnson, Jon W; Waggoner, Alan S; Watkins, Simon C; Jacob, Tija C

    2017-11-15

    Live-cell imaging methods can provide critical real-time receptor trafficking measurements. Here, we describe an optical tool to study synaptic γ-aminobutyric acid (GABA) type A receptor (GABA A R) dynamics through adaptable fluorescent-tracking capabilities. A fluorogen-activating peptide (FAP) was genetically inserted into a GABA A R γ2 subunit tagged with pH-sensitive green fluorescent protein (γ2 pH FAP). The FAP selectively binds and activates Malachite Green (MG) dyes that are otherwise non-fluorescent in solution. γ2 pH FAP GABA A Rs are expressed at the cell surface in transfected cortical neurons, form synaptic clusters and do not perturb neuronal development. Electrophysiological studies show γ2 pH FAP GABA A Rs respond to GABA and exhibit positive modulation upon stimulation with the benzodiazepine diazepam. Imaging studies using γ2 pH FAP-transfected neurons and MG dyes show time-dependent receptor accumulation into intracellular vesicles, revealing constitutive endosomal and lysosomal trafficking. Simultaneous analysis of synaptic, surface and lysosomal receptors using the γ2 pH FAP-MG dye approach reveals enhanced GABA A R turnover following a bicucculine-induced seizure paradigm, a finding not detected by standard surface receptor measurements. To our knowledge, this is the first application of the FAP-MG dye system in neurons, demonstrating the versatility to study nearly all phases of GABA A R trafficking. © 2017. Published by The Company of Biologists Ltd.

  15. Synaptic vesicle distribution by conveyor belt.

    Science.gov (United States)

    Moughamian, Armen J; Holzbaur, Erika L F

    2012-03-02

    The equal distribution of synaptic vesicles among synapses along the axon is critical for robust neurotransmission. Wong et al. show that the continuous circulation of synaptic vesicles throughout the axon driven by molecular motors ultimately yields this even distribution. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Spontaneous Vesicle Recycling in the Synaptic Bouton

    Directory of Open Access Journals (Sweden)

    Sven eTruckenbrodt

    2014-12-01

    Full Text Available The trigger for synaptic vesicle exocytosis is Ca2+, which enters the synaptic bouton following action potential stimulation. However, spontaneous release of neurotransmitter also occurs in the absence of stimulation in virtually all synaptic boutons. It has long been thought that this represents exocytosis driven by fluctuations in local Ca2+ levels. The vesicles responding to these fluctuations are thought to be the same ones that release upon stimulation, albeit potentially triggered by different Ca2+ sensors. This view has been challenged by several recent works, which have suggested that spontaneous release is driven by a separate pool of synaptic vesicles. Numerous articles appeared during the last few years in support of each of these hypotheses, and it has been challenging to bring them into accord. We speculate here on the origins of this controversy, and propose a solution that is related to developmental effects. Constitutive membrane traffic, needed for the biogenesis of vesicles and synapses, is responsible for high levels of spontaneous membrane fusion in young neurons, probably independent of Ca2+. The vesicles releasing spontaneously in such neurons are not related to other synaptic vesicle pools and may represent constitutively releasing vesicles (CRVs rather than bona fide synaptic vesicles. In mature neurons, constitutive traffic is much dampened, and the few remaining spontaneous release events probably represent bona fide spontaneously releasing synaptic vesicles (SRSVs responding to Ca2+ fluctuations, along with a handful of CRVs that participate in synaptic vesicle turnover.

  17. Active hippocampal networks undergo spontaneous synaptic modification.

    Directory of Open Access Journals (Sweden)

    Masako Tsukamoto-Yasui

    Full Text Available The brain is self-writable; as the brain voluntarily adapts itself to a changing environment, the neural circuitry rearranges its functional connectivity by referring to its own activity. How the internal activity modifies synaptic weights is largely unknown, however. Here we report that spontaneous activity causes complex reorganization of synaptic connectivity without any external (or artificial stimuli. Under physiologically relevant ionic conditions, CA3 pyramidal cells in hippocampal slices displayed spontaneous spikes with bistable slow oscillations of membrane potential, alternating between the so-called UP and DOWN states. The generation of slow oscillations did not require fast synaptic transmission, but their patterns were coordinated by local circuit activity. In the course of generating spontaneous activity, individual neurons acquired bidirectional long-lasting synaptic modification. The spontaneous synaptic plasticity depended on a rise in intracellular calcium concentrations of postsynaptic cells, but not on NMDA receptor activity. The direction and amount of the plasticity varied depending on slow oscillation patterns and synapse locations, and thus, they were diverse in a network. Once this global synaptic refinement occurred, the same neurons now displayed different patterns of spontaneous activity, which in turn exhibited different levels of synaptic plasticity. Thus, active networks continuously update their internal states through ongoing synaptic plasticity. With computational simulations, we suggest that with this slow oscillation-induced plasticity, a recurrent network converges on a more specific state, compared to that with spike timing-dependent plasticity alone.

  18. Statistical theory of synaptic connectivity in the neocortex

    Science.gov (United States)

    Escobar, Gina

    Learning and long-term memory rely on plasticity of neural circuits. In adult cerebral cortex plasticity can be mediated by modulation of existing synapses and structural reorganization of circuits through growth and retraction of dendritic spines. In the first part of this thesis, we describe a theoretical framework for the analysis of spine remodeling plasticity. New synaptic contacts appear in the neuropil where gaps between axonal and dendritic branches can be bridged by dendritic spines. Such sites are termed potential synapses. We derive expressions for the densities of potential synapses in the neuropil. We calculate the ratio of actual to potential synapses, called the connectivity fraction, and use it to find the number of structurally different circuits attainable with spine remodeling. These parameters are calculated in four systems: mouse occipital cortex, rat hippocampal area CA1, monkey primary visual (V1), and human temporal cortex. The neurogeometric results indicate that a dendritic spine can choose among an average of 4-7 potential targets in rodents, while in primates it can choose from 10-20 potential targets. The potential of the neuropil to undergo circuit remodeling is found to be highest in rat CA1 (4.9-6.0 nats/mum 3) and lowest in monkey V1 (0.9-1.0 nats/mum3). We evaluate the lower bound of neuron selectivity in the choice of synaptic partners and find that post-synaptic excitatory neurons in rodents make synaptic contacts with more than 21-30% of pre-synaptic axons encountered with new spine growth. Primate neurons appear to be more selective, making synaptic connections with more than 7-15% of encountered axons. Another plasticity mechanism is included in the second part of this work: long-term potentiation and depression of excitatory synaptic connections. Because synaptic strength is correlated with the size of the synapse, the former can be inferred from the distribution of spine head volumes. To this end we analyze and compare 166

  19. Synaptic plasticity in drug reward circuitry.

    Science.gov (United States)

    Winder, Danny G; Egli, Regula E; Schramm, Nicole L; Matthews, Robert T

    2002-11-01

    Drug addiction is a major public health issue worldwide. The persistence of drug craving coupled with the known recruitment of learning and memory centers in the brain has led investigators to hypothesize that the alterations in glutamatergic synaptic efficacy brought on by synaptic plasticity may play key roles in the addiction process. Here we review the present literature, examining the properties of synaptic plasticity within drug reward circuitry, and the effects that drugs of abuse have on these forms of plasticity. Interestingly, multiple forms of synaptic plasticity can be induced at glutamatergic synapses within the dorsal striatum, its ventral extension the nucleus accumbens, and the ventral tegmental area, and at least some of these forms of plasticity are regulated by behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the present data suggest that regulation of synaptic plasticity in reward circuits is a tractable candidate mechanism underlying aspects of addiction.

  20. Prenatal Alcohol Exposure Damages Brain Signal Transduction Systems

    National Research Council Canada - National Science Library

    Caldwell, Kevin

    2001-01-01

    .... One and twenty-four hours following fear conditioning this learning deficit is associated with altered brain signal transduction mechanisms that are dependent on an enzyme termed phosphatidylinositol...

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Anna eFassio

    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.

  3. Fragile X Mental Retardation Protein Regulates Activity-Dependent Membrane Trafficking and Trans-Synaptic Signaling Mediating Synaptic Remodeling

    Science.gov (United States)

    Sears, James C.; Broadie, Kendal

    2018-01-01

    activity-dependent repression of translation. In the well-characterized Drosophila neuromuscular junction (NMJ) model, developmental synaptogenesis and activity-dependent synaptic remodeling both require extracellular matrix metalloproteinase (MMP) enzymes interacting with the heparan sulfate proteoglycan (HSPG) glypican dally-like protein (Dlp) to restrict trans-synaptic Wnt signaling, with FXS synaptogenic defects alleviated by both MMP and HSPG reduction. This new mechanistic axis spanning from activity to FMRP to HSPG-dependent MMP regulation modulates activity-dependent synaptogenesis. We discuss future directions for these mechanisms, and intersecting research priorities for FMRP in glial and signaling interactions. PMID:29375303

  4. The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory

    NARCIS (Netherlands)

    Schmitz, Leanne J M; Klaassen, Remco V; Ruiperez-Alonso, Marta; Zamri, Azra Elia; Stroeder, Jasper; Rao-Ruiz, Priyanka; Lodder, Johannes C; van der Loo, Rolinka J; Mansvelder, Huib D; Smit, August B; Spijker, Sabine; Verhage, Matthijs

    2017-01-01

    Glutamatergic synapses rely on AMPA receptors (AMPARs) for fast synaptic transmission and plasticity. AMPAR auxiliary proteins regulate receptor trafficking, and modulate receptor mobility and its biophysical properties. The AMPAR auxiliary protein Shisa7 (CKAMP59) has been shown to interact with

  5. KV7 Channels Regulate Firing during Synaptic Integration in GABAergic Striatal Neurons

    Directory of Open Access Journals (Sweden)

    M. Belén Pérez-Ramírez

    2015-01-01

    Full Text Available Striatal projection neurons (SPNs process motor and cognitive information. Their activity is affected by Parkinson’s disease, in which dopamine concentration is decreased and acetylcholine concentration is increased. Acetylcholine activates muscarinic receptors in SPNs. Its main source is the cholinergic interneuron that responds with a briefer latency than SPNs during a cortical command. Therefore, an important question is whether muscarinic G-protein coupled receptors and their signaling cascades are fast enough to intervene during synaptic responses to regulate synaptic integration and firing. One of the most known voltage dependent channels regulated by muscarinic receptors is the KV7/KCNQ channel. It is not known whether these channels regulate the integration of suprathreshold corticostriatal responses. Here, we study the impact of cholinergic muscarinic modulation on the synaptic response of SPNs by regulating KV7 channels. We found that KV7 channels regulate corticostriatal synaptic integration and that this modulation occurs in the dendritic/spines compartment. In contrast, it is negligible in the somatic compartment. This modulation occurs on sub- and suprathreshold responses and lasts during the whole duration of the responses, hundreds of milliseconds, greatly altering SPNs firing properties. This modulation affected the behavior of the striatal microcircuit.

  6. The Chemokine MIP-1α/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory.

    Science.gov (United States)

    Marciniak, Elodie; Faivre, Emilie; Dutar, Patrick; Alves Pires, Claire; Demeyer, Dominique; Caillierez, Raphaëlle; Laloux, Charlotte; Buée, Luc; Blum, David; Humez, Sandrine

    2015-10-29

    Chemokines are signaling molecules playing an important role in immune regulations. They are also thought to regulate brain development, neurogenesis and neuroendocrine functions. While chemokine upsurge has been associated with conditions characterized with cognitive impairments, their ability to modulate synaptic plasticity remains ill-defined. In the present study, we specifically evaluated the effects of MIP1-α/CCL3 towards hippocampal synaptic transmission, plasticity and spatial memory. We found that CCL3 (50 ng/ml) significantly reduced basal synaptic transmission at the Schaffer collateral-CA1 synapse without affecting NMDAR-mediated field potentials. This effect was ascribed to post-synaptic regulations, as CCL3 did not impact paired-pulse facilitation. While CCL3 did not modulate long-term depression (LTD), it significantly impaired long-term potentiation (LTP), an effect abolished by Maraviroc, a CCR5 specific antagonist. In addition, sub-chronic intracerebroventricular (icv) injections of CCL3 also impair LTP. In accordance with these electrophysiological findings, we demonstrated that the icv injection of CCL3 in mouse significantly impaired spatial memory abilities and long-term memory measured using the two-step Y-maze and passive avoidance tasks. These effects of CCL3 on memory were inhibited by Maraviroc. Altogether, these data suggest that the chemokine CCL3 is an hippocampal neuromodulator able to regulate synaptic plasticity mechanisms involved in learning and memory functions.

  7. The role of c-AMP-dependent protein kinase in spinal cord and post synaptic dorsal column neurons in a rat model of visceral pain

    OpenAIRE

    Wu, Jing; Su, Guangxiao; Ma, Long; Zhang, Xuan; Lei, Yongzhong; Lin, Qing; Nauta, Haring J.W.; Li, Junfa; Fang, Li

    2007-01-01

    Visceral noxious stimulation induces central neuronal plasticity changes and suggests that the c-AMP-dependent protein kinase (PKA) signal transduction cascade contributes to long-term changes in nociceptive processing at the spinal cord level. Our previous studies reported the clinical neurosurgical interruption of post synaptic dorsal column neuron (PSDC) pathway by performing midline myelotomy effectively alleviating the intractable visceral pain in patients with severe pain. However, the ...

  8. Synaptic Wnt/GSK3β Signaling Hub in Autism

    Science.gov (United States)

    Caracci, Mario O.; Ávila, Miguel E.; De Ferrari, Giancarlo V.

    2016-01-01

    Hundreds of genes have been associated with autism spectrum disorders (ASDs) and the interaction of weak and de novo variants derive from distinct autistic phenotypes thus making up the “spectrum.” The convergence of these variants in networks of genes associated with synaptic function warrants the study of cell signaling pathways involved in the regulation of the synapse. The Wnt/β-catenin signaling pathway plays a central role in the development and regulation of the central nervous system and several genes belonging to the cascade have been genetically associated with ASDs. In the present paper, we review basic information regarding the role of Wnt/β-catenin signaling in excitatory/inhibitory balance (E/I balance) through the regulation of pre- and postsynaptic compartments. Furthermore, we integrate information supporting the role of the glycogen synthase kinase 3β (GSK3β) in the onset/development of ASDs through direct modulation of Wnt/β-catenin signaling. Finally, given GSK3β activity as key modulator of synaptic plasticity, we explore the potential of this kinase as a therapeutic target for ASD. PMID:26881141

  9. Synaptic proteome changes in the superior frontal gyrus and occipital cortex of the alcoholic brain.

    Science.gov (United States)

    Etheridge, Naomi; Lewohl, Joanne M; Mayfield, R Dayne; Harris, R Adron; Dodd, Peter R

    2009-06-24

    Cognitive deficits and behavioral changes that result from chronic alcohol abuse are a consequence of neuropathological changes which alter signal transmission through the neural network. To focus on the changes that occur at the point of connection between the neural network cells, synaptosomal preparations from post-mortem human brain of six chronic alcoholics and six non-alcoholic controls were compared using 2D-DIGE. Functionally affected and spared regions (superior frontal gyrus, SFG, and occipital cortex, OC, respectively) were analyzed from both groups to further investigate the specific pathological response that alcoholism has on the brain. Forty-nine proteins were differentially regulated between the SFG of alcoholics and the SFG of controls and 94 proteins were regulated in the OC with an overlap of 23 proteins. Additionally, the SFG was compared to the OC within each group (alcoholics or controls) to identify region specific differences. A selection were identified by MALDI-TOF mass spectrometry revealing proteins involved in vesicle transport, metabolism, folding and trafficking, and signal transduction, all of which have the potential to influence synaptic activity. A number of proteins identified in this study have been previously related to alcoholism; however, the focus on synaptic proteins has also uncovered novel alcoholism-affected proteins. Further exploration of these proteins will illuminate the mechanisms altering synaptic plasticity, and thus neuronal signaling and response, in the alcoholic brain.

  10. Genetic Analysis of Gravity Signal Transduction in Arabidopsis thaliana Seedlings

    Science.gov (United States)

    Boonsirichai, K.; Harrison, B.; Stanga, J.; Young, L.-S.; Neal, C.; Sabat, G.; Murthy, N.; Harms, A.; Sedbrook, J.; Masson, P.

    The primary roots of Arabidopsis thaliana seedlings respond to gravity stimulation by developing a tip curvature that results from differential cellular elongation on opposite flanks of the elongation zone. This curvature appears modulated by a lateral gradient of auxin that originates in the gravity-perceiving cells (statocytes) of the root cap through an apparent lateral repositioning of a component the auxin efflux carrier complex within these cells (Friml et al, 2002, Nature 415: 806-809). Unfortunately, little is known about the molecular mechanisms that govern early phases of gravity perception and signal transduction within the root-cap statocytes. We have used a molecular genetic approach to uncover some of these mechanisms. Mutations in the Arabidopsis ARG1 and ARL2 genes, which encode J-domain proteins, resulted in specific alterations in root and hypocotyl gravitropism, without pleiotropic phenotypes. Interestingly, ARG1 and ARL2 appear to function in the same genetic pathway. A combination of molecular genetic, biochemical and cell-biological approaches were used to demonstrate that ARG1 functions in early phases of gravity signal transduction within the root and hypocotyl statocytes, and is needed for efficient lateral auxin transport within the cap. The ARG1 protein is associated with components of the secretory and/or endosomal pathways, suggesting its role in the recycling of components of the auxin efflux carrier complex between plasma membrane and endosome (Boonsirichai et al, 2003, Plant Cell 15:2612-2625). Genetic modifiers of arg1-2 were isolated and shown to enhance the gravitropic defect of arg1-2, while resulting in little or no gravitropic defects in a wild type ARG1 background. A slight tendency for arg1-2;mar1-1 and arg1-2;mar2-1 double-mutant organs to display an opposite gravitropic response compared to wild type suggests that all three genes contribute to the interpretation of the gravity-vector information by seedling organs. The

  11. Identification of synaptic targets of Drosophila pumilio.

    Directory of Open Access Journals (Sweden)

    Gengxin Chen

    2008-02-01

    Full Text Available 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.

  12. Toward heterogeneity in feedforward network with synaptic delays based on FitzHugh-Nagumo model

    Science.gov (United States)

    Qin, Ying-Mei; Men, Cong; Zhao, Jia; Han, Chun-Xiao; Che, Yan-Qiu

    2018-01-01

    We focus on the role of heterogeneity on the propagation of firing patterns in feedforward network (FFN). Effects of heterogeneities both in parameters of neuronal excitability and synaptic delays are investigated systematically. Neuronal heterogeneity is found to modulate firing rates and spiking regularity by changing the excitability of the network. Synaptic delays are strongly related with desynchronized and synchronized firing patterns of the FFN, which indicate that synaptic delays may play a significant role in bridging rate coding and temporal coding. Furthermore, quasi-coherence resonance (quasi-CR) phenomenon is observed in the parameter domain of connection probability and delay-heterogeneity. All these phenomena above enable a detailed characterization of neuronal heterogeneity in FFN, which may play an indispensable role in reproducing the important properties of in vivo experiments.

  13. Interaural Level Difference Dependent Gain Control and Synaptic Scaling Underlying Binaural Computation

    Science.gov (United States)

    Xiong, Xiaorui R.; Liang, Feixue; Li, Haifu; Mesik, Lukas; Zhang, Ke K.; Polley, Daniel B.; Tao, Huizhong W.; Xiao, Zhongju; Zhang, Li I.

    2013-01-01

    Binaural integration in the central nucleus of inferior colliculus (ICC) plays a critical role in sound localization. However, its arithmetic nature and underlying synaptic mechanisms remain unclear. Here, we showed in mouse ICC neurons that the contralateral dominance is created by a “push-pull”-like mechanism, with contralaterally dominant excitation and more bilaterally balanced inhibition. Importantly, binaural spiking response is generated apparently from an ipsilaterally-mediated scaling of contralateral response, leaving frequency tuning unchanged. This scaling effect is attributed to a divisive attenuation of contralaterally-evoked synaptic excitation onto ICC neurons with their inhibition largely unaffected. Thus, a gain control mediates the linear transformation from monaural to binaural spike responses. The gain value is modulated by interaural level difference (ILD) primarily through scaling excitation to different levels. The ILD-dependent synaptic scaling and gain adjustment allow ICC neurons to dynamically encode interaural sound localization cues while maintaining an invariant representation of other independent sound attributes. PMID:23972599

  14. Imbalanced pattern completion vs. separation in cognitive disease: network simulations of synaptic pathologies predict a personalized therapeutics strategy

    Directory of Open Access Journals (Sweden)

    Hanson Jesse E

    2010-08-01

    Full Text Available Abstract Background Diverse Mouse genetic models of neurodevelopmental, neuropsychiatric, and neurodegenerative causes of impaired cognition exhibit at least four convergent points of synaptic malfunction: 1 Strength of long-term potentiation (LTP, 2 Strength of long-term depression (LTD, 3 Relative inhibition levels (Inhibition, and 4 Excitatory connectivity levels (Connectivity. Results To test the hypothesis that pathological increases or decreases in these synaptic properties could underlie imbalances at the level of basic neural network function, we explored each type of malfunction in a simulation of autoassociative memory. These network simulations revealed that one impact of impairments or excesses in each of these synaptic properties is to shift the trade-off between pattern separation and pattern completion performance during memory storage and recall. Each type of synaptic pathology either pushed the network balance towards intolerable error in pattern separation or intolerable error in pattern completion. Imbalances caused by pathological impairments or excesses in LTP, LTD, inhibition, or connectivity, could all be exacerbated, or rescued, by the simultaneous modulation of any of the other three synaptic properties. Conclusions Because appropriate modulation of any of the synaptic properties could help re-balance network function, regardless of the origins of the imbalance, we propose a new strategy of personalized cognitive therapeutics guided by assay of pattern completion vs. pattern separation function. Simulated examples and testable predictions of this theorized approach to cognitive therapeutics are presented.

  15. Modulation of learning and memory by cytokines: signaling mechanisms and long term consequences.

    Science.gov (United States)

    Donzis, Elissa J; Tronson, Natalie C

    2014-11-01

    This review describes the role of cytokines and their downstream signaling cascades on the modulation of learning and memory. Immune proteins are required for many key neural processes and dysregulation of these functions by systemic inflammation can result in impairments of memory that persist long after the resolution of inflammation. Recent research has demonstrated that manipulations of individual cytokines can modulate learning, memory, and synaptic plasticity. The many conflicting findings, however, have prevented a clear understanding of the precise role of cytokines in memory. Given the complexity of inflammatory signaling, understanding its modulatory role requires a shift in focus from single cytokines to a network of cytokine interactions and elucidation of the cytokine-dependent intracellular signaling cascades. Finally, we propose that whereas signal transduction and transcription may mediate short-term modulation of memory, long-lasting cellular and molecular mechanisms such as epigenetic modifications and altered neurogenesis may be required for the long lasting impact of inflammation on memory and cognition. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Presynaptic inhibition of GABAergic synaptic transmission by adenosine in mouse hypothalamic hypocretin neurons.

    Science.gov (United States)

    Xia, J X; Xiong, J X; Wang, H K; Duan, S M; Ye, J N; Hu, Z A

    2012-01-10

    Hypocretin neurons in the lateral hypothalamus, a new wakefulness-promoting center, have been recently regarded as an important target involved in endogenous adenosine-regulating sleep homeostasis. The GABAergic synaptic transmissions are the main inhibitory afferents to hypocretin neurons, which play an important role in the regulation of excitability of these neurons. The inhibitory effect of adenosine, a homeostatic sleep-promoting factor, on the excitatory glutamatergic synaptic transmissions in hypocretin neurons has been well documented, whether adenosine also modulates these inhibitory GABAergic synaptic transmissions in these neurons has not been investigated. In this study, the effect of adenosine on inhibitory postsynaptic currents (IPSCs) in hypocretin neurons was examined by using perforated patch-clamp recordings in the acute hypothalamic slices. The findings demonstrated that adenosine suppressed the amplitude of evoked IPSCs in a dose-dependent manner, which was completely abolished by 8-cyclopentyltheophylline (CPT), a selective antagonist of adenosine A1 receptor but not adenosine A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl) xanthine. A presynaptic origin was suggested as following: adenosine increased paired-pulse ratio as well as reduced GABAergic miniature IPSC frequency without affecting the miniature IPSC amplitude. Further findings demonstrated that when the frequency of electrical stimulation was raised to 10 Hz, but not 1 Hz, a time-dependent depression of evoked IPSC amplitude was detected in hypocretin neurons, which could be partially blocked by CPT. However, under a higher frequency at 100 Hz stimulation, CPT had no action on the depressed GABAergic synaptic transmission induced by such tetanic stimulation in these hypocretin neurons. These results suggest that endogenous adenosine generated under certain stronger activities of synaptic transmissions exerts an inhibitory effect on GABAergic synaptic transmission in hypocretin

  17. Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1.

    Science.gov (United States)

    Cartier, Anna E; Djakovic, Stevan N; Salehi, Afshin; Wilson, Scott M; Masliah, Eliezer; Patrick, Gentry N

    2009-06-17

    Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We found that UCH-L1 activity is rapidly upregulated by NMDA receptor activation, which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of presynaptic and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1-inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling, most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner.

  18. Regulation of Synaptic Structure by the Ubiquitin C-terminal Hydrolase UCH-L1

    Science.gov (United States)

    Cartier, Anna E.; Djakovic, Stevan N.; Salehi, Afshin; Wilson, Scott M.; Masliah, Eliezer; Patrick, Gentry N.

    2009-01-01

    UCH-L1 is a de-ubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We have found that UCH-L1 activity is rapidly up-regulated by NMDA receptor activation which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of pre and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1 inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner. PMID:19535597

  19. Levetiracetam reverses synaptic deficits produced by overexpression of SV2A.

    Directory of Open Access Journals (Sweden)

    Amy Nowack

    Full Text Available Levetiracetam is an FDA-approved drug used to treat epilepsy and other disorders of the nervous system. Although it is known that levetiracetam binds the synaptic vesicle protein SV2A, how drug binding affects synaptic functioning remains unknown. Here we report that levetiracetam reverses the effects of excess SV2A in autaptic hippocampal neurons. Expression of an SV2A-EGFP fusion protein produced a ∼1.5-fold increase in synaptic levels of SV2, and resulted in reduced synaptic release probability. The overexpression phenotype parallels that seen in neurons from SV2 knockout mice, which experience severe seizures. Overexpression of SV2A also increased synaptic levels of the calcium-sensor protein synaptotagmin, an SV2-binding protein whose stability and trafficking are regulated by SV2. Treatment with levetiracetam rescued normal neurotransmission and restored normal levels of SV2 and synaptotagmin at the synapse. These results indicate that changes in SV2 expression in either direction impact neurotransmission, and suggest that levetiracetam may modulate SV2 protein interactions.

  20. Elevated interleukin-8 enhances prefrontal synaptic transmission in mice with persistent inflammatory pain

    Directory of Open Access Journals (Sweden)

    Cui Guang-bin

    2012-02-01

    Full Text Available Abstract Background Interleukin-8 (IL-8 is known for its roles in inflammation and plays critical roles in the development of pain. Its expression increases in the brain after peripheral inflammation. Prefrontal cortex, including the anterior cingulate cortex (ACC, is a forebrain structure known for its roles in pain transmission and modulation. Painful stimuli potentiate the prefrontal synaptic transmission, however, little is known about the expression of IL-8 and its role in the enhanced ACC synaptic transmission in animals with persistent inflammatory pain. Findings In the present study, we examined IL-8 expression in the ACC, somatosensory cortex (SSC, and the dorsal horn of lumbar spinal cord following hind-paw administration of complete Freund's adjuvant (CFA in mice and its effects on the ACC synaptic transmission. Quantification of IL-8 at protein level (by ELISA revealed enhanced expression in the ACC and spinal cord during the chronic phases of CFA-induced peripheral inflammation. In vitro whole-cell patch-clamp recordings revealed that IL-8 significantly enhanced synaptic transmission through increased probability of neurotransmitter release in the ACC slice. ACC local infusion of repertaxin, a non-competitive allosteric blocker of IL-8 receptors, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in mice. Conclusions Our findings suggest that up-regulation of IL-8 in the ACC partly attributable to the enhanced prefrontal synaptic transmission in the mice with persistent inflammatory pain.

  1. F42. CHONDROTIN-6 SULFATE CLUSTERS: ASSOCIATION OF SYNAPTIC DOMAINS AND REGULATION OF SYNAPTIC PLASTICITY DURING FEAR LEARNING

    Science.gov (United States)

    Chelini, Gabriele; Berciu, Cristina; Pilobello, Kanoelani; Peter, Durning; Rachel, Jenkins; Kahn, Moazzzam; Ramikie, Teniel; Subramanian, Siva; Ressler, Kerry; Pantazopoulos, Charalampos; Berretta, Sabina

    2018-01-01

    surrounding several dendrites. CS-6 expression was dected in astrocytes surrounding the dendrites, particularly in astrocytic endfeet enveloping dendritic spines, and within spines postsynaptic densities. Following auditory fear conditioning, marked changes of CS-6 glia clusters were observed in hippocampus regions dentate gyrus (g>1.5) and CA2 (g>1.5) and basolateral amygdala (g>1). Discussion These findings suggest that CS-6 glia clusters may represent segregated microdomains, dynamically regulated during learning and contributing to the modulation of synaptic regulation machinery. Specifically, we postulate that astrocytes synthesize CS-6 CSPG and secrete it through their endfeet around dendrites, modulating structural plasticity of dendritic spines. These results suggest a relationship between the abnormalities in CSPGs expression and alteration in dendritic spines, two pathological landmarks observed in postmortem brains of people with SZ and BD.

  2. Synaptic behaviors of thin-film transistor with a Pt/HfO x /n-type indium–gallium–zinc oxide gate stack

    Science.gov (United States)

    Yang, Paul; Park, Daehoon; Beom, Keonwon; Kim, Hyung Jun; Kang, Chi Jung; Yoon, Tae-Sik

    2018-07-01

    We report a variety of synaptic behaviors in a thin-film transistor (TFT) with a metal-oxide-semiconductor gate stack that has a Pt/HfO x /n-type indium–gallium–zinc oxide (n-IGZO) structure. The three-terminal synaptic TFT exhibits a tunable synaptic weight with a drain current modulation upon repeated application of gate and drain voltages. The synaptic weight modulation is analog, voltage-polarity dependent reversible, and strong with a dynamic range of multiple orders of magnitude (>104). This modulation process emulates biological synaptic potentiation, depression, excitatory-postsynaptic current, paired-pulse facilitation, and short-term to long-term memory transition behaviors as a result of repeated pulsing with respect to the pulse amplitude, width, repetition number, and the interval between pulses. These synaptic behaviors are interpreted based on the changes in the capacitance of the Pt/HfO x /n-IGZO gate stack, the channel mobility, and the threshold voltage that result from the redistribution of oxygen ions by the applied gate voltage. These results demonstrate the potential of this structure for three-terminal synaptic transistor using the gate stack composed of the HfO x gate insulator and the IGZO channel layer.

  3. Synaptic behaviors of thin-film transistor with a Pt/HfO x /n-type indium-gallium-zinc oxide gate stack.

    Science.gov (United States)

    Yang, Paul; Park, Daehoon; Beom, Keonwon; Kim, Hyung Jun; Kang, Chi Jung; Yoon, Tae-Sik

    2018-07-20

    We report a variety of synaptic behaviors in a thin-film transistor (TFT) with a metal-oxide-semiconductor gate stack that has a Pt/HfO x /n-type indium-gallium-zinc oxide (n-IGZO) structure. The three-terminal synaptic TFT exhibits a tunable synaptic weight with a drain current modulation upon repeated application of gate and drain voltages. The synaptic weight modulation is analog, voltage-polarity dependent reversible, and strong with a dynamic range of multiple orders of magnitude (>10 4 ). This modulation process emulates biological synaptic potentiation, depression, excitatory-postsynaptic current, paired-pulse facilitation, and short-term to long-term memory transition behaviors as a result of repeated pulsing with respect to the pulse amplitude, width, repetition number, and the interval between pulses. These synaptic behaviors are interpreted based on the changes in the capacitance of the Pt/HfO x /n-IGZO gate stack, the channel mobility, and the threshold voltage that result from the redistribution of oxygen ions by the applied gate voltage. These results demonstrate the potential of this structure for three-terminal synaptic transistor using the gate stack composed of the HfO x gate insulator and the IGZO channel layer.

  4. Signal transduction in the footsteps of goethe and schiller.

    Science.gov (United States)

    Friedrich, Karlheinz; Lindquist, Jonathan A; Entschladen, Frank; Serfling, Edgar; Thiel, Gerald; Kieser, Arnd; Giehl, Klaudia; Ehrhardt, Christina; Feller, Stephan M; Ullrich, Oliver; Schaper, Fred; Janssen, Ottmar; Hass, Ralf

    2009-02-04

    The historical town of Weimar in Thuringia, the "green heart of Germany" was the sphere of Goethe and Schiller, the two most famous representatives of German literature's classic era. Not yet entirely as influential as those two cultural icons, the Signal Transduction Society (STS) has nevertheless in the last decade established within the walls of Weimar an annual interdisciplinary Meeting on "Signal Transduction - Receptors, Mediators and Genes", which is well recognized as a most attractive opportunity to exchange results and ideas in the field.The 12th STS Meeting was held from October 28 to 31 and provided a state-of-the-art overview of various areas of signal transduction research in which progress is fast and discussion lively. This report is intended to share with the readers of CCS some highlights of the Meeting Workshops devoted to specific aspects of signal transduction.

  5. Diacylglycerol kinases in the coordination of synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Dongwon Lee

    2016-08-01

    Full Text Available Synaptic plasticity is activity-dependent modification of the efficacy of synaptic transmission. Although detailed mechanisms underlying synaptic plasticity are diverse and vary at different types of synapses, diacylglycerol (DAG-associated signaling has been considered as an important regulator of many forms of synaptic plasticity, including long-term potentiation (LTP and long-term depression (LTD. Recent evidence indicate that DAG kinases (DGKs, which phosphorylate DAG to phosphatidic acid to terminate DAG signaling, are important regulators of LTP and LTD, as supported by the results from mice lacking specific DGK isoforms. This review will summarize these studies and discuss how specific DGK isoforms distinctly regulate different forms of synaptic plasticity at pre- and postsynaptic sites. In addition, we propose a general role of DGKs as coordinators of synaptic plasticity that make local synaptic environments more permissive for synaptic plasticity by regulating DAG concentration and interacting with other synaptic proteins.

  6. Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance

    Science.gov (United States)

    Cohen, Laurie D.; Zuchman, Rina; Sorokina, Oksana; Müller, Anke; Dieterich, Daniela C.; Armstrong, J. Douglas; Ziv, Tamar; Ziv, Noam E.

    2013-01-01

    Chemical synapses contain multitudes of proteins, which in common with all proteins, have finite lifetimes and therefore need to be continuously replaced. Given the huge numbers of synaptic connections typical neurons form, the demand to maintain the protein contents of these connections might be expected to place considerable metabolic demands on each neuron. Moreover, synaptic proteostasis might differ according to distance from global protein synthesis sites, the availability of distributed protein synthesis facilities, trafficking rates and synaptic protein dynamics. To date, the turnover kinetics of synaptic proteins have not been studied or analyzed systematically, and thus metabolic demands or the aforementioned relationships remain largely unknown. In the current study we used dynamic Stable Isotope Labeling with Amino acids in Cell culture (SILAC), mass spectrometry (MS), Fluorescent Non–Canonical Amino acid Tagging (FUNCAT), quantitative immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. We found that nearly all synaptic proteins identified here exhibited half-lifetimes in the range of 2–5 days. Unexpectedly, metabolic turnover rates were not significantly different for presynaptic and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. Some functionally or structurally related proteins exhibited very similar turnover rates, indicating that their biogenesis and degradation might be coupled, a possibility further supported by bioinformatics-based analyses. The relatively low turnover rates measured here (∼0.7% of synaptic protein content per hour) are in good agreement with imaging-based studies of synaptic protein trafficking, yet indicate that the metabolic load

  7. Network-based characterization of the synaptic proteome reveals that removal of epigenetic regulator Prmt8 restricts proteins associated with synaptic maturation.

    Science.gov (United States)

    Lee, Patrick Kia Ming; Goh, Wilson Wen Bin; Sng, Judy Chia Ghee

    2017-02-01

    The brain adapts to dynamic environmental conditions by altering its epigenetic state, thereby influencing neuronal transcriptional programs. An example of an epigenetic modification is protein methylation, catalyzed by protein arginine methyltransferases (PRMT). One member, Prmt8, is selectively expressed in the central nervous system during a crucial phase of early development, but little else is known regarding its function. We hypothesize Prmt8 plays a role in synaptic maturation during development. To evaluate this, we used a proteome-wide approach to characterize the synaptic proteome of Prmt8 knockout versus wild-type mice. Through comparative network-based analyses, proteins and functional clusters related to neurite development were identified to be differentially regulated between the two genotypes. One interesting protein that was differentially regulated was tenascin-R (TNR). Chromatin immunoprecipitation demonstrated binding of PRMT8 to the tenascin-r (Tnr) promoter. TNR, a component of perineuronal nets, preserves structural integrity of synaptic connections within neuronal networks during the development of visual-somatosensory cortices. On closer inspection, Prmt8 removal increased net formation and decreased inhibitory parvalbumin-positive (PV+) puncta on pyramidal neurons, thereby hindering the maturation of circuits. Consequently, visual acuity of the knockout mice was reduced. Our results demonstrated Prmt8's involvement in synaptic maturation and its prospect as an epigenetic modulator of developmental neuroplasticity by regulating structural elements such as the perineuronal nets. © 2016 International Society for Neurochemistry.

  8. Modulation of synaptic potentials and cell excitability by dendritic ...

    Indian Academy of Sciences (India)

    The nucleus accumbens (NAc), a critical structure of the brain reward circuit, is implicated in normal goal-directed behaviour ... limbic and extrapyramidal motor systems (Mogenson et al. .... A further motivation for exploring the effects of the KIR.

  9. Reversed synaptic effects of hypocretin and NPY mediated by excitatory GABA-dependent synaptic activity in developing MCH neurons.

    Science.gov (United States)

    Li, Ying; Xu, Youfen; van den Pol, Anthony N

    2013-03-01

    In mature neurons, GABA is the primary inhibitory neurotransmitter. In contrast, in developing neurons, GABA exerts excitatory actions, and in some neurons GABA-mediated excitatory synaptic activity is more prevalent than glutamate-mediated excitation. Hypothalamic neuropeptides that modulate cognitive arousal and energy homeostasis, hypocretin/orexin and neuropeptide Y (NPY), evoked reversed effects on synaptic actions that were dependent on presynaptic GABA release onto melanin-concentrating hormone (MCH) neurons. MCH neurons were identified by selective green fluorescent protein (GFP) expression in transgenic mice. In adults, hypocretin increased GABA release leading to reduced excitation. In contrast, in the developing brain as studied here with analysis of miniature excitatory postsynaptic currents, paired-pulse ratios, and evoked potentials, hypocretin acted presynaptically to enhance the excitatory actions of GABA. The ability of hypocretin to enhance GABA release increases inhibition in adult neurons but paradoxically enhances excitation in developing MCH neurons. In contrast, NPY attenuation of GABA release reduced inhibition in mature neurons but enhanced inhibition during development by attenuating GABA excitation. Both hypocretin and NPY also evoked direct actions on developing MCH neurons. Hypocretin excited MCH cells by activating a sodium-calcium exchanger and by reducing potassium currents; NPY reduced activity by increasing an inwardly rectifying potassium current. These data for the first time show that both hypocretin and NPY receptors are functional presynaptically during early postnatal hypothalamic development and that both neuropeptides modulate GABA actions during development with a valence of enhanced excitation or inhibition opposite to that of the adult state, potentially allowing neuropeptide modulation of use-dependent synapse stabilization.

  10. Absence of synaptic regulation by phosducin in retinal slices.

    Directory of Open Access Journals (Sweden)

    James H Long

    Full Text Available Phosducin is an abundant photoreceptor protein that binds G-protein βγ subunits and plays a role in modulating synaptic transmission at photoreceptor synapses under both dark-adapted and light-adapted conditions in vivo. To examine the role of phosducin at the rod-to-rod bipolar cell (RBC synapse, we used whole-cell voltage clamp recordings to measure the light-evoked currents from both wild-type (WT and phosducin knockout (Pd(-/- RBCs, in dark- and light-adapted retinal slices. Pd(-/- RBCs showed smaller dim flash responses and steeper intensity-response relationships than WT RBCs, consistent with the smaller rod responses being selectively filtered out by the non-linear threshold at the rod-to-rod bipolar synapse. In addition, Pd(-/- RBCs showed a marked delay in the onset of the light-evoked currents, similar to that of a WT response to an effectively dimmer flash. Comparison of the changes in flash sensitivity in the presence of steady adapting light revealed that Pd(-/- RBCs desensitized less than WT RBCs to the same intensity. These results are quantitatively consistent with the smaller single photon responses of Pd(-/- rods, owing to the known reduction in rod G-protein expression levels in this line. The absence of an additional synaptic phenotype in these experiments suggests that the function of phosducin at the photoreceptor synapse is abolished by the conditions of retinal slice recordings.

  11. Synaptic Correlates of Working Memory Capacity.

    Science.gov (United States)

    Mi, Yuanyuan; Katkov, Mikhail; Tsodyks, Misha

    2017-01-18

    Psychological studies indicate that human ability to keep information in readily accessible working memory is limited to four items for most people. This extremely low capacity severely limits execution of many cognitive tasks, but its neuronal underpinnings remain unclear. Here we show that in the framework of synaptic theory of working memory, capacity can be analytically estimated to scale with characteristic time of short-term synaptic depression relative to synaptic current time constant. The number of items in working memory can be regulated by external excitation, enabling the system to be tuned to the desired load and to clear the working memory of currently held items to make room for new ones. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. The Corticohippocampal Circuit, Synaptic Plasticity, and Memory

    Science.gov (United States)

    Basu, Jayeeta; Siegelbaum, Steven A.

    2015-01-01

    Synaptic plasticity serves as a cellular substrate for information storage in the central nervous system. The entorhinal cortex (EC) and hippocampus are interconnected brain areas supporting basic cognitive functions important for the formation and retrieval of declarative memories. Here, we discuss how information flow in the EC–hippocampal loop is organized through circuit design. We highlight recently identified corticohippocampal and intrahippocampal connections and how these long-range and local microcircuits contribute to learning. This review also describes various forms of activity-dependent mechanisms that change the strength of corticohippocampal synaptic transmission. A key point to emerge from these studies is that patterned activity and interaction of coincident inputs gives rise to associational plasticity and long-term regulation of information flow. Finally, we offer insights about how learning-related synaptic plasticity within the corticohippocampal circuit during sensory experiences may enable adaptive behaviors for encoding spatial, episodic, social, and contextual memories. PMID:26525152

  13. Electric Dipole Theory of Chemical Synaptic Transmission

    Science.gov (United States)

    Wei, Ling Y.

    1968-01-01

    In this paper we propose that chemicals such as acetylcholine are electric dipoles which when oriented and arranged in a large array could produce an electric field strong enough to drive positive ions over the junction barrier of the post-synaptic membrane and thus initiate excitation or produce depolarization. This theory is able to explain a great number of facts such as cleft size, synaptic delay, nonregeneration, subthreshold integration, facilitation with repetition, and the calcium and magnesium effects. It also shows why and how acetylcholine could act as excitatory or inhibitory transmitters under different circumstances. Our conclusion is that the nature of synaptic transmission is essentially electrical, be it mediated by electrical or chemical transmitters. PMID:4296121

  14. Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission

    Science.gov (United States)

    Rouach, Nathalie; Koulakoff, Annette; Abudara, Veronica; Willecke, Klaus; Giaume, Christian

    2008-12-01

    Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.

  15. Astroglial metabolic networks sustain hippocampal synaptic transmission.

    Science.gov (United States)

    Rouach, Nathalie; Koulakoff, Annette; Abudara, Veronica; Willecke, Klaus; Giaume, Christian

    2008-12-05

    Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.

  16. Synaptic Vesicle Endocytosis in Different Model Systems

    Directory of Open Access Journals (Sweden)

    Quan Gan

    2018-06-01

    Full Text Available Neurotransmission in complex animals depends on a choir of functionally distinct synapses releasing neurotransmitters in a highly coordinated manner. During synaptic signaling, vesicles fuse with the plasma membrane to release their contents. The rate of vesicle fusion is high and can exceed the rate at which synaptic vesicles can be re-supplied by distant sources. Thus, local compensatory endocytosis is needed to replenish the synaptic vesicle pools. Over the last four decades, various experimental methods and model systems have been used to study the cellular and molecular mechanisms underlying synaptic vesicle cycle. Clathrin-mediated endocytosis is thought to be the predominant mechanism for synaptic vesicle recycling. However, recent studies suggest significant contribution from other modes of endocytosis, including fast compensatory endocytosis, activity-dependent bulk endocytosis, ultrafast endocytosis, as well as kiss-and-run. Currently, it is not clear whether a universal model of vesicle recycling exist for all types of synapses. It is possible that each synapse type employs a particular mode of endocytosis. Alternatively, multiple modes of endocytosis operate at the same synapse, and the synapse toggles between different modes depending on its activity level. Here we compile review and research articles based on well-characterized model systems: frog neuromuscular junctions, C. elegans neuromuscular junctions, Drosophila neuromuscular junctions, lamprey reticulospinal giant axons, goldfish retinal ribbon synapses, the calyx of Held, and rodent hippocampal synapses. We will compare these systems in terms of their known modes and kinetics of synaptic vesicle endocytosis, as well as the underlying molecular machineries. We will also provide the future development of this field.

  17. The cellular response to vascular endothelial growth factors requires co-ordinated signal transduction, trafficking and proteolysis.

    Science.gov (United States)

    Smith, Gina A; Fearnley, Gareth W; Tomlinson, Darren C; Harrison, Michael A; Ponnambalam, Sreenivasan

    2015-08-18

    VEGFs (vascular endothelial growth factors) are a family of conserved disulfide-linked soluble secretory glycoproteins found in higher eukaryotes. VEGFs mediate a wide range of responses in different tissues including metabolic homoeostasis, cell proliferation, migration and tubulogenesis. Such responses are initiated by VEGF binding to soluble and membrane-bound VEGFRs (VEGF receptor tyrosine kinases) and co-receptors. VEGF and receptor splice isoform diversity further enhances complexity of membrane protein assembly and function in signal transduction pathways that control multiple cellular responses. Different signal transduction pathways are simultaneously activated by VEGFR-VEGF complexes with membrane trafficking along the endosome-lysosome network further modulating signal output from multiple enzymatic events associated with such pathways. Balancing VEGFR-VEGF signal transduction with trafficking and proteolysis is essential in controlling the intensity and duration of different intracellular signalling events. Dysfunction in VEGF-regulated signal transduction is important in chronic disease states including cancer, atherosclerosis and blindness. This family of growth factors and receptors is an important model system for understanding human disease pathology and developing new therapeutics for treating such ailments. © 2015 Authors.

  18. Multistate Resistive Switching Memory for Synaptic Memory Applications

    KAUST Repository

    Hota, Mrinal Kanti

    2016-07-12

    Reproducible low bias bipolar resistive switching memory in HfZnOx based memristors is reported. The modification of the concentration of oxygen vacancies in the ternary oxide film, which is facilitated by adding ZnO into HfO2, results in improved memory operation by the ternary oxide compared to the single binary oxides. A controlled multistate memory operation is achieved by controlling current compliance and RESET stop voltages. A high DC cyclic stability up to 400 cycles in the multistate memory performance is observed. Conventional synaptic operation in terms of potentiation, depression plasticity, and Ebbinghaus forgetting process are also studied. The memory mechanism is shown to originate from the migration of the oxygen vacancies and modulation of the interfacial layers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

  19. Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT.

    Science.gov (United States)

    Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana; Karam, Caline S; Farino, Zachary J; Sonders, Mark S; Choi, Se Joon; Grygoruk, Anna; Zhang, Yuchao; Cela, Carolina; Choi, Ben Jiwon; Flores, Jorge; Freyberg, Robin J; McCabe, Brian D; Mosharov, Eugene V; Krantz, David E; Javitch, Jonathan A; Sulzer, David; Sames, Dalibor; Rayport, Stephen; Freyberg, Zachary

    2017-08-30

    The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the demands of neuronal activity is critical to neurotransmission. Although vesicle content has been assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle content. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral midbrain dopamine neurons in the mouse. Together, these data suggest that in response to depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically increase the vesicular pH gradient, thereby increasing dopamine vesicle content. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Soonwook eChoi

    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

  1. Enhanced synaptic transmission at the squid giant synapse by artificial seawater based on physically modified saline

    Science.gov (United States)

    Choi, Soonwook; Yu, Eunah; Rabello, Guilherme; Merlo, Suelen; Zemmar, Ajmal; Walton, Kerry D.; Moreno, Herman; Moreira, Jorge E.; Sugimori, Mutsuyuki; Llinás, Rodolfo R.

    2014-01-01

    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 5–10 min of RNS60 ASW superfusion and was maintained for the entire recording time, up to 1 h. 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 (CCV) 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 CCV 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 transmission enhancement. PMID:24575037

  2. Reciprocity and gyrotropism in magnetic resonance transduction

    International Nuclear Information System (INIS)

    Tropp, James

    2006-01-01

    We give formulas for transduction in magnetic resonance - i.e., the appearance of an emf due to Larmor precession of spins - based upon the modified Lorentz reciprocity principle for gyrotropic (also called 'nonreciprocal') media, i.e., in which a susceptibility tensor is carried to its transpose by reversal of an external static field [cf., R. F. Harrington and A. T. Villeneuve IRE Trans. Microwave Theory and Technique MTT6, 308 (1958)]. Prior applications of reciprocity to magnetic resonance, despite much success, have ignored the gyrotropism which necessarily arises due to nuclear and/or unpaired electronic spins. For detection with linearly polarized fields, oscillating at the Larmor frequency, the emf is written in terms of a volume integral containing a product of two factors which we define as the antenna patterns, i.e. (H 1x ±iH 1y ), where, e.g., for a single transceive antenna, the H's are just the spatially dependent oscillatory magnetic field strengths, per the application of some reference current at the antenna terminals, with the negative sign obtaining for transmission, and the positive for reception. Similar expressions hold for separate transmit and receive antennas; expressions are also given for circular polarization of the fields. We then exhibit a receive-only array antenna of two elements for magnetic resonance imaging of protons, which, due an intensity artifact arising from stray reactive coupling of the elements, produces, despite its own bilateral symmetry, asymmetric proton NMR images of a symmetric cylindrical phantom containing aqueous saline solution [J. Tropp and T. Schirmer, J. Magn. Reson. 151, 146 (2001)]. Modification of this two-port antenna, to function in transmit-receive mode, allows us to demonstrate highly nonreciprocal behavior: that is, to record images (of cylindrical test phantoms containing aqueous saline solution) whose appearance dramatically changes, when the roles of transmission and reception are swapped between

  3. Different effects of bisphenol-A on memory behavior and synaptic modification in intact and estrogen-deprived female mice.

    Science.gov (United States)

    Xu, Xiaohong; Gu, Ting; Shen, Qiaoqiao

    2015-03-01

    Bisphenol-A (BPA) has the capability of interfering with the effects of estrogens on modulating brain function. The purpose of this study was to investigate the effects of BPA on memory and synaptic modification in the hippocampus of female mice under different levels of cycling estrogen. BPA exposure (40, 400 μg/kg/day) for 8 weeks did not affect spatial memory and passive avoidance task of gonadally intact mice but improved ovariectomy (Ovx)-induced memory impairment, whereas co-exposure of BPA with estradiol benzoate (EB) diminished the rescue effect of EB on memory behavior of Ovx mice. The results of morphometric measurement showed that BPA positively modified the synaptic interface structure and increased the synaptic density of CA1 pyramidal cell in the hippocampus of Ovx females, but inhibited the enhancement of EB on synaptic modification and synaptogenesis of Ovx mice. Furthermore, BPA up-regulated synaptic proteins synapsin I and PSD-95 and NMDA receptor NR2B but inhibited EB-induced increase in PSD-95 and NR2B in the hippocampus of Ovx mice. These results suggest that BPA interfered with normal hormonal regulation in synaptic plasticity and memory of female mice as a potent estrogen mimetic and as a disruptor of estrogen under various concentrations of cycling estrogen. © 2014 International Society for Neurochemistry.

  4. Synaptic control of local translation: the plot thickens with new characters.

    Science.gov (United States)

    Thomas, María Gabriela; Pascual, Malena Lucía; Maschi, Darío; Luchelli, Luciana; Boccaccio, Graciela Lidia

    2014-06-01

    The production of proteins from mRNAs localized at the synapse ultimately controls the strength of synaptic transmission, thereby affecting behavior and cognitive functions. The regulated transcription, processing, and transport of mRNAs provide dynamic control of the dendritic transcriptome, which includes thousands of messengers encoding multiple cellular functions. Translation is locally modulated by synaptic activity through a complex network of RNA-binding proteins (RBPs) and various types of non-coding RNAs (ncRNAs) including BC-RNAs, microRNAs, piwi-interacting RNAs, and small interference RNAs. The RBPs FMRP and CPEB play a well-established role in synaptic translation, and additional regulatory factors are emerging. The mRNA repressors Smaug, Nanos, and Pumilio define a novel pathway for local translational control that affects dendritic branching and spines in both flies and mammals. Recent findings support a role for processing bodies and related synaptic mRNA-silencing foci (SyAS-foci) in the modulation of synaptic plasticity and memory formation. The SyAS-foci respond to different stimuli with changes in their integrity thus enabling regulated mRNA release followed by translation. CPEB, Pumilio, TDP-43, and FUS/TLS form multimers through low-complexity regions related to prion domains or polyQ expansions. The oligomerization of these repressor RBPs is mechanistically linked to the aggregation of abnormal proteins commonly associated with neurodegeneration. Here, we summarize the current knowledge on how specificity in mRNA translation is achieved through the concerted action of multiple pathways that involve regulatory ncRNAs and RBPs, the modification of translation factors, and mRNA-silencing foci dynamics.

  5. Synaptic ribbon. Conveyor belt or safety belt?

    Science.gov (United States)

    Parsons, T D; Sterling, P

    2003-02-06

    The synaptic ribbon in neurons that release transmitter via graded potentials has been considered as a conveyor belt that actively moves vesicles toward their release sites. But evidence has accumulated to the contrary, and it now seems plausible that the ribbon serves instead as a safety belt to tether vesicles stably in mutual contact and thus facilitate multivesicular release by compound exocytosis.

  6. P2X Receptors and Synaptic Plasticity

    Czech Academy of Sciences Publication Activity Database

    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

  7. Synaptic plasticity and the warburg effect

    KAUST Repository

    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.

  8. Neuronal cytoskeleton in synaptic plasticity and regeneration.

    Science.gov (United States)

    Gordon-Weeks, Phillip R; Fournier, Alyson E

    2014-04-01

    During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo-dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre- and post-synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system. © 2013 International Society for Neurochemistry.

  9. Theory and modeling of cylindrical thermo-acoustic transduction

    Energy Technology Data Exchange (ETDEWEB)

    Tong, Lihong, E-mail: lhtong@ecjtu.edu.cn [School of Civil Engineering and Architecture, East China Jiaotong University, Nanchang, Jiangxi (China); Lim, C.W. [Department of Architecture and Civil Engineering, City University of Hong Kong, Kowloon, Hong Kong SAR (China); Zhao, Xiushao; Geng, Daxing [School of Civil Engineering and Architecture, East China Jiaotong University, Nanchang, Jiangxi (China)

    2016-06-03

    Models both for solid and thinfilm-solid cylindrical thermo-acoustic transductions are proposed and the corresponding acoustic pressure solutions are obtained. The acoustic pressure for an individual carbon nanotube (CNT) as a function of input power is investigated analytically and it is verified by comparing with the published experimental data. Further numerical analysis on the acoustic pressure response and characteristics for varying input frequency and distance are also examined both for solid and thinfilm-solid cylindrical thermo-acoustic transductions. Through detailed theoretical and numerical studies on the acoustic pressure solution for thinfilm-solid cylindrical transduction, it is concluded that a solid with smaller thermal conductivity favors to improve the acoustic performance. In general, the proposed models are applicable to a variety of cylindrical thermo-acoustic devices performing in different gaseous media. - Highlights: • Theory and modeling both for solid and thinfilm-solid cylindrical thermo-acoustic transductions are proposed. • The modeling is verified by comparing with the published experimental data. • Acoustic response characteristics of cylindrical thermo-acoustic transductions are predicted by the proposed model.

  10. Integrated Electromechanical Transduction Schemes for Polymer MEMS Sensors

    Directory of Open Access Journals (Sweden)

    Damien Thuau

    2018-04-01

    Full Text Available Polymer Micro ElectroMechanical Systems (MEMS have the potential to constitute a powerful alternative to silicon-based MEMS devices for sensing applications. Although the use of commercial photoresists as structural material in polymer MEMS has been widely reported, the integration of functional polymer materials as electromechanical transducers has not yet received the same amount of interest. In this context, we report on the design and fabrication of different electromechanical schemes based on polymeric materials ensuring different transduction functions. Piezoresistive transduction made of carbon nanotube-based nanocomposites with a gauge factor of 200 was embedded within U-shaped polymeric cantilevers operating either in static or dynamic modes. Flexible resonators with integrated piezoelectric transduction were also realized and used as efficient viscosity sensors. Finally, piezoelectric-based organic field effect transistor (OFET electromechanical transduction exhibiting a record sensitivity of over 600 was integrated into polymer cantilevers and used as highly sensitive strain and humidity sensors. Such advances in integrated electromechanical transduction schemes should favor the development of novel all-polymer MEMS devices for flexible and wearable applications in the future.

  11. The role of arachidonic acid metabolites in signal transduction in an identified neural network mediating presynaptic inhibition in Aplysia

    International Nuclear Information System (INIS)

    Shapiro, E.; Piomelli, D.; Feinmark, S.; Vogel, S.; Chin, G.; Schwartz, J.H.

    1988-01-01

    Neuromodulation is a form of signal transduction that results in the biochemical control of neuronal excitability. Many neurotransmitters act through second messengers, and the examination of biochemical cascades initiated by neurotransmitter-receptor interaction has advanced the understanding of how information is acquired and stored in the nervous system. For example, 5-HT and other facilitory transmitters increase cAMP in sensory neurons of Aplysia, which enhances excitability and facilitates transmitter output. The authors have examined the role of arachidonic acid metabolites in a neuronal circuit mediating presynaptic inhibition. L32 cells are a cluster of putative histaminergic neurons that each make dual-action synaptic potentials onto two follower neurons, L10 and L14. The synaptic connections, biophysical properties, and roles in behavior of the L10 and L14 follower cells have been well studied. The types of ion channels causing each component of the L32-L10 and L32-L14 dual actions have been characterized and application of histamine mimics the effects of stimulating L32 in both L10 and L14

  12. Synaptic remodeling, synaptic growth and the storage of long-term memory in Aplysia.

    Science.gov (United States)

    Bailey, Craig H; Kandel, Eric R

    2008-01-01

    Synaptic remodeling and synaptic growth accompany various forms of long-term memory. Storage of the long-term memory for sensitization of the gill-withdrawal reflex in Aplysia has been extensively studied in this respect and is associated with the growth of new synapses by the sensory neurons onto their postsynaptic target neurons. Recent time-lapse imaging studies of living sensory-to-motor neuron synapses in culture have monitored both functional and structural changes simultaneously so as to follow remodeling and growth at the same specific synaptic connections continuously over time and to examine the functional contribution of these learning-related structural changes to the different time-dependent phases of memory storage. Insights provided by these studies suggest the synaptic differentiation and growth induced by learning in the mature nervous system are highly dynamic and often rapid processes that can recruit both molecules and mechanisms used for de novo synapse formation during development.

  13. Dioxin exposure of human CD34+ hemopoietic cells induces gene expression modulation that recapitulates its in vivo clinical and biological effects

    International Nuclear Information System (INIS)

    Fracchiolla, Nicola Stefano; Todoerti, Katia; Bertazzi, Pier Alberto; Servida, Federica; Corradini, Paolo; Carniti, Cristiana; Colombi, Antonio; Cecilia Pesatori, Angela; Neri, Antonino; Deliliers, Giorgio Lambertenghi

    2011-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has a large number of biological effects, including skin, cardiovascular, neurologic diseases, diabetes, infertility, cancers and immunotoxicity. We analysed the in vitro TCDD effects on human CD34 + cells and tested the gene expression modulation by means of microarray analyses before and after TCDD exposure. We identified 257 differentially modulated probe sets, identifying 221 well characterized genes. A large part of these resulted associated to cell adhesion and/or angiogenesis and to transcription regulation. Synaptic transmission and visual perception functions, with the particular involvement of the GABAergic pathway were also significantly modulated. Numerous transcripts involved in cell cycle or cell proliferation, immune response, signal transduction, ion channel activity or calcium ion binding, tissue development and differentiation, female or male fertility or in several metabolic pathways were also affected after dioxin exposure. The transcriptional profile induced by TCDD treatment on human CD34 + cells strikingly reproduces the clinical and biological effects observed in individuals exposed to dioxin and in biological experimental systems. Our data support a role of dioxin in the neoplastic transformation of hemopoietic stem cells and in immune modulation processes after in vivo exposure, as indicated by the epidemiologic data in dioxin accidentally exposed populations, providing a molecular basis for it. In addition, TCDD alters genes associated to glucidic and lipidic metabolisms, to GABAergic transmission or involved in male and female fertility, thus providing a possible explanation of the diabetogenic, dyslipidemic, neurologic and fertility effects induced by TCDD in vivo exposure.

  14. Effects of dopamine and glutamate on synaptic plasticity: a computational modeling approach for drug abuse as comorbidity in mood disorders.

    Science.gov (United States)

    Qi, Z; Kikuchi, S; Tretter, F; Voit, E O

    2011-05-01

    Major depressive disorder (MDD) affects about 16% of the general population and is a leading cause of death in the United States and around the world. Aggravating the situation is the fact that "drug use disorders" are highly comorbid in MDD patients, and VICE VERSA. Drug use and MDD share a common component, the dopamine system, which is critical in many motivation and reward processes, as well as in the regulation of stress responses in MDD. A potentiating mechanism in drug use disorders appears to be synaptic plasticity, which is regulated by dopamine transmission. In this article, we describe a computational model of the synaptic plasticity of GABAergic medium spiny neurons in the nucleus accumbens, which is critical in the reward system. The model accounts for effects of both dopamine and glutamate transmission. Model simulations show that GABAergic medium spiny neurons tend to respond to dopamine stimuli with synaptic potentiation and to glutamate signals with synaptic depression. Concurrent dopamine and glutamate signals cause various types of synaptic plasticity, depending on input scenarios. Interestingly, the model shows that a single 0.5 mg/kg dose of amphetamine can cause synaptic potentiation for over 2 h, a phenomenon that makes synaptic plasticity of medium spiny neurons behave quasi as a bistable system. The model also identifies mechanisms that could potentially be critical to correcting modifications of synaptic plasticity caused by drugs in MDD patients. An example is the feedback loop between protein kinase A, phosphodiesterase, and the second messenger cAMP in the postsynapse. Since reward mechanisms activated by psychostimulants could be crucial in establishing addiction comorbidity in patients with MDD, this model might become an aid for identifying and targeting specific modules within the reward system and lead to a better understanding and potential treatment of comorbid drug use disorders in MDD. © Georg Thieme Verlag KG Stuttgart · New

  15. TRPV1 and Endocannabinoids: Emerging Molecular Signals that Modulate Mammalian Vision

    Directory of Open Access Journals (Sweden)

    Daniel A. Ryskamp

    2014-09-01

    Full Text Available Transient Receptor Potential Vanilloid 1 (TRPV1 subunits form a polymodal cation channel responsive to capsaicin, heat, acidity and endogenous metabolites of polyunsaturated fatty acids. While originally reported to serve as a pain and heat detector in the peripheral nervous system, TRPV1 has been implicated in the modulation of blood flow and osmoregulation but also neurotransmission, postsynaptic neuronal excitability and synaptic plasticity within the central nervous system. In addition to its central role in nociception, evidence is accumulating that TRPV1 contributes to stimulus transduction and/or processing in other sensory modalities, including thermosensation, mechanotransduction and vision. For example, TRPV1, in conjunction with intrinsic cannabinoid signaling, might contribute to retinal ganglion cell (RGC axonal transport and excitability, cytokine release from microglial cells and regulation of retinal vasculature. While excessive TRPV1 activity was proposed to induce RGC excitotoxicity, physiological TRPV1 activity might serve a neuroprotective function within the complex context of retinal endocannabinoid signaling. In this review we evaluate the current evidence for localization and function of TRPV1 channels within the mammalian retina and explore the potential interaction of this intriguing nociceptor with endogenous agonists and modulators.

  16. Microenvironment Dependent Photobiomodulation on Function-Specific Signal Transduction Pathways

    Directory of Open Access Journals (Sweden)

    Timon Cheng-Yi Liu

    2014-01-01

    Full Text Available Cellular photobiomodulation on a cellular function has been shown to be homeostatic. Its function-specific pathway mechanism would be further discussed in this paper. The signal transduction pathways maintaining a normal function in its function-specific homeostasis (FSH, resisting the activation of many other irrelative signal transduction pathways, are so sparse that it can be supposed that there may be normal function-specific signal transduction pathways (NSPs. A low level laser irradiation or monochromatic light may promote the activation of partially activated NSP and/or its redundant NSP so that it may induce the second-order phase transition of a function from its dysfunctional one far from its FSH to its normal one in a function-specific microenvironment and may also induce the first-order functional phase transition of the normal function from low level to high level.

  17. Physical aspects of sensory transduction on seeing, hearing and smelling.

    Science.gov (United States)

    Yoshioka, Tohru; Sakakibara, Manabu

    2013-01-01

    What is the general principle of sensory transduction? Sensory transduction is defined as energy transformation from the external world to the internal world. The energy of the external world, such as thermal energy (heat), electro-magnetic energy (light), mechanical energy (sound) and the energy from molecules (chemicals), is converted into electrochemical events in the animal nervous system. The following five classes of special sense receptors are utilized for energy conversion: vision (photo); audition (sound); taste and smell (chemo); and tactile (mechano). There are also other special sense receptors, including thermo and noxious receptors. The focus of this study is on photoreceptors, sound-receptors and odorant-receptors because the transduction mechanisms of these receptors are explained biochemically and understood by a common physical principle; these biochemical models are well known in neuroscience. The following notable problems are inherent in these biochemical models: the cGMP ionophore model of the vertebrate photoreceptor cannot explain the fast photo-response (∼msec); the tip links connection model of stereocilia in the basilar membrane for opening the K(+) channel on the tip of a hair has difficulty explaining the high frequency vibration of hair cells without a damping of the oscillation, and the odorant shape-specific receptor model for olfactory transduction has difficulty in discriminating the minute differences among similar fragrant smells of essential oils with different molecular shapes. These difficulties might arise from a lack of the physical sense when the transduction models were proposed. This article will reconsider these problems and propose rational models for visual, olfactory and auditory transduction.

  18. Hippocampal testosterone relates to reference memory performance and synaptic plasticity in male rats

    Directory of Open Access Journals (Sweden)

    Kristina eSchulz

    2010-12-01

    Full Text Available Steroids are important neuromodulators influencing cognitive performance and synaptic plasticity. While the majority of literature concerns adrenal- and gonadectomized animals, very little is known about the natural endogenous release of hormones during learning. Therefore, we measured blood and brain (hippocampus, prefrontal cortex testosterone, estradiol, and corticosterone concentrations of intact male rats undergoing a spatial learning paradigm which is known to reinforce hippocampal plasticity. We found significant modulations of all investigated hormones over the training course. Corticosterone and testosterone were correlated manifold with behaviour, while estradiol expressed fewer correlations. In the recall session, testosterone was tightly coupled to reference memory performance, which is crucial for reinforcement of synaptic plasticity in the dentate gyrus. Intriguingly, prefrontal cortex and hippocampal levels related differentially to reference memory performance. Correlations of testosterone and corticosterone switched from unspecific activity to specific cognitive functions over training. Correspondingly, exogenous application of testosterone revealed different effects on synaptic and neuronal plasticity in trained versus untrained animals. While hippocampal long-term potentiation (LTP of the field excitatory postsynaptic potential (fEPSP was prolonged in untrained rats, both the fEPSP- and the population spike amplitude-LTP was impaired in trained rats. Behavioural performance was unaffected, but correlations of hippocampal field potentials with behaviour were decoupled in treated rats. The data provide important evidence that besides adrenal, also gonadal steroids play a mechanistic role in linking synaptic plasticity to cognitive performance.

  19. HDAC2 expression in parvalbumin interneurons regulates synaptic plasticity in the mouse visual cortex

    Directory of Open Access Journals (Sweden)

    Alexi Nott

    2015-01-01

    Full Text Available An experience-dependent postnatal increase in GABAergic inhibition in the visual cortex is important for the closure of a critical period of enhanced synaptic plasticity. Although maturation of the subclass of parvalbumin (Pv–expressing GABAergic interneurons is known to contribute to critical period closure, the role of epigenetics on cortical inhibition and synaptic plasticity has not been explored. The transcription regulator, histone deacetylase 2 (HDAC2, has been shown to modulate synaptic plasticity and learning processes in hippocampal excitatory neurons. We found that genetic deletion of HDAC2 specifically from Pv interneurons reduces inhibitory input in the visual cortex of adult mice and coincides with enhanced long-term depression that is more typical of young mice. These findings show that HDAC2 loss in Pv interneurons leads to a delayed closure of the critical period in the visual cortex and supports the hypothesis that HDAC2 is a key negative regulator of synaptic plasticity in the adult brain.

  20. HDAC2 expression in parvalbumin interneurons regulates synaptic plasticity in the mouse visual cortex.

    Science.gov (United States)

    Nott, Alexi; Cho, Sukhee; Seo, Jinsoo; Tsai, Li-Huei

    2015-01-01

    An experience-dependent postnatal increase in GABAergic inhibition in the visual cortex is important for the closure of a critical period of enhanced synaptic plasticity. Although maturation of the subclass of Parvalbumin (Pv)-expressing GABAergic interneurons is known to contribute to critical period closure, the role of epigenetics on cortical inhibition and synaptic plasticity has not been explored. The transcription regulator, histone deacetylase 2 (HDAC2), has been shown to modulate synaptic plasticity and learning processes in hippocampal excitatory neurons. We found that genetic deletion of HDAC2 specifically from Pv-interneurons reduces inhibitory input in the visual cortex of adult mice, and coincides with enhanced long-term depression (LTD) that is more typical of young mice. These findings show that HDAC2 loss in Pv-interneurons leads to a delayed closure of the critical period in the visual cortex and supports the hypothesis that HDAC2 is a key negative regulator of synaptic plasticity in the adult brain.

  1. Deciphering resting microglial morphology and process motility from a synaptic prospect

    Directory of Open Access Journals (Sweden)

    Ines eHristovska

    2016-01-01

    Full Text Available Microglia, the resident immune cells of the central nervous system (CNS, were traditionally believed to be set into action only in case of injury or disease. Accordingly, microglia were assumed to be inactive or resting in the healthy brain. However, recent studies revealed that microglia carry out active tissue sampling in the intact brain by extending and retracting their ramified processes while periodically contacting synapses. Microglial morphology and motility as well as the frequency and duration of physical contacts with synaptic elements were found to be modulated by neuronal activity, sensory experience and neurotransmission; however findings have not been straightforward. Microglial cells are the most morphologically plastic element of the CNS. This unique feature confers them the possibility to locally sense activity, and to respond adequately by establishing synaptic contacts to regulate synaptic inputs by the secretion of signaling molecules. Indeed, microglial cells can hold new roles as critical players in maintaining brain homeostasis and regulating synaptic number, maturation and plasticity. For this reason, a better characterization of microglial cells and cues mediating neuron-to-microglia communication under physiological conditions may help advance our understanding of the microglial behavior and its regulation in the healthy brain. This review highlights recent findings on the instructive role of neuronal activity on microglial motility and microglia-synapse interactions, focusing on the main transmitters involved in this communication and including newly described communication at the tripartite synapse.

  2. Electrophysical properties, synaptic transmission and neuromodulation in serotonergic caudal raphe neurons.

    Science.gov (United States)

    Li, Y W; Bayliss, D A

    1998-06-01

    1. We studied electrophysiological properties, synaptic transmission and modulation by 5-hydroxytryptamine (5-HT) of caudal raphe neurons using whole-cell recording in a neonatal rat brain slice preparation; recorded neurons were identified as serotonergic by post-hoc immunohistochemical detection of tryptophan hydroxylase, the 5-HT-synthesizing enzyme. 2. Serotonergic neurons fired spontaneously (approximately 1 Hz), with maximal steady state firing rates of < 4 Hz. 5-Hydroxytryptamine caused hyperpolarization and cessation of spike activity in these neurons by activating inwardly rectifying K+ conductance via somatodendritic 5-HT1A receptors. 3. Unitary glutamatergic excitatory post-synaptic potentials (EPSP) and currents (EPSC) were evoked in serotonergic neurons by local electrical stimulation. Evoked EPSC were potently inhibited by 5-HT, an effect mediated by presynaptic 5-HT1B receptors. 4. In conclusion, serotonergic caudal raphe neurons are spontaneously active in vitro; they receive prominent glutamatergic synaptic inputs. 5-Hydroxytryptamine regulates serotonergic neuronal activity of the caudal raphe by decreasing spontaneous activity via somatodendritic 5-HT1A receptors and by inhibiting excitatory synaptic transmission onto these neurons via presynaptic 5-HT1B receptors. These local modulatory mechanisms provide multiple levels of feedback autoregulation of serotonergic raphe neurons by 5-HT.

  3. Localization of Presynaptic Plasticity Mechanisms Enables Functional Independence of Synaptic and Ectopic Transmission in the Cerebellum

    Directory of Open Access Journals (Sweden)

    Katharine L. Dobson

    2015-01-01

    Full Text Available In the cerebellar molecular layer parallel fibre terminals release glutamate from both the active zone and from extrasynaptic “ectopic” sites. Ectopic release mediates transmission to the Bergmann glia that ensheathe the synapse, activating Ca2+-permeable AMPA receptors and glutamate transporters. Parallel fibre terminals exhibit several forms of presynaptic plasticity, including cAMP-dependent long-term potentiation and endocannabinoid-dependent long-term depression, but it is not known whether these presynaptic forms of long-term plasticity also influence ectopic transmission to Bergmann glia. Stimulation of parallel fibre inputs at 16 Hz evoked LTP of synaptic transmission, but LTD of ectopic transmission. Pharmacological activation of adenylyl cyclase by forskolin caused LTP at Purkinje neurons, but only transient potentiation at Bergmann glia, reinforcing the concept that ectopic sites lack the capacity to express sustained cAMP-dependent potentiation. Activation of mGluR1 caused depression of synaptic transmission via retrograde endocannabinoid signalling but had no significant effect at ectopic sites. In contrast, activation of NMDA receptors suppressed both synaptic and ectopic transmission. The results suggest that the signalling mechanisms for presynaptic LTP and retrograde depression by endocannabinoids are restricted to the active zone at parallel fibre synapses, allowing independent modulation of synaptic transmission to Purkinje neurons and ectopic transmission to Bergmann glia.

  4. Signal transduction pathways involved in mechanotransduction in bone cells

    International Nuclear Information System (INIS)

    Liedert, Astrid; Kaspar, Daniela; Blakytny, Robert; Claes, Lutz; Ignatius, Anita

    2006-01-01

    Several in vivo and in vitro studies with different loading regimens showed that mechanical stimuli have an influence on proliferation and differentiation of bone cells. Prerequisite for this influence is the transduction of mechanical signals into the cell, a phenomenon that is termed mechanotransduction, which is essential for the maintenance of skeletal homeostasis in adults. Mechanoreceptors, such as the integrins, cadherins, and stretch-activated Ca 2+ channels, together with various signal transduction pathways, are involved in the mechanotransduction process that ultimately regulates gene expression in the nucleus. Mechanotransduction itself is considered to be regulated by hormones, the extracellular matrix of the osteoblastic cells and the mode of the mechanical stimulus

  5. The Impact of Stimulation Induced Short Term Synaptic Plasticity on Firing Patterns in the Globus Pallidus of the Rat

    Directory of Open Access Journals (Sweden)

    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.

  6. Influence of Synaptic Depression on Memory Storage Capacity

    Science.gov (United States)

    Otsubo, Yosuke; Nagata, Kenji; Oizumi, Masafumi; Okada, Masato

    2011-08-01

    Synaptic efficacy between neurons is known to change within a short time scale dynamically. Neurophysiological experiments show that high-frequency presynaptic inputs decrease synaptic efficacy between neurons. This phenomenon is called synaptic depression, a short term synaptic plasticity. Many researchers have investigated how the synaptic depression affects the memory storage capacity. However, the noise has not been taken into consideration in their analysis. By introducing ``temperature'', which controls the level of the noise, into an update rule of neurons, we investigate the effects of synaptic depression on the memory storage capacity in the presence of the noise. We analytically compute the storage capacity by using a statistical mechanics technique called Self Consistent Signal to Noise Analysis (SCSNA). We find that the synaptic depression decreases the storage capacity in the case of finite temperature in contrast to the case of the low temperature limit, where the storage capacity does not change.

  7. Mitogen-activated protein kinase and abscisic acid signal transduction

    NARCIS (Netherlands)

    Heimovaara-Dijkstra, S.; Testerink, C.; Wang, M.

    1998-01-01

    The phytohormone abscisic acid (ABA) is a classical plant hormone, responsible for regulation of abscission, diverse aspects of plant and seed development, stress responses and germination. It was found that ABA signal transduction in plants can involve the activity of type 2C-phosphatases (PP2C),

  8. Molecular methods for the study of signal transduction in plants

    KAUST Repository

    Irving, Helen R.; Gehring, Christoph A

    2013-01-01

    as well as at the systems level where transcriptomics and particularly phosphoproteomics afford a window into complex biological responses. Here we review the role of the cyclic nucleotides cAMP and cGMP in plant signal transduction as well

  9. Cell biology symposium: Membrane trafficking and signal transduction

    Science.gov (United States)

    In general, membrane trafficking is a broad group of processes where proteins and other large molecules are distributed throughout the cell as well as adjacent extracellular spaces. Whereas signal transduction is a process where signals are transmitted through a series of chemical or molecular event...

  10. Olfactory transduction pathways in the Senegalese sole Solea senegalensis.

    Science.gov (United States)

    Velez, Z; Hubbard, P C; Barata, E N; Canário, A V M

    2013-09-01

    This study tested whether differences in sensitivity between the upper and lower olfactory epithelia of Solea senegalensis are associated with different odorant receptors and transduction pathways, using the electro-olfactogram. Receptor mechanisms were assessed by cross-adaptation with amino acids (L-cysteine, L-phenylalanine and 1-methyl-L-tryptophan) and bile acids (taurocholic acid and cholic acid). This suggested that relatively specific receptors exist for 1-methyl-L-tryptophan and L-phenylalanine (food-related odorants) in the lower epithelium, and for taurocholic acid (conspecific-derived odorant) in the upper. Inhibition by U73122 [a phospholipase C (PLC) inhibitor] suggested that olfactory responses to amino acids were mediated mostly, but not entirely, by PLC-mediated transduction (IC50 ; 15-55 nM), whereas bile acid responses were mediated by both PLC and adenylate cyclase-cyclic adenosine monophosphate (AC-cAMP) (using SQ-22536; an AC inhibitor). Simultaneous application of both drugs rarely inhibited responses completely, suggesting possible involvement of non-PLC and non-AC mediated mechanisms. For aromatic amino acids and bile acids, there were differences in the contribution of each transduction pathway (PLC, AC and non-PLC and non-AC) between the two epithelia. These results suggest that differences in sensitivity of the two epithelia are associated with differences in odorant receptors and transduction mechanisms. © 2013 The Fisheries Society of the British Isles.

  11. Protein phosphorylation and its role in archaeal signal transduction

    Science.gov (United States)

    Esser, Dominik; Hoffmann, Lena; Pham, Trong Khoa; Bräsen, Christopher; Qiu, Wen; Wright, Phillip C.; Albers, Sonja-Verena; Siebers, Bettina

    2016-01-01

    Reversible protein phosphorylation is the main mechanism of signal transduction that enables cells to rapidly respond to environmental changes by controlling the functional properties of proteins in response to external stimuli. However, whereas signal transduction is well studied in Eukaryotes and Bacteria, the knowledge in Archaea is still rather scarce. Archaea are special with regard to protein phosphorylation, due to the fact that the two best studied phyla, the Euryarchaeota and Crenarchaeaota, seem to exhibit fundamental differences in regulatory systems. Euryarchaeota (e.g. halophiles, methanogens, thermophiles), like Bacteria and Eukaryotes, rely on bacterial-type two-component signal transduction systems (phosphorylation on His and Asp), as well as on the protein phosphorylation on Ser, Thr and Tyr by Hanks-type protein kinases. Instead, Crenarchaeota (e.g. acidophiles and (hyper)thermophiles) only depend on Hanks-type protein phosphorylation. In this review, the current knowledge of reversible protein phosphorylation in Archaea is presented. It combines results from identified phosphoproteins, biochemical characterization of protein kinases and protein phosphatases as well as target enzymes and first insights into archaeal signal transduction by biochemical, genetic and polyomic studies. PMID:27476079

  12. Expression of SMAD signal transduction molecules in the pancreas

    DEFF Research Database (Denmark)

    Brorson, Michael; Hougaard, D.; Nielsen, Jens Høiriis

    2001-01-01

    Members of the TGF-beta superfamily of cytokines have been implicated in pancreatic cancer, pancreatitis and in regulation and differentiation of pancreatic endocrine and exocrine cells. Different TGF-beta members signal through phosphorylation of different signal transduction proteins, which eve...

  13. Two-Component Signal Transduction System SaeRS Positively Regulates Staphylococcus epidermidis Glucose Metabolism

    Directory of Open Access Journals (Sweden)

    Qiang Lou

    2014-01-01

    Full Text Available Staphylococcus epidermidis, which is a causative pathogen of nosocomial infection, expresses its virulent traits such as biofilm and autolysis regulated by two-component signal transduction system SaeRS. In this study, we performed a proteomic analysis of differences in expression between the S. epidermidis 1457 wild-type and saeRS mutant to identify candidates regulated by saeRS using two-dimensional gel electrophoresis (2-DE combined with matrix-assisted laser desorption/lonization mass spectrometry (MALDI-TOF-MS. Of 55 identified proteins that significantly differed in expression between the two strains, 15 were upregulated and 40 were downregulated. The downregulated proteins included enzymes related to glycolysis and TCA cycle, suggesting that glucose is not properly utilized in S. epidermidis when saeRS was deleted. The study will be helpful for treatment of S. epidermidis infection from the viewpoint of metabolic modulation dependent on two-component signal transduction system SaeRS.

  14. Rab11-FIP3 Regulation of Lck Endosomal Traffic Controls TCR Signal Transduction.

    Science.gov (United States)

    Bouchet, Jérôme; Del Río-Iñiguez, Iratxe; Vázquez-Chávez, Elena; Lasserre, Rémi; Agüera-González, Sonia; Cuche, Céline; McCaffrey, Mary W; Di Bartolo, Vincenzo; Alcover, Andrés

    2017-04-01

    The role of endosomes in receptor signal transduction is a long-standing question, which remains largely unanswered. The T cell Ag receptor and various components of its proximal signaling machinery are associated with distinct endosomal compartments, but how endosomal traffic affects T cell signaling remains ill-defined. In this article, we demonstrate in human T cells that the subcellular localization and function of the protein tyrosine kinase Lck depends on the Rab11 effector FIP3 (Rab11 family interacting protein-3). FIP3 overexpression or silencing and its ability to interact with Rab11 modify Lck subcellular localization and its delivery to the immunological synapse. Importantly, FIP3-dependent Lck localization controls early TCR signaling events, such as tyrosine phosphorylation of TCRζ, ZAP70, and LAT and intracellular calcium concentration, as well as IL-2 gene expression. Interestingly, FIP3 controls both steady-state and poststimulation phosphotyrosine and calcium levels. Finally, our findings indicate that FIP3 modulates TCR-CD3 cell surface expression via the regulation of steady-state Lck-mediated TCRζ phosphorylation, which in turn controls TCRζ protein levels. This may influence long-term T cell activation in response to TCR-CD3 stimulation. Therefore, our data underscore the importance of finely regulated endosomal traffic in TCR signal transduction and T cell activation leading to IL-2 production. Copyright © 2017 by The American Association of Immunologists, Inc.

  15. Pannexin1 stabilizes synaptic plasticity and is needed for learning.

    Directory of Open Access Journals (Sweden)

    Nora Prochnow

    Full Text Available Pannexin 1 (Panx1 represents a class of vertebrate membrane channels, bearing significant sequence homology with the invertebrate gap junction proteins, the innexins and more distant similarities in the membrane topologies and pharmacological sensitivities with gap junction proteins of the connexin family. In the nervous system, cooperation among pannexin channels, adenosine receptors, and K(ATP channels modulating neuronal excitability via ATP and adenosine has been recognized, but little is known about the significance in vivo. However, the localization of Panx1 at postsynaptic sites in hippocampal neurons and astrocytes in close proximity together with the fundamental role of ATP and adenosine for CNS metabolism and cell signaling underscore the potential relevance of this channel to synaptic plasticity and higher brain functions. Here, we report increased excitability and potently enhanced early and persistent LTP responses in the CA1 region of acute slice preparations from adult Panx1(-/- mice. Adenosine application and N-methyl-D-aspartate receptor (NMDAR-blocking normalized this phenotype, suggesting that absence of Panx1 causes chronic extracellular ATP/adenosine depletion, thus facilitating postsynaptic NMDAR activation. Compensatory transcriptional up-regulation of metabotropic glutamate receptor 4 (grm4 accompanies these adaptive changes. The physiological modification, promoted by loss of Panx1, led to distinct behavioral alterations, enhancing anxiety and impairing object recognition and spatial learning in Panx1(-/- mice. We conclude that ATP release through Panx1 channels plays a critical role in maintaining synaptic strength and plasticity in CA1 neurons of the adult hippocampus. This result provides the rationale for in-depth analysis of Panx1 function and adenosine based therapies in CNS disorders.

  16. Synaptic theory of Replicator-like melioration

    Directory of Open Access Journals (Sweden)

    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.

  17. The sugarcane signal transduction (SUCAST catalogue: prospecting signal transduction in sugarcane

    Directory of Open Access Journals (Sweden)

    Glaucia Mendes Souza

    2001-12-01

    Full Text Available EST sequencing has enabled the discovery of many new genes in a vast array of organisms, and the utility of this approach to the scientific community is greatly increased by the establishment of fully annotated databases. The present study aimed to identify sugarcane ESTs sequenced in the sugarcane expressed sequence tag (SUCEST project (http://sucest.lad.ic.unicamp.br that corresponded to signal transduction components. We also produced a sugarcane signal transduction (SUCAST catalogue (http://sucest.lad.ic.unicamp.br/private/mining-reports/QG/QG-mining.htm that covered the main categories and pathways. Expressed sequence tags (ESTs encoding enzymes for hormone (gibberellins, ethylene, auxins, abscisic acid and jasmonic acid biosynthetic pathways were found and tissue specificity was inferred from their relative frequency of occurrence in the different libraries. Whenever possible, transducers of hormones and plant peptide signaling were catalogued to the respective pathway. Over 100 receptors were found in sugarcane, which contains a large family of Ser/Thr kinase receptors and also photoreceptors, histidine kinase receptors and their response regulators. G-protein and small GTPases were analyzed and compared to known members of these families found in mammalian and plant systems. Major kinase and phosphatase pathways were mapped, with special attention being given to the MAP kinase and the inositol pathway, both of which are well known in plants.O sequenciamento de ESTs (etiquetas de sequencias transcritas tem possibilitado a descoberta de muitos novos genes em uma ampla variedade de organismos. Um aumento do aproveitamento desta informação pela comunidade científica tem sido possível graças ao desenvolvimento de base de dados contendo seqüências completamente anotadas. O trabalho aqui relatado teve como objetivo a identificação de ESTs de cana de açúcar seqüenciadas através do projeto SUCEST (http://sucest.lad.ic. unicamp.br que

  18. Dynamic Control of Synaptic Adhesion and Organizing Molecules in Synaptic Plasticity

    Energy Technology Data Exchange (ETDEWEB)

    Rudenko, Gabby (Texas-MED)

    2017-01-01

    Synapses play a critical role in establishing and maintaining neural circuits, permitting targeted information transfer throughout the brain. A large portfolio of synaptic adhesion/organizing molecules (SAMs) exists in the mammalian brain involved in synapse development and maintenance. SAMs bind protein partners, formingtrans-complexes spanning the synaptic cleft orcis-complexes attached to the same synaptic membrane. SAMs play key roles in cell adhesion and in organizing protein interaction networks; they can also provide mechanisms of recognition, generate scaffolds onto which partners can dock, and likely take part in signaling processes as well. SAMs are regulated through a portfolio of different mechanisms that affect their protein levels, precise localization, stability, and the availability of their partners at synapses. Interaction of SAMs with their partners can further be strengthened or weakened through alternative splicing, competing protein partners, ectodomain shedding, or astrocytically secreted factors. Given that numerous SAMs appear altered by synaptic activity, in vivo, these molecules may be used to dynamically scale up or scale down synaptic communication. Many SAMs, including neurexins, neuroligins, cadherins, and contactins, are now implicated in neuropsychiatric and neurodevelopmental diseases, such as autism spectrum disorder, schizophrenia, and bipolar disorder and studying their molecular mechanisms holds promise for developing novel therapeutics.

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

    Science.gov (United States)

    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

  20. [Transduction peptides, the useful face of a new signaling mechanism].

    Science.gov (United States)

    Joliot, Alain; Prochiantz, Alain

    2005-03-01

    Transduction peptides that cross the plasma membrane of live cells are commonly used for the in vitro and in vivo targeting of hydrophilic drugs into the cell interior. Although this family of peptides has recently increased and will probably continue to do so, the two mainly used peptides are derived from transcription factors. Indeed, TAT is a 12 amino acid long arginine-rich peptide present in the HIV transcription factor, and penetratin - or its variants - corresponds to 16 amino acids that define the highly conserved third helix of the DNA-binding domain (homeodomain) of homeoprotein transcription factors. In this review, we shall recall the different steps that have led to the discovery of transduction peptides and present the most likely hypotheses concerning the mechanisms involved in their internalization. At the risk of being incomplete or, even, biased, we shall concentrate on penetratins and TAT. The reason is that these peptides have been studied for over ten years leading to the edification of robust knowledge regarding their properties. This attitude will not preclude comparisons with other peptides, if necessary. Our goal is to describe the mode of action of these transduction peptides, their range of activity in term of cell types that accept them and cargoes that they can transport, and, also, some of the limitations that one can encounter in their use. Finally, based on the idea that peptide transduction is the technological face of a physiological property of some transcription factors, we shall discuss the putative physiological function of homeoprotein transduction, and, as a consequence, the possibility to use these factors as therapeutic proteins.

  1. Protein kinase inhibitor peptide (PKI): a family of endogenous neuropeptides that modulate neuronal cAMP-dependent protein kinase function.

    Science.gov (United States)

    Dalton, George D; Dewey, William L

    2006-02-01

    Signal transduction cascades involving cAMP-dependent protein kinase are highly conserved among a wide variety of organisms. Given the universal nature of this enzyme it is not surprising that cAMP-dependent protein kinase plays a critical role in numerous cellular processes. This is particularly evident in the nervous system where cAMP-dependent protein kinase is involved in neurotransmitter release, gene transcription, and synaptic plasticity. Protein kinase inhibitor peptide (PKI) is an endogenous thermostable peptide that modulates cAMP-dependent protein kinase function. PKI contains two distinct functional domains within its amino acid sequence that allow it to: (1) potently and specifically inhibit the activity of the free catalytic subunit of cAMP-dependent protein kinase and (2) export the free catalytic subunit of cAMP-dependent protein kinase from the nucleus. Three distinct PKI isoforms (PKIalpha, PKIbeta, PKIgamma) have been identified and each isoform is expressed in the brain. PKI modulates neuronal synaptic activity, while PKI also is involved in morphogenesis and symmetrical left-right axis formation. In addition, PKI also plays a role in regulating gene expression induced by cAMP-dependent protein kinase. Future studies should identify novel physiological functions for endogenous PKI both in the nervous system and throughout the body. Most interesting will be the determination whether functional differences exist between individual PKI isoforms which is an intriguing possibility since these isoforms exhibit: (1) cell-type specific tissue expression patterns, (2) different potencies for the inhibition of cAMP-dependent protein kinase activity, and (3) expression patterns that are hormonally, developmentally and cell-cycle regulated. Finally, synthetic peptide analogs of endogenous PKI will continue to be invaluable tools that are used to elucidate the role of cAMP-dependent protein kinase in a variety of cellular processes throughout the nervous

  2. Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease.

    Science.gov (United States)

    Ma, Qiu-Lan; Teng, Edmond; Zuo, Xiaohong; Jones, Mychica; Teter, Bruce; Zhao, Evan Y; Zhu, Cansheng; Bilousova, Tina; Gylys, Karen H; Apostolova, Liana G; LaDu, Mary Jo; Hossain, Mir Ahamed; Frautschy, Sally A; Cole, Gregory M

    2018-06-01

    Synaptic neurodegeneration is thought to be an early event initiated by soluble β-amyloid (Aβ) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein ε4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Aβ aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking. We evaluated neuronal pentraxin 1 (NP1), a potential CNS-derived plasma biomarker of excitatory synaptic pathology. NP1 is preferentially expressed in brain and involved in glutamate receptor internalization. NP1 is secreted presynaptically induced by Aβ oligomers, and implicated in excitatory synaptic and mitochondrial deficits. Levels of NP1 and its fragments were increased in a correlated fashion in both brain and plasma of 7-8 month-old E4FAD mice relative to E3FAD mice. NP1 was also found in exosome preparations and reduced by dietary DHA supplementation. Plasma NP1 was higher in E4FAD+ (APOE4 +/+ /FAD +/- ) relative to E4FAD- (non-carrier; APOE4 +/+ /FAD -/- ) mice, suggesting NP1 is modulated by Aβ expression. Finally, relative to normal elderly, plasma NP1 was also elevated in patients with mild cognitive impairment (MCI) and elevated further in the subset who progressed to early-stage AD. In those patients, there was a trend towards increased NP1 levels in APOE4 carriers relative to non-carriers. These findings indicate that NP1 may represent a potential synapse-derived plasma biomarker relevant to early alterations in excitatory synapses in MCI and early-stage AD. Copyright © 2018. Published by Elsevier Inc.

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    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....... Neurons responded to electrical stimulation by monosynaptic EPSCs (excitatory monosynaptic postsynaptic currents). 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...

  4. Involvement of neurotrophin-3 (NT-3) in the functional elimination of synaptic contacts during neuromuscular development.

    Science.gov (United States)

    Garcia, Neus; Santafé, Manel M; Tomàs, Marta; Lanuza, Maria A; Besalduch, Nuria; Tomàs, Josep

    2010-04-05

    Confocal immunohistochemistry shows that neurotrophin-3 (NT-3) and its receptor tropomyosin-related tyrosin kinase C (trkC) are present in both neonatal (P6) and adult (P45) mouse motor nerve terminals in neuromuscular junctions (NMJ) colocalized with several synaptic proteins. NT-3 incubation (1-3h, in the range 10-200ng/ml) does not change the size of the evoked and spontaneous endplate potentials at P45. However, NT-3 (1h, 100ng/ml) strongly potentiates evoked ACh release from the weak (70%) and the strong (50%) axonal inputs on dually innervated postnatal endplates (P6) but not in the most developed postnatal singly innervated synapses at P6. The present results indicate that NT-3 has a role in the developmental mechanism that eliminates redundant synapses though it cannot modulate synaptic transmission locally as the NMJ matures.

  5. Effects of 17beta-estradiol on glutamate synaptic transmission and neuronal excitability in the rat medial vestibular nuclei.

    Science.gov (United States)

    Grassi, S; Frondaroli, A; Scarduzio, M; Dutia, M B; Dieni, C; Pettorossi, V E

    2010-02-17

    We investigated the effects of the neurosteroid 17beta-estradiol (E(2)) on the evoked and spontaneous activity of rat medial vestibular nucleus (MVN) neurons in brainstem slices. E(2) enhances the synaptic response to vestibular nerve stimulation in type B neurons and depresses the spontaneous discharge in both type A and B neurons. The amplitude of the field potential, as well as the excitatory post-synaptic potential (EPSP) and current (EPSC), in type B neurons, are enhanced by E(2). Both effects are long-term phenomena since they outlast the drug washout. The enhancement of synaptic response is mainly due to facilitation of glutamate release mediated by pre-synaptic N-methyl-D-aspartate receptors (NMDARs), since the reduction of paired pulse ratio (PPR) and the increase of miniature EPSC frequency after E(2) are abolished under D-(-)-2-amino-5-phosphonopentanoic acid (AP-5). E(2) also facilitates post-synaptic NMDARs, but it does not affect directly alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and group I-metabotropic glutamate receptors (mGluRs-I). In contrast, the depression of the spontaneous discharge of type A and type B neurons appears to depend on E(2) modulation of intrinsic ion conductances, as the effect remains after blockade of glutamate, GABA and glycine receptors (GlyRs). The net effect of E(2) is to enhance the signal-to-noise ratio of the synaptic response in type B neurons, relative to resting activity of all MVN neurons. These findings provide evidence for a novel potential mechanism to modulate the responsiveness of vestibular neurons to afferent inputs, and so regulate vestibular function in vivo.

  6. Characterization of sur-2, a Novel Ras-Mediated Signal Transduction Component in C. elegans

    National Research Council Canada - National Science Library

    DesJardins, Edward

    1998-01-01

    ... (oncogenes). A subset of proto-oncogenes comprise the RAS signal transduction pathway. Vulval development in the nematode worm Caenorhabditis elegans is controlled by a RAS signal transduction pathway...

  7. Characterization of sur-2, a Novel Ras-Mediated Signal Transduction Component in C. elegans

    National Research Council Canada - National Science Library

    DesJardins, Edward

    1999-01-01

    ... (oncogenes). A subset of proto-oncogenes comprise the RAS signal transduction pathway. Vulval development in the nematode worm Caenorhabditis elegans is controlled by a RAS signal transduction pathway. C...

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

    Directory of Open Access Journals (Sweden)

    Chang-Gyu Hahn

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

  9. Mechanisms of glycine release, which build up synaptic and extrasynaptic glycine levels: the role of synaptic and non-synaptic glycine transporters.

    Science.gov (United States)

    Harsing, Laszlo G; Matyus, Peter

    2013-04-01

    Glycine is an amino acid neurotransmitter that is involved in both inhibitory and excitatory neurochemical transmission in the central nervous system. The role of glycine in excitatory neurotransmission is related to its coagonist action at glutamatergic N-methyl-D-aspartate receptors. The glycine levels in the synaptic cleft rise many times higher during synaptic activation assuring that glycine spills over into the extrasynaptic space. Another possible origin of extrasynaptic glycine is the efflux of glycine occurring from astrocytes associated with glutamatergic synapses. The release of glycine from neuronal or glial origins exhibits several differences compared to that of biogenic amines or other amino acid neurotransmitters. These differences appear in an external Ca(2+)- and temperature-dependent manner, conferring unique characteristics on glycine as a neurotransmitter. Glycine transporter type-1 at synapses may exhibit neural and glial forms and plays a role in controlling synaptic glycine levels and the spill over rate of glycine from the synaptic cleft into the extrasynaptic biophase. Non-synaptic glycine transporter type-1 regulates extrasynaptic glycine concentrations, either increasing or decreasing them depending on the reverse or normal mode operation of the carrier molecule. While we can, at best, only estimate synaptic glycine levels at rest and during synaptic activation, glycine concentrations are readily measurable via brain microdialysis technique applied in the extrasynaptic space. The non-synaptic N-methyl-D-aspartate receptor may obtain glycine for activation following its spill over from highly active synapses or from its release mediated by the reverse operation of non-synaptic glycine transporter-1. The sensitivity of non-synaptic N-methyl-D-aspartate receptors to glutamate and glycine is many times higher than that of synaptic N-methyl-D-aspartate receptors making the former type of receptor the primary target for drug action. Synaptic

  10. Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Skavland, J; Jørgensen, K M [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway); Hadziavdic, K [Department of Informatics, University of Bergen, Bergen (Norway); Hovland, R [Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen (Norway); Jonassen, I [Department of Informatics, University of Bergen, Bergen (Norway); Computational Biology Unit, Bergen Centre for Computational Science, University of Bergen, Bergen (Norway); Bruserud, Ø; Gjertsen, B T, E-mail: bjorn.gjertsen@med.uib.no [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway); Hematology Section, Department of Medicine, Haukeland University Hospital, Bergen (Norway)

    2011-02-01

    Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial.

  11. Calcium current homeostasis and synaptic deficits in hippocampal neurons from Kelch-like 1 knockout mice

    Directory of Open Access Journals (Sweden)

    Paula Patricia Perissinotti

    2015-01-01

    Full Text Available Kelch-like 1 (KLHL1 is a neuronal actin-binding protein that modulates voltage-gated CaV2.1 (P/Q-type and CaV3.2 (α1H T-type calcium channels; KLHL1 knockdown experiments (KD cause down-regulation of both channel types and altered synaptic properties in cultured rat hippocampal neurons (Perissinotti et al., 2014. Here, we studied the effect of ablation of KLHL1 on calcium channel function and synaptic properties in cultured hippocampal neurons from KLHL1 knockout (KO mice. Western blot data showed the P/Q-type channel α1A subunit was less abundant in KO hippocampus compared to wildtype (WT; and PQ-type calcium currents were smaller in KO neurons than WT during early days in vitro, although this decrease was compensated for at late stages by increases in L-type calcium current. In contrast, T-type currents did not change in culture. However, biophysical properties and western blot analysis revealed a differential contribution of T-type channel isoforms in the KO, with CaV3.2 α1H subunit being down-regulated and CaV3.1 α1G up-regulated. Synapsin I levels were reduced in the KO hippocampus; cultured neurons displayed a concomitant reduction in synapsin I puncta and decreased miniature excitatory postsynaptic current (mEPSC frequency. In summary, genetic ablation of the calcium channel modulator resulted in compensatory mechanisms to maintain calcium current homeostasis in hippocampal KO neurons; however, synaptic alterations resulted in a reduction of excitatory synapse number, causing an imbalance of the excitatory-inhibitory synaptic input ratio favoring inhibition.

  12. Role for astroglial α1-adrenoreceptors in gliotransmission and control of synaptic plasticity in the neocortex

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    Yuriy ePankratov

    2015-06-01

    Full Text Available Communication between neuronal and glial cells is thought to be very important for many brain functions. Acting via release of gliotransmitters, astrocytes can modulate synaptic strength. The mechanisms underlying gliotransmission remain uncertain with exocytosis being the most intriguing and debated pathway.We demonstrate that astroglial α1-adrenoreceptors are very sensitive to noradrenaline and make a significant contribution to intracellular Ca2+-signalling in layer 2/3 neocortical astrocytes. We also show that astroglial α1-adrenoreceptors are prone to desensitization upon prolonged exposure to noradrenaline.We show that within neocortical slices, α-1adrenoreceptors can activate vesicular release of ATP and D-serine from cortical astrocytes which initiate a burst of ATP receptor-mediated currents in adjacent pyramidal neurons. These purinergic currents can be inhibited by intracellular perfusion of astrocytes with Tetanus Toxin light chain, verifying their origin via astroglial exocytosis.We show that α1 adrenoreceptor-activated release of gliotransmitters is important for the induction of synaptic plasticity in the neocortex:long-term potentiation (LTP of neocortical excitatory synaptic potentials can be abolished by the selective α1-adrenoreceptor antagonist terazosin. We show that weak sub-threshold theta-burst stimulation can induce LTP when astrocytes are additionally activated by 1 μM noradrenaline. This facilitation is dependent on the activation of neuronal ATP receptors and is abolished in neocortical slices from dn-SNARE mice which have impaired glial exocytosis. Importantly, facilitation of LTP by noradrenaline can be significantly reduced by perfusion of individual astrocytes with Tetanus Toxin. Our results strongly support the physiological importance of astroglial adrenergic signalling and exocytosis of gliotransmitters for modulation of synaptic transmission and plasticity .

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

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    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.

  14. Attractor neural networks with resource-efficient synaptic connectivity

    Science.gov (United States)

    Pehlevan, Cengiz; Sengupta, Anirvan

    Memories are thought to be stored in the attractor states of recurrent neural networks. Here we explore how resource constraints interplay with memory storage function to shape synaptic connectivity of attractor networks. We propose that given a set of memories, in the form of population activity patterns, the neural circuit choses a synaptic connectivity configuration that minimizes a resource usage cost. We argue that the total synaptic weight (l1-norm) in the network measures the resource cost because synaptic weight is correlated with synaptic volume, which is a limited resource, and is proportional to neurotransmitter release and post-synaptic current, both of which cost energy. Using numerical simulations and replica theory, we characterize optimal connectivity profiles in resource-efficient attractor networks. Our theory explains several experimental observations on cortical connectivity profiles, 1) connectivity is sparse, because synapses are costly, 2) bidirectional connections are overrepresented and 3) are stronger, because attractor states need strong recurrence.

  15. Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants

    OpenAIRE

    Hirata, Hiromi; Carta, Eloisa; Yamanaka, Iori; Harvey, Robert J.; Kuwada, John Y.

    2010-01-01

    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 ...

  16. Molecular methods for the study of signal transduction in plants

    KAUST Repository

    Irving, Helen R.

    2013-09-03

    Novel and improved analytical methods have led to a rapid increase in our understanding of the molecular mechanism underlying plant signal transduction. Progress has been made both at the level of single-component analysis and in vivo imaging as well as at the systems level where transcriptomics and particularly phosphoproteomics afford a window into complex biological responses. Here we review the role of the cyclic nucleotides cAMP and cGMP in plant signal transduction as well as the discovery and biochemical and biological characterization of an increasing number of complex multi-domain nucleotide cyclases that catalyze the synthesis of cAMP and cGMP from ATP and GTP, respectively. © Springer Science+Business Media New York 2013.

  17. Statistical mechanics of attractor neural network models with synaptic depression

    International Nuclear Information System (INIS)

    Igarashi, Yasuhiko; Oizumi, Masafumi; Otsubo, Yosuke; Nagata, Kenji; Okada, Masato

    2009-01-01

    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.

  18. Experimental Implementation of a Biometric Laser Synaptic Sensor

    Directory of Open Access Journals (Sweden)

    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.

  19. A pivotal role of GSK-3 in synaptic plasticity

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    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.

  20. The emerging role of phosphoinositide clustering in intracellular trafficking and signal transduction [version 1; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Laura Picas

    2016-03-01

    Full Text Available Phosphoinositides are master regulators of multiple cellular processes: from vesicular trafficking to signaling, cytoskeleton dynamics, and cell growth. They are synthesized by the spatiotemporal regulated activity of phosphoinositide-metabolizing enzymes. The recent observation that some protein modules are able to cluster phosphoinositides suggests that alternative or complementary mechanisms might operate to stabilize the different phosphoinositide pools within cellular compartments. Herein, we discuss the different known and potential molecular players that are prone to engage phosphoinositide clustering and elaborate on how such a mechanism might take part in the regulation of intracellular trafficking and signal transduction.

  1. Investigation of the ferroelectric switching behavior of P(VDF-TrFE)-PMMA blended films for synaptic device applications

    International Nuclear Information System (INIS)

    Kim, E J; Kim, K A; Yoon, S M

    2016-01-01

    Synaptic plasticity can be mimicked by electronic synaptic devices. By using ferroelectric thin films as gate insulator for thin-film transistors (TFT), channel conductance can be defined as the synaptic plasticity, and gradually modulated by the variations in amounts of aligned ferroelectric dipoles. Poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)]-poly(methyl methacrylate) (PMMA) blended films are chosen and their switching kinetics are investigated by using the Kolmogorov-Avrami-Ishibashi model. The switching time for ferroelectric polarization is sensitively influenced by the amplitude of applied electric field and volumetric ratio of ferroelectric beta-phases in the P(VDF-TrFE)-PMMA films. The switching time of the P(VDF-TrFE) increases with decreasing the pulse amplitude and/or the ratio of ferroelectric beta-phases by incorporation of PMMA. The activation electric field is also found to increase as the increase in blended amount of PMMA. Synapse TFTs are fabricated using the P(VDF-TrFE)-PMMA as gate insulator and In-Ga-Zn-O active channels. The drain currents of the synapse TFTs gradually increased when the voltage pulse signals with given duration are repeatedly applied. This suggests that the synaptic weights can be modulated by the number of external pulse signals, and that the proposed synapse TFT can be applied for mimicking the operations of bio-synapses. (paper)

  2. Efficiency of Energy Transduction in a Molecular Chemical Engine

    OpenAIRE

    Sasaki, Kazuo; Kanada, Ryo; Amari, Satoshi

    2006-01-01

    A simple model of the two-state ratchet type is proposed for molecular chemical engines that convert chemical free energy into mechanical work and vice versa. The engine works by catalyzing a chemical reaction and turning a rotor. Analytical expressions are obtained for the dependences of rotation and reaction rates on the concentrations of reactant and product molecules, from which the performance of the engine is analyzed. In particular, the efficiency of energy transduction is discussed in...

  3. Dynamic Testing of Signal Transduction Deregulation During Breast Cancer Initiation

    Science.gov (United States)

    2012-07-01

    Std. Z39.18 Victoria Seewaldt, M.D. Dynamic Testing of Signal Transduction Deregulation During Breast Cancer Initiation Duke University Durham...attomole- zeptomole range. Internal dilution curves insure a high-dynamic calibration range. DU -26 8L DU -26 6L DU -29 5R DU -22 9.2 L DU...3: Nanobiosensor technology is translated to test for pathway deregulation in RPFNA cytology obtained from 10 high-risk women with cytological

  4. State–time spectrum of signal transduction logic models

    International Nuclear Information System (INIS)

    MacNamara, Aidan; Terfve, Camille; Henriques, David; Bernabé, Beatriz Peñalver; Saez-Rodriguez, Julio

    2012-01-01

    Despite the current wealth of high-throughput data, our understanding of signal transduction is still incomplete. Mathematical modeling can be a tool to gain an insight into such processes. Detailed biochemical modeling provides deep understanding, but does not scale well above relatively a few proteins. In contrast, logic modeling can be used where the biochemical knowledge of the system is sparse and, because it is parameter free (or, at most, uses relatively a few parameters), it scales well to large networks that can be derived by manual curation or retrieved from public databases. Here, we present an overview of logic modeling formalisms in the context of training logic models to data, and specifically the different approaches to modeling qualitative to quantitative data (state) and dynamics (time) of signal transduction. We use a toy model of signal transduction to illustrate how different logic formalisms (Boolean, fuzzy logic and differential equations) treat state and time. Different formalisms allow for different features of the data to be captured, at the cost of extra requirements in terms of computational power and data quality and quantity. Through this demonstration, the assumptions behind each formalism are discussed, as well as their advantages and disadvantages and possible future developments. (paper)

  5. Signal Transduction Pathways of TNAP: Molecular Network Analyses.

    Science.gov (United States)

    Négyessy, László; Györffy, Balázs; Hanics, János; Bányai, Mihály; Fonta, Caroline; Bazsó, Fülöp

    2015-01-01

    Despite the growing body of evidence pointing on the involvement of tissue non-specific alkaline phosphatase (TNAP) in brain function and diseases like epilepsy and Alzheimer's disease, our understanding about the role of TNAP in the regulation of neurotransmission is severely limited. The aim of our study was to integrate the fragmented knowledge into a comprehensive view regarding neuronal functions of TNAP using objective tools. As a model we used the signal transduction molecular network of a pyramidal neuron after complementing with TNAP related data and performed the analysis using graph theoretic tools. The analyses show that TNAP is in the crossroad of numerous pathways and therefore is one of the key players of the neuronal signal transduction network. Through many of its connections, most notably with molecules of the purinergic system, TNAP serves as a controller by funnelling signal flow towards a subset of molecules. TNAP also appears as the source of signal to be spread via interactions with molecules involved among others in neurodegeneration. Cluster analyses identified TNAP as part of the second messenger signalling cascade. However, TNAP also forms connections with other functional groups involved in neuronal signal transduction. The results indicate the distinct ways of involvement of TNAP in multiple neuronal functions and diseases.

  6. Synaptic Democracy and Vesicular Transport in Axons

    Science.gov (United States)

    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".

  7. Exploring Transduction Mechanisms of Protein Transduction Domains (PTDs in Living Cells Utilizing Single-Quantum Dot Tracking (SQT Technology

    Directory of Open Access Journals (Sweden)

    Yasuhiro Suzuki

    2012-01-01

    Full Text Available Specific protein domains known as protein transduction domains (PTDs can permeate cell membranes and deliver proteins or bioactive materials into living cells. Various approaches have been applied for improving their transduction efficacy. It is, therefore, crucial to clarify the entry mechanisms and to identify the rate-limiting steps. Because of technical limitations for imaging PTD behavior on cells with conventional fluorescent-dyes, how PTDs enter the cells has been a topic of much debate. Utilizing quantum dots (QDs, we recently tracked the behavior of PTD that was derived from HIV-1 Tat (TatP in living cells at the single-molecule level with 7-nm special precision. In this review article, we initially summarize the controversy on TatP entry mechanisms; thereafter, we will focus on our recent findings on single-TatP-QD tracking (SQT, to identify the major sequential steps of intracellular delivery in living cells and to discuss how SQT can easily provide direct information on TatP entry mechanisms. As a primer for SQT study, we also discuss the latest findings on single particle tracking of various molecules on the plasma membrane. Finally, we discuss the problems of QDs and the challenges for the future in utilizing currently available QD probes for SQT. In conclusion, direct identification of the rate-limiting steps of PTD entry with SQT should dramatically improve the methods for enhancing transduction efficiency.

  8. Endocannabinoid System and Synaptic Plasticity: Implications for Emotional Responses

    Directory of Open Access Journals (Sweden)

    María-Paz Viveros

    2007-01-01

    Full Text Available The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long- term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity

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    Lemtiri-Chlieh Fouad

    2011-12-01

    Full Text Available Abstract Background Dendritic spines represent the postsynaptic component of the vast majority of excitatory synapses present in the mammalian forebrain. The ability of spines to rapidly alter their shape, size, number and receptor content in response to stimulation is considered to be of paramount importance during the development of synaptic plasticity. Indeed, long-term potentiation (LTP, widely believed to be a cellular correlate of learning and memory, has been repeatedly shown to induce both spine enlargement and the formation of new dendritic spines. In our studies, we focus on Kalirin-7 (Kal7, a Rho GDP/GTP exchange factor (Rho-GEF localized to the postsynaptic density that plays a crucial role in the development and maintenance of dendritic spines both in vitro and in vivo. Previous studies have shown that mice lacking Kal7 (Kal7KO have decreased dendritic spine density in the hippocampus as well as focal hippocampal-dependent learning impairments. Results We have performed a detailed electrophysiological characterization of the role of Kal7 in hippocampal synaptic plasticity. We show that loss of Kal7 results in impaired NMDA receptor-dependent LTP and long-term depression, whereas a NMDA receptor-independent form of LTP is shown to be normal in the absence of Kal7. Conclusions These results indicate that Kal7 is an essential and selective modulator of NMDA receptor-dependent synaptic plasticity in the hippocampus.

  11. Inferior Olive HCN1 Channels Coordinate Synaptic Integration and Complex Spike Timing

    Directory of Open Access Journals (Sweden)

    Derek L.F. Garden

    2018-02-01

    Full Text Available Cerebellar climbing-fiber-mediated complex spikes originate from neurons in the inferior olive (IO, are critical for motor coordination, and are central to theories of cerebellar learning. Hyperpolarization-activated cyclic-nucleotide-gated (HCN channels expressed by IO neurons have been considered as pacemaker currents important for oscillatory and resonant dynamics. Here, we demonstrate that in vitro, network actions of HCN1 channels enable bidirectional glutamatergic synaptic responses, while local actions of HCN1 channels determine the timing and waveform of synaptically driven action potentials. These roles are distinct from, and may complement, proposed pacemaker functions of HCN channels. We find that in behaving animals HCN1 channels reduce variability in the timing of cerebellar complex spikes, which serve as a readout of IO spiking. Our results suggest that spatially distributed actions of HCN1 channels enable the IO to implement network-wide rules for synaptic integration that modulate the timing of cerebellar climbing fiber signals.

  12. UV irradiation to mouse skin decreases hippocampal neurogenesis and synaptic protein expression via HPA axis activation.

    Science.gov (United States)

    Han, Mira; Ban, Jae-Jun; Bae, Jung-Soo; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

    2017-11-14

    The skin senses external environment, including ultraviolet light (UV). Hippocampus is a brain region that is responsible for memory and emotion. However, changes in hippocampus by UV irradiation to the skin have not been studied. In this study, after 2 weeks of UV irradiation to the mouse skin, we examined molecular changes related to cognitive functions in the hippocampus and activation of the hypothalamic-pituitary-adrenal (HPA) axis. UV exposure to the skin decreased doublecortin-positive immature neurons and synaptic proteins, including N-methyl-D-aspartate receptor 2 A and postsynaptic density protein-95, in the hippocampus. Moreover, we observed that UV irradiation to the skin down-regulated brain-derived neurotrophic factor expression and ERK signaling in the hippocampus, which are known to modulate neurogenesis and synaptic plasticity. The cutaneous and central HPA axes were activated by UV, which resulted in significant increases in serum levels of corticosterone. Subsequently, UV irradiation to the skin activated the glucocorticoid-signaling pathway in the hippocampal dentate gyrus. Interestingly, after 6 weeks of UV irradiation, mice showed depression-like behavior in the tail suspension test. Taken together, our data suggest that repeated UV exposure through the skin may negatively affect hippocampal neurogenesis and synaptic plasticity along with HPA axis activation.

  13. Kalirin-7 is necessary for normal NMDA receptor-dependent synaptic plasticity

    KAUST Repository

    Lemtiri-Chlieh, Fouad

    2011-12-19

    Background: Dendritic spines represent the postsynaptic component of the vast majority of excitatory synapses present in the mammalian forebrain. The ability of spines to rapidly alter their shape, size, number and receptor content in response to stimulation is considered to be of paramount importance during the development of synaptic plasticity. Indeed, long-term potentiation (LTP), widely believed to be a cellular correlate of learning and memory, has been repeatedly shown to induce both spine enlargement and the formation of new dendritic spines. In our studies, we focus on Kalirin-7 (Kal7), a Rho GDP/GTP exchange factor (Rho-GEF) localized to the postsynaptic density that plays a crucial role in the development and maintenance of dendritic spines both in vitro and in vivo. Previous studies have shown that mice lacking Kal7 (Kal7 KO) have decreased dendritic spine density in the hippocampus as well as focal hippocampal-dependent learning impairments.Results: We have performed a detailed electrophysiological characterization of the role of Kal7 in hippocampal synaptic plasticity. We show that loss of Kal7 results in impaired NMDA receptor-dependent LTP and long-term depression, whereas a NMDA receptor-independent form of LTP is shown to be normal in the absence of Kal7.Conclusions: These results indicate that Kal7 is an essential and selective modulator of NMDA receptor-dependent synaptic plasticity in the hippocampus. 2011 Lemtiri-Chlieh et al; licensee BioMed Central Ltd.

  14. pH during non-synaptic epileptiform activity—computational simulations

    Science.gov (United States)

    Márcio Rodrigues, Antônio; Canton Santos, Luiz Eduardo; Covolan, Luciene; Hamani, Clement; Guimarães de Almeida, Antônio-Carlos

    2015-10-01

    The excitability of neuronal networks is strongly modulated by changes in pH. The origin of these changes, however, is still under debate. The high complexity of neural systems justifies the use of computational simulation to investigate mechanisms that are possibly involved. Simulated neuronal activity includes non-synaptic epileptiform events (NEA) induced in hippocampal slices perfused with high-K+ and zero-Ca2+, therefore in the absence of the synaptic circuitry. A network of functional units composes the NEA model. Each functional unit represents one interface of neuronal/extracellular space/glial segments. Each interface contains transmembrane ionic transports, such as ionic channels, cotransporters, exchangers and pumps. Neuronal interconnections are mediated by gap-junctions, electric field effects and extracellular ionic fluctuations modulated by extracellular electrodiffusion. Mechanisms investigated are those that change intracellular and extracellular ionic concentrations and are able to affect [H+]. Our simulations suggest that the intense fluctuations in intra and extracellular concentrations of Na+, K+ and Cl- that accompany NEA are able to affect the combined action of the Na+/H+ exchanger (NHE), {{{HCO}}}3-/Cl- exchanger (HCE), H+ pump and the catalytic activity of intra and extracellular carbonic anhydrase. Cellular volume changes and extracellular electrodiffusion are responsible for modulating pH.

  15. Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala.

    Science.gov (United States)

    Di, Shi; Itoga, Christy A; Fisher, Marc O; Solomonow, Jonathan; Roltsch, Emily A; Gilpin, Nicholas W; Tasker, Jeffrey G

    2016-08-10

    regulation of anxiogenesis in rats. We demonstrate a nongenomic glucocorticoid induction of long-lasting suppression of synaptic inhibition that is mediated by retrograde endocannabinoid release at GABA synapses. The rapid glucocorticoid-induced endocannabinoid suppression of synaptic inhibition is initiated by a membrane-associated glucocorticoid receptor in BLA principal neurons. We show that acute stress increases anxiety-like behavior via an endocannabinoid-dependent mechanism centered in the BLA. The stress-induced endocannabinoid modulation of synaptic transmission in the BLA contributes, therefore, to the stress regulation of anxiety, and may play a role in anxiety disorders of the amygdala. Copyright © 2016 the authors 0270-6474/16/368461-10$15.00/0.

  16. A presynaptic role for PKA in synaptic tagging and memory.

    Science.gov (United States)

    Park, Alan Jung; Havekes, Robbert; Choi, Jennifer Hk; Luczak, Vince; Nie, Ting; Huang, Ted; Abel, Ted

    2014-10-01

    Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and memory because PKA also regulates presynaptic transmitter release. Here, we examine this issue using genetic and pharmacological application of Ht31, a PKA anchoring disrupting peptide. At the hippocampal Schaffer collateral CA3-CA1 synapse, Ht31 treatment elicits a rapid decay of synaptic responses to repetitive stimuli, indicating a fast depletion of the readily releasable pool of synaptic vesicles. The interaction between PKA and proteins involved in producing this pool of synaptic vesicles is supported by biochemical assays showing that synaptic vesicle protein 2 (SV2), Rim1, and SNAP25 are components of a complex that interacts with cAMP. Moreover, acute treatment with Ht31 reduces the levels of SV2. Finally, experiments with transgenic mouse lines, which express Ht31 in excitatory neurons at the Schaffer collateral CA3-CA1 synapse, highlight a requirement for presynaptically anchored PKA in pathway-specific synaptic tagging and long-term contextual fear memory. These results suggest that a presynaptically compartmentalized PKA is critical for synaptic plasticity and memory by regulating the readily releasable pool of synaptic vesicles. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

    Directory of Open Access Journals (Sweden)

    Aile evan Huijstee

    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.

  18. Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer's Disease

    Science.gov (United States)

    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.

  19. Synaptogenic proteins and synaptic organizers: "many hands make light work".

    Science.gov (United States)

    Brose, Nils

    2009-03-12

    Synaptogenesis is thought to be mediated by cell adhesion proteins, which induce the initial contact between an axon and its target cell and subsequently recruit and organize the presynaptic and postsynaptic protein machinery required for synaptic transmission. A new study by Linhoff and colleagues in this issue of Neuron identifies adhesion proteins of the LRRTM family as novel synaptic organizers.

  20. Synaptic Tagging, Evaluation of Memories, and the Distal Reward Problem

    Science.gov (United States)

    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…

  1. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

    Science.gov (United States)

    van Huijstee, Aile N.; Mansvelder, Huibert D.

    2015-01-01

    Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) 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 behavior, 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 behavioral 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. Remodeling 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. PMID:25653591

  2. Voltage-dependent amplification of synaptic inputs in respiratory motoneurones

    Science.gov (United States)

    Enríquez Denton, M; Wienecke, J; Zhang, M; Hultborn, H; Kirkwood, P A

    2012-01-01

    The role of persistent inward currents (PICs) in cat respiratory motoneurones (phrenic inspiratory and thoracic expiratory) was investigated by studying the voltage-dependent amplification of central respiratory drive potentials (CRDPs), recorded intracellularly, with action potentials blocked with the local anaesthetic derivative, QX-314. Decerebrate unanaesthetized or barbiturate-anaesthetized preparations were used. In expiratory motoneurones, plateau potentials were observed in the decerebrates, but not under anaesthesia. For phrenic motoneurones, no plateau potentials were observed in either state (except in one motoneurone after the abolition of the respiratory drive by means of a medullary lesion), but all motoneurones showed voltage-dependent amplification of the CRDPs, over a wide range of membrane potentials, too wide to result mainly from PIC activation. The measurements of the amplification were restricted to the phase of excitation, thus excluding the inhibitory phase. Amplification was found to be greatest for the smallest CRDPs in the lowest resistance motoneurones and was reduced or abolished following intracellular injection of the NMDA channel blocker, MK-801. Plateau potentials were readily evoked in non-phrenic cervical motoneurones in the same (decerebrate) preparations. We conclude that the voltage-dependent amplification of synaptic excitation in phrenic motoneurones is mainly the result of NMDA channel modulation rather than the activation of Ca2+ channel mediated PICs, despite phrenic motoneurones being strongly immunohistochemically labelled for CaV1.3 channels. The differential PIC activation in different motoneurones, all of which are CaV1.3 positive, leads us to postulate that the descending modulation of PICs is more selective than has hitherto been believed. PMID:22495582

  3. Neuromodulation of activity-dependent synaptic enhancement at crayfish neuromuscular junction.

    Science.gov (United States)

    Qian, S M; Delaney, K R

    1997-10-17

    Action potential-evoked transmitter release is enhanced for many seconds after moderate-frequency stimulation (e.g. 15 Hz for 30 s) at the excitor motorneuron synapse of the crayfish dactyl opener muscle. Beginning about 1.5 s after a train, activity-dependent synaptic enhancement (ADSE) is dominated by a process termed augmentation (G.D. Bittner, D.A. Baxter, Synaptic plasticity at crayfish neuromuscular junctions: facilitation and augmentation, Synapse 7 (1991) 235-243'[4]; K.L. Magleby, Short-term changes in synaptic efficacy, in: G.M. Edelman, L.E. Gall, C.W. Maxwell (Eds.), Synaptic Function, John Wiley and Sons, New York, 1987, pp. 21-56; K.L. Magleby; J.E. Zengel, Augmentation: a process that acts to increase transmitter release at the frog neuromuscular junction, J. Physiol. (Lond.) 257 (1976) 449-470) which decays approximately exponentially with a time constant of about 10 s at 16 degrees C, reflecting the removal of Ca2+ which accumulates during the train in presynaptic terminals (K.R. Delaney, D.W. Tank, R.S. Zucker, Serotonin-mediated enhancement of transmission at crayfish neuromuscular junction is independent of changes in calcium, J. Neurosci. 11 (1991) 2631-2643). Serotonin (5-HT, 1 microM) increases evoked and spontaneous transmitter release several-fold (D. Dixon, H.L. Atwood, Crayfish motor nerve terminal's response to serotonin examined by intracellular microelectrode, J. Neurobiol. 16 (1985) 409-424; J. Dudel, Modulation of quantal synaptic release by serotonin and forskolin in crayfish motor nerve terminals, in: Modulation of Synaptic Transmission and Plasticity in Nervous Systems, G. Hertting, H.-C. Spatz (Eds.), Springer-Verlag, Berlin, 1988; S. Glusman, E.A. Kravitz. The action of serotonin on excitatory nerve terminals in lobster nerve-muscle preparations, J. Physiol. (Lond.) 325 (1982) 223-241). We found that ADSE persists about 2-3 times longer after moderate-frequency presynaptic stimulation in the presence of 5-HT. This slowing of the

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

    Directory of Open Access Journals (Sweden)

    A.A.C. Albuquerque

    1997-07-01

    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

  5. Nicotinic mechanisms influencing synaptic plasticity in the hippocampus

    Institute of Scientific and Technical Information of China (English)

    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.

  6. [Involvement of aquaporin-4 in synaptic plasticity, learning and memory].

    Science.gov (United States)

    Wu, Xin; Gao, Jian-Feng

    2017-06-25

    Aquaporin-4 (AQP-4) is the predominant water channel in the central nervous system (CNS) and primarily expressed in astrocytes. Astrocytes have been generally believed to play important roles in regulating synaptic plasticity and information processing. However, the role of AQP-4 in regulating synaptic plasticity, learning and memory, cognitive function is only beginning to be investigated. It is well known that synaptic plasticity is the prime candidate for mediating of learning and memory. Long term potentiation (LTP) and long term depression (LTD) are two forms of synaptic plasticity, and they share some but not all the properties and mechanisms. Hippocampus is a part of limbic system that is particularly important in regulation of learning and memory. This article is to review some research progresses of the function of AQP-4 in synaptic plasticity, learning and memory, and propose the possible role of AQP-4 as a new target in the treatment of cognitive dysfunction.

  7. A perisynaptic ménage à trois between Dlg, DLin-7, and Metro controls proper organization of Drosophila synaptic junctions.

    Science.gov (United States)

    Bachmann, André; Kobler, Oliver; Kittel, Robert J; Wichmann, Carolin; Sierralta, Jimena; Sigrist, Stephan J; Gundelfinger, Eckart D; Knust, Elisabeth; Thomas, Ulrich

    2010-04-28

    Structural plasticity of synaptic junctions is a prerequisite to achieve and modulate connectivity within nervous systems, e.g., during learning and memory formation. It demands adequate backup systems that allow remodeling while retaining sufficient stability to prevent unwanted synaptic disintegration. The strength of submembranous scaffold complexes, which are fundamental to the architecture of synaptic junctions, likely constitutes a crucial determinant of synaptic stability. Postsynaptic density protein-95 (PSD-95)/ Discs-large (Dlg)-like membrane-associated guanylate kinases (DLG-MAGUKs) are principal scaffold proteins at both vertebrate and invertebrate synapses. At Drosophila larval glutamatergic neuromuscular junctions (NMJs) DlgA and DlgS97 exert pleiotropic functions, probably reflecting a few known and a number of yet-unknown binding partners. In this study we have identified Metro, a novel p55/MPP-like Drosophila MAGUK as a major binding partner of perisynaptic DlgS97 at larval NMJs. Based on homotypic LIN-2,-7 (L27) domain interactions, Metro stabilizes junctional DlgS97 in a complex with the highly conserved adaptor protein DLin-7. In a remarkably interdependent manner, Metro and DLin-7 act downstream of DlgS97 to control NMJ expansion and proper establishment of synaptic boutons. Using quantitative 3D-imaging we further demonstrate that the complex controls the size of postsynaptic glutamate receptor fields. Our findings accentuate the importance of perisynaptic scaffold complexes for synaptic stabilization and organization.

  8. Modulatory Effect of Aerobic Physical Activity on Synaptic Ultrastructure in the Old Mouse Hippocampus

    Directory of Open Access Journals (Sweden)

    Patrizia Fattoretti

    2018-05-01

    Full Text Available Aerobic physical exercise (APE leads to improved brain functions. To better understand the beneficial effect of APE on the aging brain, a morphometric study was carried out of changes in hippocampal synapses of old (>27 months Balb/c mice undergoing treadmill training (OTT for 4 weeks in comparison with old sedentary (OS, middle-aged sedentary (MAS and middle-aged treadmill training (MATT mice. The inner molecular layer of the hippocampal dentate gyrus (IMLDG and the molecular stratum of Ammon’s horn1 neurons (SMCA1 were investigated. The number of synapses per cubic micron of tissue (numeric density, Nv, overall synaptic area per cubic micron of tissue (surface density, Sv, average area of synaptic contact zones (S, and frequency (% of perforated synapses (PS were measured in electron micrographs of ethanol-phosphotungstic acid (E-PTA stained tissue. Data were analyzed with analysis of variance (ANOVA. In IMLDG, an effect of age was found for Nv and Sv, but not S and %PS. Similar results were found for exercise and the interaction of age and exercise. In post hoc analysis Nv was higher (60.6% to 75.1%; p < 0.001 in MATT vs. MAS, OS and OTT. Sv was higher (32.3% to 54.6%; p < 0.001 in MATT vs. MAS, OS and OTT. In SMCA1, age affected Nv, Sv and %PS, but not S. The effect of exercise was significant for Sv only. The interaction of age and exercise was significant for Nv, Sv and %PS. In post hoc analysis Nv was lower in OS vs. MAS, MATT and OTT (−26.1% to −32.1%; p < 0.038. MAS and OTT were similar. Sv was lower in OS vs. MAS, MATT and OTT (−23.4 to −30.3%, p < 0.004. MAS and OTT were similar. PS frequency was higher in OS vs. MAS, MATT and OTT (48.3% to +96.6%, p < 0.023. APE positively modulated synaptic structural dynamics in the aging hippocampus, possibly in a region-specific way. The APE-associated reduction in PS frequency in SMCA1 of old mice suggests that an increasing complement of PS is a compensatory phenomenon to maintain

  9. Stochastic lattice model of synaptic membrane protein domains.

    Science.gov (United States)

    Li, Yiwei; Kahraman, Osman; Haselwandter, Christoph A

    2017-05-01

    Neurotransmitter receptor molecules, concentrated in synaptic membrane domains along with scaffolds and other kinds of proteins, are crucial for signal transmission across chemical synapses. In common with other membrane protein domains, synaptic domains are characterized by low protein copy numbers and protein crowding, with rapid stochastic turnover of individual molecules. We study here in detail a stochastic lattice model of the receptor-scaffold reaction-diffusion dynamics at synaptic domains that was found previously to capture, at the mean-field level, the self-assembly, stability, and characteristic size of synaptic domains observed in experiments. We show that our stochastic lattice model yields quantitative agreement with mean-field models of nonlinear diffusion in crowded membranes. Through a combination of analytic and numerical solutions of the master equation governing the reaction dynamics at synaptic domains, together with kinetic Monte Carlo simulations, we find substantial discrepancies between mean-field and stochastic models for the reaction dynamics at synaptic domains. Based on the reaction and diffusion properties of synaptic receptors and scaffolds suggested by previous experiments and mean-field calculations, we show that the stochastic reaction-diffusion dynamics of synaptic receptors and scaffolds provide a simple physical mechanism for collective fluctuations in synaptic domains, the molecular turnover observed at synaptic domains, key features of the observed single-molecule trajectories, and spatial heterogeneity in the effective rates at which receptors and scaffolds are recycled at the cell membrane. Our work sheds light on the physical mechanisms and principles linking the collective properties of membrane protein domains to the stochastic dynamics that rule their molecular components.

  10. Alteration of synaptic connectivity of oligodendrocyte precursor cells following demyelination

    Science.gov (United States)

    Sahel, Aurélia; Ortiz, Fernando C.; Kerninon, Christophe; Maldonado, Paloma P.; Angulo, María Cecilia; Nait-Oumesmar, Brahim

    2015-01-01

    Oligodendrocyte precursor cells (OPCs) are a major source of remyelinating oligodendrocytes in demyelinating diseases such as Multiple Sclerosis (MS). While OPCs are innervated by unmyelinated axons in the normal brain, the fate of such synaptic contacts after demyelination is still unclear. By combining electrophysiology and immunostainings in different transgenic mice expressing fluorescent reporters, we studied the synaptic innervation of OPCs in the model of lysolecithin (LPC)-induced demyelination of corpus callosum. Synaptic innervation of reactivated OPCs in the lesion was revealed by the presence of AMPA receptor-mediated synaptic currents, VGluT1+ axon-OPC contacts in 3D confocal reconstructions and synaptic junctions observed by electron microscopy. Moreover, 3D confocal reconstructions of VGluT1 and NG2 immunolabeling showed the existence of glutamatergic axon-OPC contacts in post-mortem MS lesions. Interestingly, patch-clamp recordings in LPC-induced lesions demonstrated a drastic decrease in spontaneous synaptic activity of OPCs early after demyelination that was not caused by an impaired conduction of compound action potentials. A reduction in synaptic connectivity was confirmed by the lack of VGluT1+ axon-OPC contacts in virtually all rapidly proliferating OPCs stained with EdU (50-ethynyl-20-deoxyuridine). At the end of the massive proliferation phase in lesions, the proportion of innervated OPCs rapidly recovers, although the frequency of spontaneous synaptic currents did not reach control levels. In conclusion, our results demonstrate that newly-generated OPCs do not receive synaptic inputs during their active proliferation after demyelination, but gain synapses during the remyelination process. Hence, glutamatergic synaptic inputs may contribute to inhibit OPC proliferation and might have a physiopathological relevance in demyelinating disorders. PMID:25852473

  11. Dual functional extracellular recording using a light-addressable potentiometric sensor for bitter signal transduction.

    Science.gov (United States)

    Du, Liping; Wang, Jian; Chen, Wei; Zhao, Luhang; Wu, Chunsheng; Wang, Ping

    2018-08-31

    This paper presents a dual functional extracellular recording biosensor based on a light-addressable potentiometric sensor (LAPS). The design and fabrication of this biosensor make it possible to record both extracellular membrane potential changes and ATP release from a single taste bud cell for the first time. For detecting ATP release, LAPS chip was functionalized with ATP-sensitive DNA aptamer by covalent immobilization. Taste bud cells isolated from rat were cultured on LAPS surface. When the desired single taste bud cell was illuminated by modulated light, ATP release from single taste bud cells can be measured by recording the shifts of bias voltage-photocurrent curves (I-V curves) when the LAPS chip is working in discrete mode. On the other hand, extracellular membrane potential changes can be monitored by recording the fluctuation of LAPS photocurrent when the LAPS chip is working in continuous mode. The results show this biosensor can effectively record the enhancive effect of the bitter substance and inhibitory effect of the carbenoxolone (CBX) on the extracellular membrane potential changes and ATP release of single taste bud cells. In addition, the inhibitory effect of CBX also confirms LAPS extracellular recordings are originated from bitter signal transduction. It is proved this biosensor is suitable for extracellular recording of ATP release and membrane potential changes of single taste bud cells. It is suggested this biosensor could be applied to investigating taste signal transduction at the single-cell level as well as applied to other types of cells which have similar functions to taste bud cells. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Orientation selectivity of synaptic input to neurons in mouse and cat primary visual cortex.

    Science.gov (United States)

    Tan, Andrew Y Y; Brown, Brandon D; Scholl, Benjamin; Mohanty, Deepankar; Priebe, Nicholas J

    2011-08-24

    Primary visual cortex (V1) is the site at which orientation selectivity emerges in mammals: visual thalamus afferents to V1 respond equally to all stimulus orientations, whereas their target V1 neurons respond selectively to stimulus orientation. The emergence of orientation selectivity in V1 has long served as a model for investigating cortical computation. Recent evidence for orientation selectivity in mouse V1 opens cortical computation to dissection by genetic and imaging tools, but also raises two essential questions: (1) How does orientation selectivity in mouse V1 neurons compare with that in previously described species? (2) What is the synaptic basis for orientation selectivity in mouse V1? A comparison of orientation selectivity in mouse and in cat, where such measures have traditionally been made, reveals that orientation selectivity in mouse V1 is weaker than in cat V1, but that spike threshold plays a similar role in narrowing selectivity between membrane potential and spike rate. To uncover the synaptic basis for orientation selectivity, we made whole-cell recordings in vivo from mouse V1 neurons, comparing neuronal input selectivity-based on membrane potential, synaptic excitation, and synaptic inhibition-to output selectivity based on spiking. We found that a neuron's excitatory and inhibitory inputs are selective for the same stimulus orientations as is its membrane potential response, and that inhibitory selectivity is not broader than excitatory selectivity. Inhibition has different dynamics than excitation, adapting more rapidly. In neurons with temporally modulated responses, the timing of excitation and inhibition was different in mice and cats.

  13. Synaptic and intrinsic activation of GABAergic neurons in the cardiorespiratory brainstem network.

    Directory of Open Access Journals (Sweden)

    Julie G Frank

    Full Text Available GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67 gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA. These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca(2+ currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a

  14. Synaptic and intrinsic activation of GABAergic neurons in the cardiorespiratory brainstem network.

    Science.gov (United States)

    Frank, Julie G; Mendelowitz, David

    2012-01-01

    GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca(2+) currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for

  15. Exocytosis of gliotransmitters from cortical astrocytes: implications for synaptic plasticity and aging.

    Science.gov (United States)

    Lalo, Ulyana; Rasooli-Nejad, Seyed; Pankratov, Yuriy

    2014-10-01

    Maintaining brain function during aging is very important for mental and physical health. Recent studies showed a crucial importance of communication between two major types of brain cells: neurons transmitting electrical signals, and glial cells, which maintain the well-being and function of neurons. Still, the study of age-related changes in neuron-glia signalling is far from complete. We have shown previously that cortical astrocytes are capable of releasing ATP by a quantal soluble N-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) complex-dependent mechanism. Release of ATP from cortical astrocytes can be activated via various pathways, including direct UV-uncaging of intracellular Ca²⁺ or G-protein-coupled receptors. Importantly, release of both ATP and glutamate from neocortical astrocytes was not observed in brain slices of dominant-negative SNARE (dnSNARE) mice, expressing dnSNARE domain selectively in astrocytes. We also discovered that astrocyte-driven ATP can cause significant attenuation of synaptic inhibition in the pyramidal neurons via Ca²⁺-interaction between the neuronal ATP and γ-aminobutyric acid (GABA) receptors. Furthermore, we showed that astrocyte-derived ATP can facilitate the induction of long-term potentiation of synaptic plasticity in the neocortex. Our recent data have shown that an age-related decrease in the astroglial Ca²⁺ signalling can cause a substantial decrease in the exocytosis of gliotransmitters, in particular ATP. Age-related impairment of ATP release from cortical astrocytes can cause a decrease in the extent of astroglial modulation of synaptic transmission in the neocortex and can therefore contribute to the age-related impairment of synaptic plasticity and cognitive decline. Combined, our results strongly support the physiological relevance of glial exocytosis for glia-neuron communications and brain function.

  16. FY1995 transduction method and CAD database systems for integrated design; 1995 nendo transduction ho to CAD database togo sekkei shien system

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-03-01

    Transduction method developed by the research coordinator and Prof. Muroga is one of the most popular methods to design large-scale integrated circuits, and thus used by major design tool companies in USA and Japan. The major objectives of the research is to improve capability and utilize its reusable property by combining with CAD databases. Major results of the project is as follows, (1) Improvement of Transduction method : Efficiency, capability and the maximum circuit size are improved. Error compensation method is also improved. (2) Applications to new logic elements : Transduction method is modified to cope with wired logic and FPGAs. (3) CAD databases : One of the major advantages of Transduction methods is 'reusability' of already designed circuits. It is suitable to combine with CAD databases. We design CAD databases suitable for cooperative design using Transduction method. (4) Program development : Programs for Windows95 and developed for distribution. (NEDO)

  17. FY1995 transduction method and CAD database systems for integrated design; 1995 nendo transduction ho to CAD database togo sekkei shien system

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-03-01

    Transduction method developed by the research coordinator and Prof. Muroga is one of the most popular methods to design large-scale integrated circuits, and thus used by major design tool companies in USA and Japan. The major objectives of the research is to improve capability and utilize its reusable property by combining with CAD databases. Major results of the project is as follows, (1) Improvement of Transduction method : Efficiency, capability and the maximum circuit size are improved. Error compensation method is also improved. (2) Applications to new logic elements : Transduction method is modified to cope with wired logic and FPGAs. (3) CAD databases : One of the major advantages of Transduction methods is 'reusability' of already designed circuits. It is suitable to combine with CAD databases. We design CAD databases suitable for cooperative design using Transduction method. (4) Program development : Programs for Windows95 and developed for distribution. (NEDO)

  18. Leucine-rich repeat-containing synaptic adhesion molecules as organizers of synaptic specificity and diversity.

    Science.gov (United States)

    Schroeder, Anna; de Wit, Joris

    2018-04-09

    The brain harbors billions of neurons that form distinct neural circuits with exquisite specificity. Specific patterns of connectivity between distinct neuronal cell types permit the transfer and computation of information. The molecular correlates that give rise to synaptic specificity are incompletely understood. Recent studies indicate that cell-surface molecules are important determinants of cell type identity and suggest that these are essential players in the specification of synaptic connectivity. Leucine-rich repeat (LRR)-containing adhesion molecules in particular have emerged as key organizers of excitatory and inhibitory synapses. Here, we discuss emerging evidence that LRR proteins regulate the assembly of specific connectivity patterns across neural circuits, and contribute to the diverse structural and functional properties of synapses, two key features that are critical for the proper formation and function of neural circuits.

  19. Lack of Pannexin 1 Alters Synaptic GluN2 Subunit Composition and Spatial Reversal Learning in Mice.

    Science.gov (United States)

    Gajardo, Ivana; Salazar, Claudia S; Lopez-Espíndola, Daniela; Estay, Carolina; Flores-Muñoz, Carolina; Elgueta, Claudio; Gonzalez-Jamett, Arlek M; Martínez, Agustín D; Muñoz, Pablo; Ardiles, Álvaro O

    2018-01-01

    Long-term potentiation (LTP) and long-term depression (LTD) are two forms of synaptic plasticity that have been considered as the cellular substrate of memory formation. Although LTP has received considerable more attention, recent evidences indicate that LTD plays also important roles in the acquisition and storage of novel information in the brain. Pannexin 1 (Panx1) is a membrane protein that forms non-selective channels which have been shown to modulate the induction of hippocampal synaptic plasticity. Animals lacking Panx1 or blockade of Pannexin 1 channels precludes the induction of LTD and facilitates LTP. To evaluate if the absence of Panx1 also affects the acquisition of rapidly changing information we trained Panx1 knockout (KO) mice and wild type (WT) littermates in a visual and hidden version of the Morris water maze (MWM). We found that KO mice find the hidden platform similarly although slightly quicker than WT animals, nonetheless, when the hidden platform was located in the opposite quadrant (OQ) to the previous learned location, KO mice spent significantly more time in the previous quadrant than in the new location indicating that the absence of Panx1 affects the reversion of a previously acquired spatial memory. Consistently, we observed changes in the content of synaptic proteins critical to LTD, such as GluN2 subunits of N-methyl-D-aspartate receptors (NMDARs), which changed their contribution to synaptic plasticity in conditions of Panx1 ablation. Our findings give further support to the role of Panx1 channels on the modulation of synaptic plasticity induction, learning and memory processes.

  20. Lack of Pannexin 1 Alters Synaptic GluN2 Subunit Composition and Spatial Reversal Learning in Mice

    Science.gov (United States)

    Gajardo, Ivana; Salazar, Claudia S.; Lopez-Espíndola, Daniela; Estay, Carolina; Flores-Muñoz, Carolina; Elgueta, Claudio; Gonzalez-Jamett, Arlek M.; Martínez, Agustín D.; Muñoz, Pablo; Ardiles, Álvaro O.

    2018-01-01

    Long-term potentiation (LTP) and long-term depression (LTD) are two forms of synaptic plasticity that have been considered as the cellular substrate of memory formation. Although LTP has received considerable more attention, recent evidences indicate that LTD plays also important roles in the acquisition and storage of novel information in the brain. Pannexin 1 (Panx1) is a membrane protein that forms non-selective channels which have been shown to modulate the induction of hippocampal synaptic plasticity. Animals lacking Panx1 or blockade of Pannexin 1 channels precludes the induction of LTD and facilitates LTP. To evaluate if the absence of Panx1 also affects the acquisition of rapidly changing information we trained Panx1 knockout (KO) mice and wild type (WT) littermates in a visual and hidden version of the Morris water maze (MWM). We found that KO mice find the hidden platform similarly although slightly quicker than WT animals, nonetheless, when the hidden platform was located in the opposite quadrant (OQ) to the previous learned location, KO mice spent significantly more time in the previous quadrant than in the new location indicating that the absence of Panx1 affects the reversion of a previously acquired spatial memory. Consistently, we observed changes in the content of synaptic proteins critical to LTD, such as GluN2 subunits of N-methyl-D-aspartate receptors (NMDARs), which changed their contribution to synaptic plasticity in conditions of Panx1 ablation. Our findings give further support to the role of Panx1 channels on the modulation of synaptic plasticity induction, learning and memory processes. PMID:29692709

  1. Lack of Pannexin 1 Alters Synaptic GluN2 Subunit Composition and Spatial Reversal Learning in Mice

    Directory of Open Access Journals (Sweden)

    Ivana Gajardo

    2018-04-01

    Full Text Available Long-term potentiation (LTP and long-term depression (LTD are two forms of synaptic plasticity that have been considered as the cellular substrate of memory formation. Although LTP has received considerable more attention, recent evidences indicate that LTD plays also important roles in the acquisition and storage of novel information in the brain. Pannexin 1 (Panx1 is a membrane protein that forms non-selective channels which have been shown to modulate the induction of hippocampal synaptic plasticity. Animals lacking Panx1 or blockade of Pannexin 1 channels precludes the induction of LTD and facilitates LTP. To evaluate if the absence of Panx1 also affects the acquisition of rapidly changing information we trained Panx1 knockout (KO mice and wild type (WT littermates in a visual and hidden version of the Morris water maze (MWM. We found that KO mice find the hidden platform similarly although slightly quicker than WT animals, nonetheless, when the hidden platform was located in the opposite quadrant (OQ to the previous learned location, KO mice spent significantly more time in the previous quadrant than in the new location indicating that the absence of Panx1 affects the reversion of a previously acquired spatial memory. Consistently, we observed changes in the content of synaptic proteins critical to LTD, such as GluN2 subunits of N-methyl-D-aspartate receptors (NMDARs, which changed their contribution to synaptic plasticity in conditions of Panx1 ablation. Our findings give further support to the role of Panx1 channels on the modulation of synaptic plasticity induction, learning and memory processes.

  2. Alzheimer's disease: synaptic dysfunction and Abeta

    LENUS (Irish Health Repository)

    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.

  3. Optogenetic acidification of synaptic vesicles and lysosomes.

    Science.gov (United States)

    Rost, Benjamin R; Schneider, Franziska; Grauel, M Katharina; Wozny, Christian; Bentz, Claudia; Blessing, Anja; Rosenmund, Tanja; Jentsch, Thomas J; Schmitz, Dietmar; Hegemann, Peter; Rosenmund, Christian

    2015-12-01

    Acidification is required for the function of many intracellular organelles, but methods to acutely manipulate their intraluminal pH have not been available. Here we present a targeting strategy to selectively express the light-driven proton pump Arch3 on synaptic vesicles. Our new tool, pHoenix, can functionally replace endogenous proton pumps, enabling optogenetic control of vesicular acidification and neurotransmitter accumulation. Under physiological conditions, glutamatergic vesicles are nearly full, as additional vesicle acidification with pHoenix only slightly increased the quantal size. By contrast, we found that incompletely filled vesicles exhibited a lower release probability than full vesicles, suggesting preferential exocytosis of vesicles with high transmitter content. Our subcellular targeting approach can be transferred to other organelles, as demonstrated for a pHoenix variant that allows light-activated acidification of lysosomes.

  4. Polybrene inhibits human mesenchymal stem cell proliferation during lentiviral transduction.

    Directory of Open Access Journals (Sweden)

    Paul Lin

    Full Text Available Human mesenchymal stem cells (hMSCs can be engineered to express specific genes, either for their use in cell-based therapies or to track them in vivo over long periods of time. To obtain long-term expression of these genes, a lentivirus- or retrovirus-mediated cell transduction is often used. However, given that the efficiency with these viruses is typically low in primary cells, additives such as polybrene are always used for efficient viral transduction. Unfortunately, as presented here, exposure to polybrene alone at commonly used concentratons (1-8 µg/mL negatively impacts hMSC proliferation in a dose-dependent manner as measured by CyQUANT, EdU incorporation, and cell cycle analysis. This inhibition of proliferation was observable in culture even 3 weeks after exposure. Culturing the cells in the presence of FGF-2, a potent mitogen, did not abrogate this negative effect of polybrene. In fact, the normally sharp increase in hMSC proliferation that occurs during the first days of exposure to FGF-2 was absent at 4 µg/mL or higher concentrations of polybrene. Similarly, the effect of stimulating cell proliferation under simulated hypoxic conditions was also decreased when cells were exposed to polybrene, though overall proliferation rates were higher. The negative influence of polybrene was, however, reduced when the cells were exposed to polybrene for a shorter period of time (6 hr vs 24 hr. Thus, careful evaluation should be done when using polybrene to aid in lentiviral transduction of human MSCs or other primary cells, especially when cell number is critical.

  5. Age-related changes in the hippocampus (loss of synaptophysin and glial-synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL.

    Science.gov (United States)

    Ojo, Bunmi; Rezaie, Payam; Gabbott, Paul L; Davies, Heather; Colyer, Frances; Cowley, Thelma R; Lynch, Marina; Stewart, Michael G

    2012-07-01

    Altered synaptic morphology, progressive loss of synapses and glial (astrocyte and microglial) cell activation are considered as characteristic hallmarks of aging. Recent evidence suggests that there is a concomitant age-related decrease in expression of the presynaptic protein, synaptophysin, and the neuronal glycoprotein CD200, which, by interacting with its receptor, plays a role in maintaining microglia in a quiescent state. These age-related changes may be indicative of reduced neuroglial support of synapses. FG Loop (FGL) peptide synthesized from the second fibronectin type III module of neural cell adhesion molecule (NCAM), has previously been shown to attenuate age-related glial cell activation, and to 'restore' cognitive function in aged rats. The mechanisms by which FGL exerts these neuroprotective effects remain unclear, but could involve regulation of CD200, modifying glial-synaptic interactions (affecting neuroglial 'support' at synapses), or impacting directly on synaptic function. Light and electron microscopic (EM) analyses were undertaken to investigate whether systemic treatment with FGL (i) alters CD200, synaptophysin (presynaptic) and PSD-95 (postsynaptic) immunohistochemical expression levels, (ii) affects synaptic number, or (iii) exerts any effects on glial-synaptic interactions within young (4 month-old) and aged (22 month-old) rat hippocampus. Treatment with FGL attenuated the age-related loss of synaptophysin immunoreactivity (-ir) within CA3 and hilus (with no major effect on PSD-95-ir), and of CD200-ir specifically in the CA3 region. Ultrastructural morphometric analyses showed that FGL treatment (i) prevented age-related loss in astrocyte-synaptic contacts, (ii) reduced microglia-synaptic contacts in the CA3 stratum radiatum, but (iii) had no effect on the mean number of synapses in this region. These data suggest that FGL mediates its neuroprotective effects by regulating glial-synaptic interaction. Copyright © 2011 Elsevier Inc. All

  6. Modeling evolution of crosstalk in noisy signal transduction networks

    Science.gov (United States)

    Tareen, Ammar; Wingreen, Ned S.; Mukhopadhyay, Ranjan

    2018-02-01

    Signal transduction networks can form highly interconnected systems within cells due to crosstalk between constituent pathways. To better understand the evolutionary design principles underlying such networks, we study the evolution of crosstalk for two parallel signaling pathways that arise via gene duplication. We use a sequence-based evolutionary algorithm and evolve the network based on two physically motivated fitness functions related to information transmission. We find that one fitness function leads to a high degree of crosstalk while the other leads to pathway specificity. Our results offer insights on the relationship between network architecture and information transmission for noisy biomolecular networks.

  7. Signal transduction by the major histocompatibility complex class I molecule

    DEFF Research Database (Denmark)

    Pedersen, A E; Skov, Svend; Bregenholt, S

    1999-01-01

    Ligation of cell surface major histocompatibility class I (MHC-I) proteins by antibodies, or by their native counter receptor, the CD8 molecule, mediates transduction of signals into the cells. MHC-I-mediated signaling can lead to both increased and decreased activity of the MHC-I-expressing cell...... and functioning, MHC-I molecules might be of importance for the maintenance of cellular homeostasis not only within the immune system, but also in the interplay between the immune system and other organ systems....

  8. Signaling transduction pathways involved in basophil adhesion and histamine release

    DEFF Research Database (Denmark)

    Sha, Quan; Poulsen, Lars K.; Gerwien, Jens

    2006-01-01

    Little is known about basophil with respect to the different signaling transduction pathways involved in spontaneous, cytokine or anti-IgE induced adhesion and how this compares to IgE-dependent and IgE-independent mediator secretion. The purpose of the present study was to investigate the roles...... of beta1 and beta2 integrins in basophil adhesion as well as hosphatidylinositol 3-kinase (PI3K), src-kinases and extracellular signal regulated kinase (ERK) 1/2 in basophil adhesion and histamine release (HR)....

  9. Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders.

    Science.gov (United States)

    Sala, Carlo; Vicidomini, Cinzia; Bigi, Ilaria; Mossa, Adele; Verpelli, Chiara

    2015-12-01

    Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia. Thus, the term 'Shankopathies' identifies a number of neuronal diseases caused by alteration of Shank protein expression leading to abnormal synaptic development. With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations and also patients affected by other neurodevelopmental and neuropsychiatric disorders. Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia (SCZ). With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations. © 2015 International Society for Neurochemistry.

  10. Spine Calcium Transients Induced by Synaptically-Evoked Action Potentials Can Predict Synapse Location and Establish Synaptic Democracy

    Science.gov (United States)

    Meredith, Rhiannon M.; van Ooyen, Arjen

    2012-01-01

    CA1 pyramidal neurons receive hundreds of synaptic inputs at different distances from the soma. Distance-dependent synaptic scaling enables distal and proximal synapses to influence the somatic membrane equally, a phenomenon called “synaptic democracy”. How this is established is unclear. The backpropagating action potential (BAP) is hypothesised to provide distance-dependent information to synapses, allowing synaptic strengths to scale accordingly. Experimental measurements show that a BAP evoked by current injection at the soma causes calcium currents in the apical shaft whose amplitudes decay with distance from the soma. However, in vivo action potentials are not induced by somatic current injection but by synaptic inputs along the dendrites, which creates a different excitable state of the dendrites. Due to technical limitations, it is not possible to study experimentally whether distance information can also be provided by synaptically-evoked BAPs. Therefore we adapted a realistic morphological and electrophysiological model to measure BAP-induced voltage and calcium signals in spines after Schaffer collateral synapse stimulation. We show that peak calcium concentration is highly correlated with soma-synapse distance under a number of physiologically-realistic suprathreshold stimulation regimes and for a range of dendritic morphologies. Peak calcium levels also predicted the attenuation of the EPSP across the dendritic tree. Furthermore, we show that peak calcium can be used to set up a synaptic democracy in a homeostatic manner, whereby synapses regulate their synaptic strength on the basis of the difference between peak calcium and a uniform target value. We conclude that information derived from synaptically-generated BAPs can indicate synapse location and can subsequently be utilised to implement a synaptic democracy. PMID:22719238

  11. Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.

    Science.gov (United States)

    Lim, Chae-Seok; Hoang, Elizabeth T; Viar, Kenneth E; Stornetta, Ruth L; Scott, Michael M; Zhu, J Julius

    2014-02-01

    Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (5HT) subtype 2B receptors (5HT2B-Rs) or dopamine (DA) subtype 1-like receptors (D1-Rs) and/or those inhibiting 5HT2A-Rs or D2-Rs moderately enhance Ras-PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras-PI3K/PKB signal transduction and GluA1-dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome.

  12. All-optical functional synaptic connectivity mapping in acute brain slices using the calcium integrator CaMPARI.

    Science.gov (United States)

    Zolnik, Timothy A; Sha, Fern; Johenning, Friedrich W; Schreiter, Eric R; Looger, Loren L; Larkum, Matthew E; Sachdev, Robert N S

    2017-03-01

    The genetically encoded fluorescent calcium integrator calcium-modulated photoactivatable ratiobetric integrator (CaMPARI) reports calcium influx induced by synaptic and neural activity. Its fluorescence is converted from green to red in the presence of violet light and calcium. The rate of conversion - the sensitivity to activity - is tunable and depends on the intensity of violet light. Synaptic activity and action potentials can independently initiate significant CaMPARI conversion. The level of conversion by subthreshold synaptic inputs is correlated to the strength of input, enabling optical readout of relative synaptic strength. When combined with optogenetic activation of defined presynaptic neurons, CaMPARI provides an all-optical method to map synaptic connectivity. The calcium-modulated photoactivatable ratiometric integrator (CaMPARI) is a genetically encoded calcium integrator that facilitates the study of neural circuits by permanently marking cells active during user-specified temporal windows. Permanent marking enables measurement of signals from large swathes of tissue and easy correlation of activity with other structural or functional labels. One potential application of CaMPARI is labelling neurons postsynaptic to specific populations targeted for optogenetic stimulation, giving rise to all-optical functional connectivity mapping. Here, we characterized the response of CaMPARI to several common types of neuronal calcium signals in mouse acute cortical brain slices. Our experiments show that CaMPARI is effectively converted by both action potentials and subthreshold synaptic inputs, and that conversion level is correlated to synaptic strength. Importantly, we found that conversion rate can be tuned: it is linearly related to light intensity. At low photoconversion light levels CaMPARI offers a wide dynamic range due to slower conversion rate; at high light levels conversion is more rapid and more sensitive to activity. Finally, we employed Ca

  13. Analysis and logical modeling of biological signaling transduction networks

    Science.gov (United States)

    Sun, Zhongyao

    The study of network theory and its application span across a multitude of seemingly disparate fields of science and technology: computer science, biology, social science, linguistics, etc. It is the intrinsic similarities embedded in the entities and the way they interact with one another in these systems that link them together. In this dissertation, I present from both the aspect of theoretical analysis and the aspect of application three projects, which primarily focus on signal transduction networks in biology. In these projects, I assembled a network model through extensively perusing literature, performed model-based simulations and validation, analyzed network topology, and proposed a novel network measure. The application of network modeling to the system of stomatal opening in plants revealed a fundamental question about the process that has been left unanswered in decades. The novel measure of the redundancy of signal transduction networks with Boolean dynamics by calculating its maximum node-independent elementary signaling mode set accurately predicts the effect of single node knockout in such signaling processes. The three projects as an organic whole advance the understanding of a real system as well as the behavior of such network models, giving me an opportunity to take a glimpse at the dazzling facets of the immense world of network science.

  14. Signal perception, transduction, and gene expression involved in anthocyanin biosynthesis

    International Nuclear Information System (INIS)

    Mol, J.; Jenkins, G.; Schäfer, E.; Weiss, D.

    1996-01-01

    Anthocyanin pigments provide fruits and flowers with their bright red and blue colors and are induced in vegetative tissues by various signals. The biosynthetic pathway probably represents one of the best‐studied examples of higher plant secondary metabolism. It has attracted much attention of plant geneticists because of the dispensable nature of the compounds it produces. Not unexpectedly, several excellent reviews on anthocyanin biosynthesis have been published over the last 5 years (Dooner et al., 1991; Martin and Gerats, 1993a, 1993b; Koes et al., 1994; Holton and Cornish, 1995). These reviews emphasize the late steps of pigment biosynthesis rather than the early and intermediate events of signal perception and transduction. This review is broader and not only covers the identification of components of the anthocyanin signal perception/transduction networks but also provides a description of our current understanding of how they evoke the responses that they do. Progress has derived from a combination of biochemical, molecular and genetic studies. We discuss a range of relevant research to highlight the different experimental approaches being used and the diverse biological systems under investigation. (author)

  15. Discriminative clustering on manifold for adaptive transductive classification.

    Science.gov (United States)

    Zhang, Zhao; Jia, Lei; Zhang, Min; Li, Bing; Zhang, Li; Li, Fanzhang

    2017-10-01

    In this paper, we mainly propose a novel adaptive transductive label propagation approach by joint discriminative clustering on manifolds for representing and classifying high-dimensional data. Our framework seamlessly combines the unsupervised manifold learning, discriminative clustering and adaptive classification into a unified model. Also, our method incorporates the adaptive graph weight construction with label propagation. Specifically, our method is capable of propagating label information using adaptive weights over low-dimensional manifold features, which is different from most existing studies that usually predict the labels and construct the weights in the original Euclidean space. For transductive classification by our formulation, we first perform the joint discriminative K-means clustering and manifold learning to capture the low-dimensional nonlinear manifolds. Then, we construct the adaptive weights over the learnt manifold features, where the adaptive weights are calculated through performing the joint minimization of the reconstruction errors over features and soft labels so that the graph weights can be joint-optimal for data representation and classification. Using the adaptive weights, we can easily estimate the unknown labels of samples. After that, our method returns the updated weights for further updating the manifold features. Extensive simulations on image classification and segmentation show that our proposed algorithm can deliver the state-of-the-art performance on several public datasets. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Fetus Sound Stimulation: Cilia Memristor Effect of Signal Transduction

    Directory of Open Access Journals (Sweden)

    Svetlana Jankovic-Raznatovic

    2014-01-01

    Full Text Available Background. This experimental study evaluates fetal middle cerebral artery (MCA circulation after the defined prenatal acoustical stimulation (PAS and the role of cilia in hearing and memory and could explain signal transduction and memory according to cilia optical-acoustical properties. Methods. PAS was performed twice on 119 no-risk term pregnancies. We analyzed fetal MCA circulation before, after first and second PAS. Results. Analysis of the Pulsatility index basic (PIB and before PAS and Pulsatility index reactive after the first PAS (PIR 1 shows high statistical difference, representing high influence on the brain circulation. Analysis of PIB and Pulsatility index reactive after the second PAS (PIR 2 shows no statistical difference. Cilia as nanoscale structure possess magnetic flux linkage that depends on the amount of charge that has passed between two-terminal variable resistors of cilia. Microtubule resistance, as a function of the current through and voltage across the structure, leads to appearance of cilia memory with the “memristor” property. Conclusion. Acoustical and optical cilia properties play crucial role in hearing and memory processes. We suggest that fetuses are getting used to sound, developing a kind of memory patterns, considering acoustical and electromagnetically waves and involving cilia and microtubules and try to explain signal transduction.

  17. Molecular mechanisms of root gravity sensing and signal transduction.

    Science.gov (United States)

    Strohm, Allison K; Baldwin, Katherine L; Masson, Patrick H

    2012-01-01

    Plants use gravity as a guide to direct their roots down into the soil to anchor themselves and to find resources needed for growth and development. In higher plants, the columella cells of the root tip form the primary site of gravity sensing, and in these cells the sedimentation of dense, starch-filled plastids (amyloplasts) triggers gravity signal transduction. This generates an auxin gradient across the root cap that is transmitted to the elongation zone where it promotes differential cell elongation, allowing the root to direct itself downward. It is still not well understood how amyloplast sedimentation leads to auxin redistribution. Models have been proposed to explain how mechanosensitive ion channels or ligand-receptor interactions could connect these events. Although their roles are still unclear, possible second messengers in this process include protons, Ca(2+), and inositol 1,4,5-triphosphate. Upon gravistimulation, the auxin efflux facilitators PIN3 and PIN7 relocalize to the lower side of the columella cells and mediate auxin redistribution. However, evidence for an auxin-independent secondary mechanism of gravity sensing and signal transduction suggests that this physiological process is quite complex. Furthermore, plants must integrate a variety of environmental cues, resulting in multifaceted relationships between gravitropism and other directional growth responses such as hydro-, photo-, and thigmotropism. Copyright © 2011 Wiley Periodicals, Inc.

  18. A Single Aplysia Neurotrophin Mediates Synaptic Facilitation via Differentially Processed Isoforms Secreted as Mature or Precursor Forms

    Science.gov (United States)

    Kassabov, Stefan R.; Choi, Yun-Beom; Karl, Kevin A.; Vishwasrao, Harshad D.; Bailey, Craig H.; Kandel, Eric R.

    2014-01-01

    Summary Neurotrophins control the development and adult plasticity of the vertebrate nervous system. Failure to identify invertebrate neurotrophin orthologs, however, has precluded studies in invertebrate models, limiting understanding of fundamental aspects of neurotrophin biology and function. We identified a neurotrophin (ApNT) and Trk receptor (ApTrk) in the mollusk Aplysia and find they play a central role in learning related synaptic plasticity. ApNT increases the magnitude and lowers the threshold for induction of long-term facilitation and initiates the growth of new synaptic varicosities at the monosynaptic connection between sensory and motor neurons of the gill-withdrawal reflex. Unlike vertebrate neurotrophins, ApNT has multiple coding exons and exerts distinct synaptic effects through differentially processed and secreted splice isoforms. Our findings demonstrate the existence of bona-fide neurotrophin signaling in invertebrates and reveal a novel, post-transcriptional mechanism, regulating neurotrophin processing and the release of pro- and mature neurotrophins which differentially modulate synaptic plasticity. PMID:23562154

  19. Neutralization of Nogo-A Enhances Synaptic Plasticity in the Rodent Motor Cortex and Improves Motor Learning in Vivo

    Science.gov (United States)

    Weinmann, Oliver; Kellner, Yves; Yu, Xinzhu; Vicente, Raul; Gullo, Miriam; Kasper, Hansjörg; Lussi, Karin; Ristic, Zorica; Luft, Andreas R.; Rioult-Pedotti, Mengia; Zuo, Yi; Zagrebelsky, Marta; Schwab, Martin E.

    2014-01-01

    The membrane protein Nogo-A is known as an inhibitor of axonal outgrowth and regeneration in the CNS. However, its physiological functions in the normal adult CNS remain incompletely understood. Here, we investigated the role of Nogo-A in cortical synaptic plasticity and motor learning in the uninjured adult rodent motor cortex. Nogo-A and its receptor NgR1 are present at cortical synapses. Acute treatment of slices with function-blocking antibodies (Abs) against Nogo-A or against NgR1 increased long-term potentiation (LTP) induced by stimulation of layer 2/3 horizontal fibers. Furthermore, anti-Nogo-A Ab treatment increased LTP saturation levels, whereas long-term depression remained unchanged, thus leading to an enlarged synaptic modification range. In vivo, intrathecal application of Nogo-A-blocking Abs resulted in a higher dendritic spine density at cortical pyramidal neurons due to an increase in spine formation as revealed by in vivo two-photon microscopy. To investigate whether these changes in synaptic plasticity correlate with motor learning, we trained rats to learn a skilled forelimb-reaching task while receiving anti-Nogo-A Abs. Learning of this cortically controlled precision movement was improved upon anti-Nogo-A Ab treatment. Our results identify Nogo-A as an influential molecular modulator of synaptic plasticity and as a regulator for learning of skilled movements in the motor cortex. PMID:24966370

  20. Genetic analysis of gravity signal transduction in roots

    Science.gov (United States)

    Masson, Patrick; Strohm, Allison; Baldwin, Katherine

    To grow downward into the soil, roots use gravity as a guide. Specialized cells, named stato-cytes, enable this directional growth response by perceiving gravity. Located in the columella region of the cap, these cells sense a reorientation of the root within the gravity field through the sedimentation of, and/or tension/pressure exerted by, dense amyloplasts. This process trig-gers a gravity signal transduction pathway that leads to a fast alkalinization of the cytoplasm and a change in the distribution of the plasma membrane-associated auxin-efflux carrier PIN3. The latter protein is uniformly distributed within the plasma membrane on all sides of the cell in vertically oriented roots. However, it quickly accumulates at the bottom side upon gravis-timulation. This process correlates with a preferential transport of auxin to the bottom side of the root cap, resulting in a lateral gradient across the tip. This gradient is then transported to the elongation zone where it promotes differential cellular elongation, resulting in downward curvature. We isolated mutations that affect gravity signal transduction at a step that pre-cedes cytoplasmic alkalinization and/or PIN3 relocalization and lateral auxin transport across the cap. arg1 and arl2 mutations identify a common genetic pathway that is needed for all three gravity-induced processes in the cap statocytes, indicating these genes function early in the pathway. On the other hand, adk1 affects gravity-induced PIN3 relocalization and lateral auxin transport, but it does not interfere with cytoplasmic alkalinization. ARG1 and ARL2 encode J-domain proteins that are associated with membranes of the vesicular trafficking path-way whereas ADK1 encodes adenosine kinase, an enzyme that converts adenosine derived from nucleic acid metabolism and the AdoMet cycle into AMP, thereby alleviating feedback inhibi-tion of this important methyl-donor cycle. Because mutations in ARG1 (and ARL2) do not completely eliminate

  1. Synaptic Homeostasis and Allostasis in the Dentate Gyrus Caused by Inflammatory and Neuropathic Pain Conditions

    Directory of Open Access Journals (Sweden)

    Rui-Rui Wang

    2018-01-01

    Full Text Available It has been generally accepted that pain can cause imbalance between excitation and inhibition (homeostasis at the synaptic level. However, it remains poorly understood how this imbalance (allostasis develops in the CNS under different pain conditions. Here, we analyzed the changes in both excitatory and inhibitory synaptic transmission and modulation of the dentate gyrus (DG under two pain conditions with different etiology and duration. First, it was revealed that the functions of the input-output (I/O curves for evoked excitatory postsynaptic currents (eEPSCs following the perforant path (PP stimulation were gained under both acute inflammatory and chronic neuropathic pain conditions relative to the controls. However, the functions of I/O curves for the PP-evoked inhibitory postsynaptic currents (eIPSCs differed between the two conditions, namely it was greatly gained under inflammatory condition, but was reduced under neuropathic condition in reverse. Second, both the frequency and amplitude of miniature IPSCs (mIPSCs were increased under inflammatory condition, however a decrease in frequency of mIPSCs was observed under neuropathic condition. Finally, the spike discharge of the DG granule cells in response to current injection was significantly increased by neuropathic pain condition, however, no different change was found between inflammatory pain condition and the control. These results provide another line of evidence showing homeostatic and allostatic modulation of excitatory synaptic transmission by inhibitory controls under different pathological pain conditions, hence implicating use of different therapeutic approaches to maintain the homeostasis between excitation and inhibition while treating different conditions of pathological pain.

  2. Synaptic and functional linkages between spinal premotor interneurons and hand-muscle activity during precision grip

    Directory of Open Access Journals (Sweden)

    Tomohiko eTakei

    2013-04-01

    Full Text Available Grasping is a highly complex movement that requires the coordination of a number of hand joints and muscles. Previous studies showed that spinal premotor interneurons (PreM-INs in the primate cervical spinal cord have divergent synaptic effects on hand motoneurons and that they might contribute to hand-muscle synergies. However, the extent to which these PreM-IN synaptic connections functionally contribute to modulating hand-muscle activity is not clear. In this paper, we explored the contribution of spinal PreM-INs to hand-muscle activation by quantifying the synaptic linkage (SL and functional linkage (FL of the PreM-INs with hand-muscle activities. The activity of 23 PreM-INs was recorded from the cervical spinal cord (C6–T1, with EMG signals measured simultaneously from hand and arm muscles in two macaque monkeys performing a precision grip task. Spike-triggered averages (STAs of rectified EMGs were compiled for 456 neuron–muscle pairs; 63 pairs showed significant post-spike effects (i.e., SL. Conversely, 231 of 456 pairs showed significant cross-correlations between the IN firing rate and rectified EMG (i.e., FL. Importantly, a greater proportion of the neuron–muscle pairs with SL showed FL (43/63 pairs, 68% compared with the pairs without SL (203/393, 52%, and the presence of SL was significantly associated with that of FL. However, a significant number of pairs had SL without FL (SL∩!FL, n = 20 or FL without SL (!SL∩FL, n = 203, and the proportions of these incongruities exceeded the number expected by chance. These results suggested that spinal PreM-INs function to significantly modulate hand-muscle activity during precision grip, but the contribution of other neural structures is also needed to recruit an adequate combination of hand-muscle motoneurons.

  3. A Voltage Mode Memristor Bridge Synaptic Circuit with Memristor Emulators

    Directory of Open Access Journals (Sweden)

    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.

  4. Neurotrophin-3 Enhances the Synaptic Organizing Function of TrkC-Protein Tyrosine Phosphatase σ in Rat Hippocampal Neurons.

    Science.gov (United States)

    Ammendrup-Johnsen, Ina; Naito, Yusuke; Craig, Ann Marie; Takahashi, Hideto

    2015-09-09

    Neurotrophin-3 (NT-3) and its high-affinity receptor TrkC play crucial trophic roles in neuronal differentiation, axon outgrowth, and synapse development and plasticity in the nervous system. We demonstrated previously that postsynaptic TrkC functions as a glutamatergic synapse-inducing (synaptogenic) cell adhesion molecule trans-interacting with presynaptic protein tyrosine phosphatase σ (PTPσ). Given that NT-3 and PTPσ bind distinct domains of the TrkC extracellular region, here we tested the hypothesis that NT-3 modulates TrkC/PTPσ binding and synaptogenic activity. NT-3 enhanced PTPσ binding to cell surface-expressed TrkC and facilitated the presynapse-inducing activity of TrkC in rat hippocampal neurons. Imaging of recycling presynaptic vesicles combined with TrkC knockdown and rescue approaches demonstrated that NT-3 rapidly potentiates presynaptic function via binding endogenous postsynaptic TrkC in a tyrosine kinase-independent manner. Thus, NT-3 positively modulates the TrkC-PTPσ complex for glutamatergic presynaptic assembly and function independently from TrkC kinase activation. Our findings provide new insight into synaptic roles of neurotrophin signaling and mechanisms controlling synaptic organizing complexes. Significance statement: Although many synaptogenic adhesion complexes have been identified in recent years, little is known about modulatory mechanisms. Here, we demonstrate a novel role of neurotrophin-3 in synaptic assembly and function as a positive modulator of the TrkC-protein tyrosine phosphatase σ complex. This study provides new insight into the involvement of neurotrophin signaling in synapse development and plasticity, presenting a molecular mechanism that may underlie previous observations of short- and long-term enhancement of presynaptic function by neurotrophin. Given the links of synaptogenic adhesion molecules to autism and schizophrenia, this study might also contribute to a better understanding of the pathogenesis of

  5. Synaptic Remodeling Generates Synchronous Oscillations in the Degenerated Outer Mouse Retina

    Directory of Open Access Journals (Sweden)

    Wadood eHaq

    2014-09-01

    Full Text Available During neuronal degenerative diseases, neuronal microcircuits undergo severe structural alterations, leading to remodeling of synaptic connectivity. The functional consequences of such remodeling are mostly unknown. For instance, in mutant rd1 mouse retina, a common model for Retinitis Pigmentosa, rod bipolar cells (RBCs establish contacts with remnant cone photoreceptors (cones as a consequence of rod photoreceptor cell death and the resulting lack of presynaptic input. To assess the functional connectivity in the remodeled, light-insensitive outer rd1 retina, we recorded spontaneous population activity in retinal wholemounts using Ca2+ imaging and identified the participating cell types. Focusing on cones, RBCs and horizontal cells (HCs, we found that these cell types display spontaneous oscillatory activity and form synchronously active clusters. Overall activity was modulated by GABAergic inhibition from HCs. Many of the activity clusters comprised both cones and RBCs. Opposite to what is expected from the intact (wild-type cone-ON bipolar cell pathway, cone and RBC activity was positively correlated and, at least partially, mediated by glutamate transporters expressed on RBCs. Deletion of gap junctional coupling between cones reduced the number of clusters, indicating that electrical cone coupling plays a crucial role for generating the observed synchronized oscillations. In conclusion, degeneration-induced synaptic remodeling of the rd1 retina results in a complex self-sustained outer retinal oscillatory network, that complements (and potentially modulates the recently described inner retinal oscillatory network consisting of amacrine, bipolar and ganglion cells.

  6. Corticothalamic Synaptic Noise as a Mechanism for Selective Attention in Thalamic Neurons

    Science.gov (United States)

    Béhuret, Sébastien; Deleuze, Charlotte; Bal, Thierry

    2015-01-01

    A reason why the thalamus is more than a passive gateway for sensory signals is that two-third of the synapses of thalamocortical neurons are directly or indirectly related to the activity of corticothalamic axons. While the responses of thalamocortical neurons evoked by sensory stimuli are well characterized, with ON- and OFF-center receptive field structures, the prevalence of synaptic noise resulting from neocortical feedback in intracellularly recorded thalamocortical neurons in vivo has attracted little attention. However, in vitro and modeling experiments point to its critical role for the integration of sensory signals. Here we combine our recent findings in a unified framework suggesting the hypothesis that corticothalamic synaptic activity is adapted to modulate the transfer efficiency of thalamocortical neurons during selective attention at three different levels: First, on ionic channels by interacting with intrinsic membrane properties, second at the neuron level by impacting on the input-output gain, and third even more effectively at the cell assembly level by boosting the information transfer of sensory features encoded in thalamic subnetworks. This top-down population control is achieved by tuning the correlations in subthreshold membrane potential fluctuations and is adapted to modulate the transfer of sensory features encoded by assemblies of thalamocortical relay neurons. We thus propose that cortically-controlled (de-)correlation of subthreshold noise is an efficient and swift dynamic mechanism for selective attention in the thalamus. PMID:26733818

  7. Corticothalamic Synaptic Noise as a Mechanism for Selective Attention in Thalamic Neurons.

    Science.gov (United States)

    Béhuret, Sébastien; Deleuze, Charlotte; Bal, Thierry

    2015-01-01

    A reason why the thalamus is more than a passive gateway for sensory signals is that two-third of the synapses of thalamocortical neurons are directly or indirectly related to the activity of corticothalamic axons. While the responses of thalamocortical neurons evoked by sensory stimuli are well characterized, with ON- and OFF-center receptive field structures, the prevalence of synaptic noise resulting from neocortical feedback in intracellularly recorded thalamocortical neurons in vivo has attracted little attention. However, in vitro and modeling experiments point to its critical role for the integration of sensory signals. Here we combine our recent findings in a unified framework suggesting the hypothesis that corticothalamic synaptic activity is adapted to modulate the transfer efficiency of thalamocortical neurons during selective attention at three different levels: First, on ionic channels by interacting with intrinsic membrane properties, second at the neuron level by impacting on the input-output gain, and third even more effectively at the cell assembly level by boosting the information transfer of sensory features encoded in thalamic subnetworks. This top-down population control is achieved by tuning the correlations in subthreshold membrane potential fluctuations and is adapted to modulate the transfer of sensory features encoded by assemblies of thalamocortical relay neurons. We thus propose that cortically-controlled (de-)correlation of subthreshold noise is an efficient and swift dynamic mechanism for selective attention in the thalamus.

  8. Corticothalamic Synaptic Noise as a Mechanism for Selective Attention in Thalamic Neurons

    Directory of Open Access Journals (Sweden)

    Sébastien eBéhuret

    2015-12-01

    Full Text Available A reason why the thalamus is more than a passive gateway for sensory signals is that two-third of the synapses of thalamocortical neurons are directly or indirectly related to the activity of corticothalamic axons. While the responses of thalamocortical neurons evoked by sensory stimuli are well characterized, with ON- and OFF-center receptive field structures, the prevalence of synaptic noise resulting from neocortical feedback in intracellularly recorded thalamocortical neurons in vivo has attracted little attention. However, in vitro and modeling experiments point to its critical role for the integration of sensory signals. Here we combine our recent findings in a unified framework suggesting the hypothesis that corticothalamic synaptic activity is adapted to modulate the transfer efficiency of thalamocortical neurons during selective attention at three different levels: First, on ionic channels by interacting with intrinsic membrane properties, second at the neuron level by impacting on the input-output gain, and third even more effectively at the cell assembly level by boosting the information transfer of sensory features encoded in thalamic subnetworks. This top-down population control is achieved by tuning the correlations in subthreshold membrane potential fluctuations and is adapted to modulate the transfer of sensory features encoded by assemblies of thalamocortical relay neurons. We thus propose that cortically-controlled (de-correlation of subthreshold noise is an efficient and swift dynamic mechanism for selective attention in the thalamus.

  9. Staurosporine Increases Lentiviral Vector Transduction Efficiency of Human Hematopoietic Stem and Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Gretchen Lewis

    2018-06-01

    Full Text Available Lentiviral vector (LVV-mediated transduction of human CD34+ hematopoietic stem and progenitor cells (HSPCs holds tremendous promise for the treatment of monogenic hematological diseases. This approach requires the generation of a sufficient proportion of gene-modified cells. We identified staurosporine, a serine/threonine kinase inhibitor, as a small molecule that could be added to the transduction process to increase the proportion of genetically modified HSPCs by overcoming a LVV entry barrier. Staurosporine increased vector copy number (VCN approximately 2-fold when added to mobilized peripheral blood (mPB CD34+ cells prior to transduction. Limited staurosporine treatment did not affect viability of cells post-transduction, and there was no difference in in vitro colony formation compared to vehicle-treated cells. Xenotransplantation studies identified a statistically significant increase in VCN in engrafted human cells in mouse bone marrow at 4 months post-transplantation compared to vehicle-treated cells. Prostaglandin E2 (PGE2 is known to increase transduction efficiency of HSPCs through a different mechanism. Combining staurosporine and PGE2 resulted in further enhancement of transduction efficiency, particularly in short-term HSPCs. The combinatorial use of small molecules, such as staurosporine and PGE2, to enhance LVV transduction of human CD34+ cells is a promising method to improve transduction efficiency and subsequent potential therapeutic benefit of gene therapy drug products. Keywords: lentiviral, HSPC, transduction

  10. Polymerase chain reaction-based detection of myc transduction in feline leukemia virus-infected cats.

    Science.gov (United States)

    Sumi, Ryosuke; Miyake, Ariko; Endo, Taiji; Ohsato, Yoshiharu; Ngo, Minh Ha; Nishigaki, Kazuo

    2018-04-01

    Feline lymphomas are associated with the transduction and activation of cellular proto-oncogenes, such as c-myc, by feline leukemia virus (FeLV). We describe a polymerase chain reaction assay for detection of myc transduction usable in clinical diagnosis. The assay targets c-myc exons 2 and 3, which together result in a FeLV-specific fusion gene following c-myc transduction. When this assay was conducted on FeLV-infected feline tissues submitted for clinical diagnosis of tumors, myc transduction was detected in 14% of T-cell lymphoma/leukemias. This newly established system could become a useful diagnostic tool in veterinary medicine.

  11. Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex

    Directory of Open Access Journals (Sweden)

    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.

  12. Human-Specific Cortical Synaptic Connections and Their Plasticity: Is That What Makes Us Human?

    Directory of Open Access Journals (Sweden)

    Joana Lourenço

    2017-01-01

    Full Text Available One outstanding difference between Homo sapiens and other mammals is the ability to perform highly complex cognitive tasks and behaviors, such as language, abstract thinking, and cultural diversity. How is this accomplished? According to one prominent theory, cognitive complexity is proportional to the repetition of specific computational modules over a large surface expansion of the cerebral cortex (neocortex. However, the human neocortex was shown to also possess unique features at the cellular and synaptic levels, raising the possibility that expanding the computational module is not the only mechanism underlying complex thinking. In a study published in PLOS Biology, Szegedi and colleagues analyzed a specific cortical circuit from live postoperative human tissue, showing that human-specific, very powerful excitatory connections between principal pyramidal neurons and inhibitory neurons are highly plastic. This suggests that exclusive plasticity of specific microcircuits might be considered among the mechanisms endowing the human neocortex with the ability to perform highly complex cognitive tasks.

  13. Serotonin increases synaptic activity in olfactory bulb glomeruli.

    Science.gov (United States)

    Brill, Julia; Shao, Zuoyi; Puche, Adam C; Wachowiak, Matt; Shipley, Michael T

    2016-03-01

    Serotoninergic fibers densely innervate olfactory bulb glomeruli, the first sites of synaptic integration in the olfactory system. Acting through 5HT2A receptors, serotonin (5HT) directly excites external tufted cells (ETCs), key excitatory glomerular neurons, and depolarizes some mitral cells (MCs), the olfactory bulb's main output neurons. We further investigated 5HT action on MCs and determined its effects on the two major classes of glomerular interneurons: GABAergic/dopaminergic short axon cells (SACs) and GABAergic periglomerular cells (PGCs). In SACs, 5HT evoked a depolarizing current mediated by 5HT2C receptors but did not significantly impact spike rate. 5HT had no measurable direct effect in PGCs. Serotonin increased spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) in PGCs and SACs. Increased sEPSCs were mediated by 5HT2A receptors, suggesting that they are primarily due to enhanced excitatory drive from ETCs. Increased sIPSCs resulted from elevated excitatory drive onto GABAergic interneurons and augmented GABA release from SACs. Serotonin-mediated GABA release from SACs was action potential independent and significantly increased miniature IPSC frequency in glomerular neurons. When focally applied to a glomerulus, 5HT increased MC spontaneous firing greater than twofold but did not increase olfactory nerve-evoked responses. Taken together, 5HT modulates glomerular network activity in several ways: 1) it increases ETC-mediated feed-forward excitation onto MCs, SACs, and PGCs; 2) it increases inhibition of glomerular interneurons; 3) it directly triggers action potential-independent GABA release from SACs; and 4) these network actions increase spontaneous MC firing without enhancing responses to suprathreshold sensory input. This may enhance MC sensitivity while maintaining dynamic range. Copyright © 2016 the American Physiological Society.

  14. A presynaptic role for PKA in synaptic tagging and memory

    NARCIS (Netherlands)

    Park, Alan Jung; Havekes, Robbert; Choi, Jennifer H K; Luczak, Vincent; Nie, Ting; Huang, Ted; Abel, Ted

    2014-01-01

    Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and

  15. Memristor-based neural networks: Synaptic versus neuronal stochasticity

    KAUST Repository

    Naous, Rawan; Alshedivat, Maruan; Neftci, Emre; Cauwenberghs, Gert; Salama, Khaled N.

    2016-01-01

    In neuromorphic circuits, stochasticity in the cortex can be mapped into the synaptic or neuronal components. The hardware emulation of these stochastic neural networks are currently being extensively studied using resistive memories or memristors

  16. Neuro-inspired computing using resistive synaptic devices

    CERN Document Server

    2017-01-01

    This book summarizes the recent breakthroughs in hardware implementation of neuro-inspired computing using resistive synaptic devices. The authors describe how two-terminal solid-state resistive memories can emulate synaptic weights in a neural network. Readers will benefit from state-of-the-art summaries of resistive synaptic devices, from the individual cell characteristics to the large-scale array integration. This book also discusses peripheral neuron circuits design challenges and design strategies. Finally, the authors describe the impact of device non-ideal properties (e.g. noise, variation, yield) and their impact on the learning performance at the system-level, using a device-algorithm co-design methodology. • Provides single-source reference to recent breakthroughs in resistive synaptic devices, not only at individual cell-level, but also at integrated array-level; • Includes detailed discussion of the peripheral circuits and array architecture design of the neuro-crossbar system; • Focuses on...

  17. Learning and Memory, Part II: Molecular Mechanisms of Synaptic Plasticity

    Science.gov (United States)

    Lombroso, Paul; Ogren, Marilee

    2009-01-01

    The molecular events that are responsible for strengthening synaptic connections and how these are linked to memory and learning are discussed. The laboratory preparations that allow the investigation of these events are also described.

  18. Multistate Resistive Switching Memory for Synaptic Memory Applications

    KAUST Repository

    Hota, Mrinal Kanti; Hedhili, Mohamed N.; Wehbe, Nimer; McLachlan, Martyn A.; Alshareef, Husam N.

    2016-01-01

    memory performance is observed. Conventional synaptic operation in terms of potentiation, depression plasticity, and Ebbinghaus forgetting process are also studied. The memory mechanism is shown to originate from the migration of the oxygen vacancies

  19. Binocular Rivalry in a Competitive Neural Network with Synaptic Depression

    KAUST Repository

    Kilpatrick, Zachary P.; Bressloff, Paul C.

    2010-01-01

    We study binocular rivalry in a competitive neural network with synaptic depression. In particular, we consider two coupled hypercolums within primary visual cortex (V1), representing orientation selective cells responding to either left or right

  20. Synaptic Control of Secretory Trafficking in Dendrites

    Directory of Open Access Journals (Sweden)

    Cyril Hanus

    2014-06-01

    Full Text Available Localized signaling in neuronal dendrites requires tight spatial control of membrane composition. Upon initial synthesis, nascent secretory cargo in dendrites exits the endoplasmic reticulum (ER from local zones of ER complexity that are spatially coupled to post-ER compartments. Although newly synthesized membrane proteins can be processed locally, the mechanisms that control the spatial range of secretory cargo transport in dendritic segments are unknown. Here, we monitored the dynamics of nascent membrane proteins in dendritic post-ER compartments under regimes of low or increased neuronal activity. In response to activity blockade, post-ER carriers are highly mobile and are transported over long distances. Conversely, increasing synaptic activity dramatically restricts the spatial scale of post-ER trafficking along dendrites. This activity-induced confinement of secretory cargo requires site-specific phosphorylation of the kinesin motor KIF17 by Ca2+/calmodulin-dependent protein kinases (CaMK. Thus, the length scales of early secretory trafficking in dendrites are tuned by activity-dependent regulation of microtubule-dependent transport.

  1. Cholesterol asymmetry in synaptic plasma membranes.

    Science.gov (United States)

    Wood, W Gibson; Igbavboa, Urule; Müller, Walter E; Eckert, Gunter P

    2011-03-01

    Lipids are essential for the structural and functional integrity of membranes. Membrane lipids are not randomly distributed but are localized in different domains. A common characteristic of these membrane domains is their association with cholesterol. Lipid rafts and caveolae are examples of cholesterol enriched domains, which have attracted keen interest. However, two other important cholesterol domains are the exofacial and cytofacial leaflets of the plasma membrane. The two leaflets that make up the bilayer differ in their fluidity, electrical charge, lipid distribution, and active sites of certain proteins. The synaptic plasma membrane (SPM) cytofacial leaflet contains over 85% of the total SPM cholesterol as compared with the exofacial leaflet. This asymmetric distribution of cholesterol is not fixed or immobile but can be modified by different conditions in vivo: (i) chronic ethanol consumption; (ii) statins; (iii) aging; and (iv) apoE isoform. Several potential candidates have been proposed as mechanisms involved in regulation of SPM cholesterol asymmetry: apoE, low-density lipoprotein receptor, sterol carrier protein-2, fatty acid binding proteins, polyunsaturated fatty acids, P-glycoprotein and caveolin-1. This review examines cholesterol asymmetry in SPM, potential mechanisms of regulation and impact on membrane structure and function. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  2. Reduced Synaptic Vesicle Recycling during Hypoxia in Cultured Cortical Neurons

    OpenAIRE

    Fedorovich, Sergei; Hofmeijer, Jeannette; van Putten, Michel Johannes Antonius Maria; le Feber, Jakob

    2017-01-01

    Improvement of neuronal recovery in the ischemic penumbra, an area around the core of a brain infarct with some remaining perfusion, has a large potential for the development of therapy against acute ischemic stroke. However, mechanisms that lead to either recovery or secondary damage in the penumbra largely remain unclear. Recent studies in cultured networks of cortical neurons showed that failure of synaptic transmission (referred to as synaptic failure) is a critical factor in the penumbra...

  3. Common mechanisms of synaptic plasticity in vertebrates and invertebrates

    Science.gov (United States)

    Glanzman, David L.

    2016-01-01

    Until recently, the literature on learning-related synaptic plasticity in invertebrates has been dominated by models assuming plasticity is mediated by presynaptic changes, whereas the vertebrate literature has been dominated by models assuming it is mediated by postsynaptic changes. Here I will argue that this situation does not reflect a biological reality and that, in fact, invertebrate and vertebrate nervous systems share a common set of mechanisms of synaptic plasticity. PMID:20152143

  4. Mechanistic Insights in Ethylene Perception and Signal Transduction1

    Science.gov (United States)

    Ju, Chuanli; Chang, Caren

    2015-01-01

    The gaseous hormone ethylene profoundly affects plant growth, development, and stress responses. Ethylene perception occurs at the endoplasmic reticulum membrane, and signal transduction leads to a transcriptional cascade that initiates diverse responses, often in conjunction with other signals. Recent findings provide a more complete picture of the components and mechanisms in ethylene signaling, now rendering a more dynamic view of this conserved pathway. This includes newly identified protein-protein interactions at the endoplasmic reticulum membrane, as well as the major discoveries that the central regulator ETHYLENE INSENSITIVE2 (EIN2) is the long-sought phosphorylation substrate for the CONSTITUTIVE RESPONSE1 protein kinase, and that cleavage of EIN2 transmits the signal to the nucleus. In the nucleus, hundreds of potential gene targets of the EIN3 master transcription factor have been identified and found to be induced in transcriptional waves, and transcriptional coregulation has been shown to be a mechanism of ethylene cross talk. PMID:26246449

  5. Piezoelectric Multilayer-Stacked Hybrid Actuation/Transduction System

    Science.gov (United States)

    Xu, Tian-Bing (Inventor); Jiang, Xiaoning (Inventor); Su, Ji (Inventor)

    2014-01-01

    A novel full piezoelectric multilayer stacked hybrid actuation/transduction system. The system demonstrates significantly-enhanced electromechanical performance by utilizing the cooperative contributions of the electromechanical responses of multilayer stacked negative and positive strain components. Both experimental and theoretical studies indicate that for this system, the displacement is over three times that of a same-sized conventional flextensional actuator/transducer. The system consists of at least 2 layers which include electromechanically active components. The layers are arranged such that when electric power is applied, one layer contracts in a transverse direction while the second layer expands in a transverse direction which is perpendicular to the transverse direction of the first layer. An alternate embodiment includes a third layer. In this embodiment, the outer two layers contract in parallel transverse directions while the middle layer expands in a transverse direction which is perpendicular to the transverse direction of the outer layers.

  6. Influence of Unweighting on Insulin Signal Transduction in Muscle

    Science.gov (United States)

    Tischler, Marc E.

    2002-01-01

    Unweighting of the juvenile soleus muscle is characterized by an increased binding capacity for insulin relative to muscle mass due to sparing of the receptors during atrophy. Although carbohydrate metabolism and protein degradation in the unweighted muscle develop increased sensitivity to insulin in vivo, protein synthesis in vivo and system A amino acid transport in vitro do not appear to develop such an enhanced response. The long-term goal is to identify the precise nature of this apparent resistance in the insulin signal transduction pathway and to consider how reduced weight-bearing may elicit this effect, by evaluating specific components of the insulin signalling pathway. Because the insulin-signalling pathway has components in common with the signal transduction pathway for insulin-like growth factor (IGF-1) and potentially other growth factors, the study could have important implications in the role of weight-bearing function on muscle growth and development. Since the insulin signalling pathway diverges following activation of insulin receptor tyrosine kinase, the immediate specific aims will be to study the receptor tyrosine kinase (IRTK) and those branches, which lead to phosphorylation of insulin receptor substrate-1 (IRS-1) and of Shc protein. To achieve these broader objectives, we will test in situ, by intramuscular injection, the responses of glucose transport, system A amino acid transport and protein synthesis to insulin analogues for which the receptor has either a weaker or much stronger binding affinity compared to insulin. Studies will include: (1) estimation of the ED(sub 50) for each analogue for these three processes; (2) the effect of duration (one to four days) of unweighting on the response of each process to all analogues tested; (3) the effect of unweighting and the analogues on IRTK activity; and (4) the comparative effects of unweighting and analogue binding on the tyrosine phosphorylation of IRTK, IRS-1, and Shc protein.

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

    Science.gov (United States)

    Calafate, Sara; Buist, Arjan; Miskiewicz, Katarzyna; Vijayan, Vinoy; Daneels, Guy; de Strooper, Bart; de Wit, Joris; Verstreken, Patrik; Moechars, Diederik

    2015-05-26

    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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  8. SYNAPTIC DEPRESSION IN DEEP NEURAL NETWORKS FOR SPEECH PROCESSING.

    Science.gov (United States)

    Zhang, Wenhao; Li, Hanyu; Yang, Minda; Mesgarani, Nima

    2016-03-01

    A characteristic property of biological neurons is their ability to dynamically change the synaptic efficacy in response to variable input conditions. This mechanism, known as synaptic depression, significantly contributes to the formation of normalized representation of speech features. Synaptic depression also contributes to the robust performance of biological systems. In this paper, we describe how synaptic depression can be modeled and incorporated into deep neural network architectures to improve their generalization ability. We observed that when synaptic depression is added to the hidden layers of a neural network, it reduces the effect of changing background activity in the node activations. In addition, we show that when synaptic depression is included in a deep neural network trained for phoneme classification, the performance of the network improves under noisy conditions not included in the training phase. Our results suggest that more complete neuron models may further reduce the gap between the biological performance and artificial computing, resulting in networks that better generalize to novel signal conditions.

  9. Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell

    Directory of Open Access Journals (Sweden)

    Regina A. Mangieri

    2017-08-01

    Full Text Available Anaplastic lymphoma kinase (ALK is a receptor tyrosine kinase recently implicated in biochemical, physiological, and behavioral responses to ethanol. Thus, manipulation of ALK signaling may represent a novel approach to treating alcohol use disorder (AUD. Ethanol induces adaptations in glutamatergic synapses onto nucleus accumbens shell (NAcSh medium spiny neurons (MSNs, and putative targets for treating AUD may be validated for further development by assessing how their manipulation modulates accumbal glutamatergic synaptic transmission and plasticity. Here, we report that Alk knockout (AlkKO mice consumed greater doses of ethanol, relative to wild-type (AlkWT mice, in an operant self-administration model. Using ex vivo electrophysiology to examine excitatory synaptic transmission and plasticity at NAcSh MSNs that express dopamine D1 receptors (D1MSNs, we found that the amplitude of spontaneous excitatory post-synaptic currents (EPSCs in NAcSh D1MSNs was elevated in AlkKO mice and in the presence of an ALK inhibitor, TAE684. Furthermore, when ALK was absent or inhibited, glutamatergic synaptic plasticity – long-term depression of evoked EPSCs – in D1MSNs was attenuated. Thus, loss of ALK activity in mice is associated with elevated ethanol consumption and enhanced excitatory transmission in NAcSh D1MSNs. These findings add to the mounting evidence of a relationship between excitatory synaptic transmission onto NAcSh D1MSNs and ethanol consumption, point toward ALK as one important molecular mediator of this interaction, and further validate ALK as a target for therapeutic intervention in the treatment of AUD.

  10. Molecular machinery of signal transduction and cell cycle regulation in Plasmodium.

    Science.gov (United States)

    Koyama, Fernanda C; Chakrabarti, Debopam; Garcia, Célia R S

    2009-05-01

    The regulation of the Plasmodium cell cycle is not understood. Although the Plasmodium falciparum genome is completely sequenced, about 60% of the predicted proteins share little or no sequence similarity with other eukaryotes. This feature impairs the identification of important proteins participating in the regulation of the cell cycle. There are several open questions that concern cell cycle progression in malaria parasites, including the mechanism by which multiple nuclear divisions is controlled and how the cell cycle is managed in all phases of their complex life cycle. Cell cycle synchrony of the parasite population within the host, as well as the circadian rhythm of proliferation, are striking features of some Plasmodium species, the molecular basis of which remains to be elucidated. In this review we discuss the role of indole-related molecules as signals that modulate the cell cycle in Plasmodium and other eukaryotes, and we also consider the possible role of kinases in the signal transduction and in the responses it triggers.

  11. Scraping through the ice: uncovering the role of TRPM8 in cold transduction

    Science.gov (United States)

    McCoy, Daniel D.; Knowlton, Wendy M.

    2011-01-01

    The proper detection of environmental temperatures is essential for the optimal growth and survival of organisms of all shapes and phyla, yet only recently have the molecular mechanisms for temperature sensing been elucidated. The discovery of temperature-sensitive ion channels of the transient receptor potential (TRP) superfamily has been pivotal in explaining how temperatures are sensed in vivo, and here we will focus on the lone member of this cohort, TRPM8, which has been unequivocally shown to be cold sensitive. TRPM8 is expressed in somatosensory neurons that innervate peripheral tissues such as the skin and oral cavity, and recent genetic evidence has shown it to be the principal transducer of cool and cold stimuli. It is remarkable that this one channel, unlike other thermosensitive TRP channels, is associated with both innocuous and noxious temperature transduction, as well as cold hypersensitivity during injury and, paradoxically, cold-mediated analgesia. With ongoing research, the field is getting closer to answering a number of fundamental questions regarding this channel, including the cellular mechanisms of TRPM8 modulation, the molecular context of TRPM8 expression, as well as the full extent of the role of TRPM8 in cold signaling in vivo. These findings will further our understanding of basic thermotransduction and sensory coding, and may have important implications for treatments for acute and chronic pain. PMID:21411765

  12. An agent-based model of signal transduction in bacterial chemotaxis.

    Directory of Open Access Journals (Sweden)

    Jameson Miller

    2010-05-01

    Full Text Available We report the application of agent-based modeling to examine the signal transduction network and receptor arrays for chemotaxis in Escherichia coli, which are responsible for regulating swimming behavior in response to environmental stimuli. Agent-based modeling is a stochastic and bottom-up approach, where individual components of the modeled system are explicitly represented, and bulk properties emerge from their movement and interactions. We present the Chemoscape model: a collection of agents representing both fixed membrane-embedded and mobile cytoplasmic proteins, each governed by a set of rules representing knowledge or hypotheses about their function. When the agents were placed in a simulated cellular space and then allowed to move and interact stochastically, the model exhibited many properties similar to the biological system including adaptation, high signal gain, and wide dynamic range. We found the agent based modeling approach to be both powerful and intuitive for testing hypotheses about biological properties such as self-assembly, the non-linear dynamics that occur through cooperative protein interactions, and non-uniform distributions of proteins in the cell. We applied the model to explore the role of receptor type, geometry and cooperativity in the signal gain and dynamic range of the chemotactic response to environmental stimuli. The model provided substantial qualitative evidence that the dynamic range of chemotactic response can be traced to both the heterogeneity of receptor types present, and the modulation of their cooperativity by their methylation state.

  13. An agent-based model of signal transduction in bacterial chemotaxis.

    Science.gov (United States)

    Miller, Jameson; Parker, Miles; Bourret, Robert B; Giddings, Morgan C

    2010-05-13

    We report the application of agent-based modeling to examine the signal transduction network and receptor arrays for chemotaxis in Escherichia coli, which are responsible for regulating swimming behavior in response to environmental stimuli. Agent-based modeling is a stochastic and bottom-up approach, where individual components of the modeled system are explicitly represented, and bulk properties emerge from their movement and interactions. We present the Chemoscape model: a collection of agents representing both fixed membrane-embedded and mobile cytoplasmic proteins, each governed by a set of rules representing knowledge or hypotheses about their function. When the agents were placed in a simulated cellular space and then allowed to move and interact stochastically, the model exhibited many properties similar to the biological system including adaptation, high signal gain, and wide dynamic range. We found the agent based modeling approach to be both powerful and intuitive for testing hypotheses about biological properties such as self-assembly, the non-linear dynamics that occur through cooperative protein interactions, and non-uniform distributions of proteins in the cell. We applied the model to explore the role of receptor type, geometry and cooperativity in the signal gain and dynamic range of the chemotactic response to environmental stimuli. The model provided substantial qualitative evidence that the dynamic range of chemotactic response can be traced to both the heterogeneity of receptor types present, and the modulation of their cooperativity by their methylation state.

  14. Nitric oxide agents impair insulin-mediated signal transduction in rat skeletal muscle

    Directory of Open Access Journals (Sweden)

    Ragoobirsingh Dalip

    2006-05-01

    Full Text Available Abstract Background Evidence demonstrates that exogenously administered nitric oxide (NO can induce insulin resistance in skeletal muscle. We have investigated the modulatory effects of two NO donors, S-nitroso-N-acetyl-D, L-penicillamine (SNAP and S-nitrosoglutathione (GSNO on the early events in insulin signaling in rat skeletal myocytes. Results Skeletal muscle cells from 6–8 week old Sprague-Dawley rats were treated with SNAP or GSNO (25 ng/ml in the presence or absence of glucose (25 mM and insulin (100 nM. Cellular insulin receptor-β levels and tyrosine phosphorylation in IRS-1 were significantly reduced, while serine phosphorylation in IRS-1 was significantly increased in these cells, when compared to the insulin-stimulated control. Reversal to near normal levels was achieved using the NO scavenger, 2-(4-carboxyphenyl-4, 4, 5, 5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO. Conclusion These data suggest that NO is a potent modulator of insulin-mediated signal transduction and may play a significant role in the pathogenesis of type 2 diabetes mellitus.

  15. Synaptic dimorphism in Onychophoran cephalic ganglia

    Directory of Open Access Journals (Sweden)

    Z Peña-Contreras

    2007-03-01

    Full Text Available The taxonomic location of the Onychophora has been controversial because of their phenotypic and genotypic characteristics, related to both annelids and arthropods. We analyzed the ultrastructure of the neurons and their synapses in the cephalic ganglion of a poorly known invertebrate, the velvet worm Peripatus sedgwicki, from the mountainous region of El Valle, Mérida, Venezuela. Cephalic ganglia were dissected, fixed and processed for transmission electron microscopy. The animal has a high degree of neurobiological development, as evidenced by the presence of asymmetric (excitatory and symmetric (inhibitory synapses, as well as the existence of glial cell processes in a wide neuropile zone. The postsynaptic terminals were seen to contain subsynaptic cisterns formed by membranes of smooth endoplasmic reticulum beneath the postsynaptic density, whereas the presynaptic terminal showed numerous electron transparent synaptic vesicles. From the neurophylogenetic perspectives, the ultrastructural characteristics of the central nervous tissue of the Onychophora show important evolutionary acquirements, such as the presence of both excitatory and inhibitory synapses, indicating functional synaptic transmission, and the appearance of mature glial cells. Rev. Biol . Trop. 55 (1: 261-267. Epub 2007 March. 31.Estudiamos la ultraestructura de las neuronas y sus sinapsis del ganglio cefálico de un invertebrado poco conocido del phylum Onychophora: Peripatus sedgwicki de los Andes Venezolanos, utilizando para ello la microscopía electrónica de transmisión. La localización taxonómica de los onicóforos ha sido controversial debido a sus características fenotípicas y genotípicas que los relacionan tanto con los anélidos como con los artrópodos. Para este trabajo se estudió el ganglio cefálico de P. sedgwicki de la zona montañosa de El Valle, Mérida, Venezuela. El ganglio cefálico se localiza en la región anterior del animal y fue diseccionado

  16. Multidrug resistance and retroviral transduction potential in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Theilade, M D; Gram, G J; Jensen, P B

    1999-01-01

    of blue colonies after X-Gal staining of the cells grown in soft agar. All examined SCLC cell lines were transducible with either vector. Transduction efficiencies varied from 5.7% to 33.5% independent of the presence of MDR. These results indicate that MDR does not severely impair transduction of SCLC...

  17. Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex

    Science.gov (United States)

    Pinto, Joshua G. A.; Jones, David G.; Williams, C. Kate; Murphy, Kathryn M.

    2015-01-01

    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 (V1) 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 four proteins and include a stage during early development (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. PMID:25729353

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

    Science.gov (United States)

    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. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Opposite long-term synaptic effects of 17β-estradiol and 5α-dihydrotestosterone and localization of their receptors in the medial vestibular nucleus of rats.

    Science.gov (United States)

    Grassi, Silvarosa; Scarduzio, Mariangela; Panichi, Roberto; Dall'Aglio, Cecilia; Boiti, Cristiano; Pettorossi, Vito E

    2013-08-01

    In brainstem slices of male rats, we examined in single neurons of the medial vestibular nucleus (MVN) the effect of exogenous administration of estrogenic (17β-estradiol, E2) and androgenic (5α-dihydrotestosterone, DHT) steroids on the synaptic response to vestibular afferent stimulation. By whole cell patch clamp recordings we showed that E2 induced synaptic long-term potentiation (LTP) that was cancelled by the subsequent administration of DHT. Conversely, DHT induced synaptic long-term depression (LTD) that was partially reversed by E2. The electrophysiological findings were supported by immunohistochemical analysis showing the presence of estrogen (ER: α and β) and androgen receptors (AR) in the MVN neurons. We found that a large number of neurons were immunoreactive for ERα, ERβ, and AR and most of them co-localized ERβ and AR. We also showed the presence of P450-aromatase (ARO) in the MVN neurons, clearly proving that E2 can be locally synthesized in the MVN. On the whole, these results demonstrate a role of estrogenic and androgenic signals in modulating vestibular synaptic plasticity and suggest that the enhancement or depression of vestibular synaptic response may depend on the local conversion of T into E2 or DHT. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. NMDA receptor GluN2A/GluN2B subunit ratio as synaptic trait of levodopa-induced dyskinesias: from experimental models to patients

    Directory of Open Access Journals (Sweden)

    Manuela eMellone

    2015-07-01

    Full Text Available Levodopa-induced dyskinesias (LIDs are major complications in the pharmacological management of Parkinson’s disease (PD. Abnormal glutamatergic transmission in the striatum is considered a key factor in the development of LIDs. This work aims at i. characterizing NMDA receptor GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models of LIDs and in dyskinetic PD patients, and ii. validating the potential therapeutic effect of a cell-permeable peptide interfering with GluN2A synaptic localization on the dyskinetic behavior of these experimental models of LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing NMDA receptors in the striatum of levodopa-treated dyskinetic rats and monkeys as well as in post-mortem tissue from dyskinetic PD patients. The modulation of synaptic NMDA receptor composition by a cell-permeable peptide interfering with GluN2A subunit interaction with the scaffolding protein PSD-95 leads to a reduction in the dyskinetic motor behavior in the two animal models of LIDs. Our results indicate that targeting synaptic NMDA receptor subunit composition may represent an intriguing therapeutic approach aimed at ameliorating levodopa motor side effects.

  1. The LHRH-astroglial network of signals as a model to study neuroimmune interactions: assessment of messenger systems and transduction mechanisms at cellular and molecular levels.

    Science.gov (United States)

    Marchetti, B

    1996-01-01

    Neurons and astrocytes have a close anatomic and functional relationship that plays a crucial role during development and in the adult brain. Astrocytes in the central nervous system (CNS) express receptors for a variety of growth factors (GFs), neurotransmitters and/or neuromodulators; in turn, neuronal cells can respond to astrocyte-derived GFs and control astrocyte function via a common set of signaling molecules and intracellular transducing pathways. There is also increasing evidence that soluble factors from lymphoid/mononuclear cells are able to modulate the growth and function of cells found in the CNS, specifically macroglial and microglial cells. Furthermore, glial cells can secrete immunoregulatory molecules that influence immune cells as well as the glial cells themselves. As neuronal and immune cells share common signaling systems, the potential exists for bidirectional communication not only between lymphoid and glial cells, but also between neuronal cells and immune and glial cells. In the present work, interactions of luteinizing-hormone-releasing hormone (LHRH) and the astroglial cell are proposed as a prototype for the study of neuroimmune communication within the CNS in the light of (1) the commonality of signal molecules (hormones, neurotransmitters and cytokines) and transduction mechanisms shared by glia LHRH neurons and lymphoid cells; (2) the central role of glia in the developmental organization and pattern of LHRH neuronal migration during embryogenesis, and (3) the strong modulatory role played by sex steroids in mechanisms involved in synaptic and interneuronal organization, as well as in the sexual dimorphisms of neuroendocrine-immune functions. During their maturation and differentiation in vitro, astroglial cells release factors able to accelerate markedly the LHRH neuronal phenotypic differentiation as well as the acquisition of mature LHRH secretory potential, with a potency depending on both the 'age' and the specific brain

  2. The Role of Cgrp-Receptor Component Protein (Rcp in Cgrp-Mediated Signal Transduction

    Directory of Open Access Journals (Sweden)

    M. A. Prado

    2001-01-01

    Full Text Available The calcitonin gene-related peptide (CGRP-receptor component protein (RCP is a 17-kDa intracellular peripheral membrane protein required for signal transduction at CGRP receptors. To determine the role of RCP in CGRP-mediated signal transduction, RCP was depleted from NIH3T3 cells using antisense strategy. Loss of RCP protein correlated with loss of cAMP production by CGRP in the antisense cells. In contrast, loss of RCP had no effect on CGRP-mediated binding; therefore RCP is not acting as a chaperone for the CGRP receptor. Instead, RCP is a novel signal transduction molecule that couples the CGRP receptor to the cellular signal transduction machinery. RCP thus represents a prototype for a new class of signal transduction proteins that are required for regulation of G protein-coupled receptors.

  3. Synaptic vesicle dynamic changes in a model of fragile X.

    Science.gov (United States)

    Broek, Jantine A C; Lin, Zhanmin; de Gruiter, H Martijn; van 't Spijker, Heleen; Haasdijk, Elize D; Cox, David; Ozcan, Sureyya; van Cappellen, Gert W A; Houtsmuller, Adriaan B; Willemsen, Rob; de Zeeuw, Chris I; Bahn, Sabine

    2016-01-01

    Fragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs). The extent of expression level alterations of synaptic proteins affected by FMRP loss and their consequences on synaptic dynamics in FXS has not been fully investigated. Here, we used an Fmr1 knockout (KO) mouse model to investigate the molecular mechanisms underlying FXS by monitoring protein expression changes using shotgun label-free liquid-chromatography mass spectrometry (LC-MS(E)) in brain tissue and synaptosome fractions. FXS-associated candidate proteins were validated using selected reaction monitoring (SRM) in synaptosome fractions for targeted protein quantification. Furthermore, functional alterations in synaptic release and dynamics were evaluated using live-cell imaging, and interpretation of synaptic dynamics differences was investigated using electron microscopy. Key findings relate to altered levels of proteins involved in GABA-signalling, especially in the cerebellum. Further exploration using microscopy studies found reduced synaptic vesicle unloading of hippocampal neurons and increased vesicle unloading in cerebellar neurons, which suggests a general decrease of synaptic transmission. Our findings suggest that FMRP is a regulator of synaptic vesicle dynamics, which supports the role of FMRP in presynaptic functions. Taken together, these studies provide novel insights into the molecular changes associated with FXS.

  4. Effects of the pyrethroid insecticide, deltamethrin, on respiratory modulated hypoglossal motoneurons in a brain stem slice from newborn mice

    DEFF Research Database (Denmark)

    Rekling, J C; Theophilidis, G

    1995-01-01

    We have studied the action of deltamethrin on respiratory modulated hypoglossal motoneurons in a brain stem slice from newborn mice. Deltamethrin depolarized the hypoglossal motoneurons, increased the background synaptic noise and reduced the frequency and amplitude of current elicited action...

  5. Overelaborated synaptic architecture and reduced synaptomatrix glycosylation in a Drosophila classic galactosemia disease model

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  7. A tale of two stories: astrocyte regulation of synaptic depression and facilitation.

    Directory of Open Access Journals (Sweden)

    Maurizio De Pittà

    2011-12-01

    Full Text Available Short-term presynaptic plasticity designates variations of the amplitude of synaptic information transfer whereby the amount of neurotransmitter released upon presynaptic stimulation changes over seconds as a function of the neuronal firing activity. While a consensus has emerged that the resulting decrease (depression and/or increase (facilitation of the synapse strength are crucial to neuronal computations, their modes of expression in vivo remain unclear. Recent experimental studies have reported that glial cells, particularly astrocytes in the hippocampus, are able to modulate short-term plasticity but the mechanism of such a modulation is poorly understood. Here, we investigate the characteristics of short-term plasticity modulation by astrocytes using a biophysically realistic computational model. Mean-field analysis of the model, supported by intensive numerical simulations, unravels that astrocytes may mediate counterintuitive effects. Depending on the expressed presynaptic signaling pathways, astrocytes may globally inhibit or potentiate the synapse: the amount of released neurotransmitter in the presence of the astrocyte is transiently smaller or larger than in its absence. But this global effect usually coexists with the opposite local effect on paired pulses: with release-decreasing astrocytes most paired pulses become facilitated, namely the amount of neurotransmitter released upon spike i+1 is larger than that at spike i, while paired-pulse depression becomes prominent under release-increasing astrocytes. Moreover, we show that the frequency of astrocytic intracellular Ca(2+ oscillations controls the effects of the astrocyte on short-term synaptic plasticity. Our model explains several experimental observations yet unsolved, and uncovers astrocytic gliotransmission as a possible transient switch between short-term paired-pulse depression and facilitation. This possibility has deep implications on the processing of neuronal spikes

  8. Deep brain stimulation of the amygdala alleviates fear conditioning-induced alterations in synaptic plasticity in the cortical-amygdala pathway and fear memory.

    Science.gov (United States)

    Sui, Li; Huang, SiJia; Peng, BinBin; Ren, Jie; Tian, FuYing; Wang, Yan

    2014-07-01

    Deep brain stimulation (DBS) of the amygdala has been demonstrated to modulate hyperactivity of the amygdala, which is responsible for the symptoms of post-traumatic stress disorder (PTSD), and thus might be used for the treatment of PTSD. However, the underlying mechanism of DBS of the amygdala in the modulation of the amygdala is unclear. The present study investigated the effects of DBS of the amygdala on synaptic transmission and synaptic plasticity at cortical inputs to the amygdala, which is critical for the formation and storage of auditory fear memories, and fear memories. The results demonstrated that auditory fear conditioning increased single-pulse-evoked field excitatory postsynaptic potentials in the cortical-amygdala pathway. Furthermore, auditory fear conditioning decreased the induction of paired-pulse facilitation and long-term potentiation, two neurophysiological models for studying short-term and long-term synaptic plasticity, respectively, in the cortical-amygdala pathway. In addition, all these auditory fear conditioning-induced changes could be reversed by DBS of the amygdala. DBS of the amygdala also rescued auditory fear conditioning-induced enhancement of long-term retention of fear memory. These findings suggested that DBS of the amygdala alleviating fear conditioning-induced alterations in synaptic plasticity in the cortical-amygdala pathway and fear memory may underlie the neuromodulatory role of DBS of the amygdala in activities of the amygdala.

  9. Limited distal organelles and synaptic function in extensive monoaminergic innervation.

    Science.gov (United States)

    Tao, Juan; Bulgari, Dinara; Deitcher, David L; Levitan, Edwin S

    2017-08-01

    Organelles such as neuropeptide-containing dense-core vesicles (DCVs) and mitochondria travel down axons to supply synaptic boutons. DCV distribution among en passant boutons in small axonal arbors is mediated by circulation with bidirectional capture. However, it is not known how organelles are distributed in extensive arbors associated with mammalian dopamine neuron vulnerability, and with volume transmission and neuromodulation by monoamines and neuropeptides. Therefore, we studied presynaptic organelle distribution in Drosophila octopamine neurons that innervate ∼20 muscles with ∼1500 boutons. Unlike in smaller arbors, distal boutons in these arbors contain fewer DCVs and mitochondria, although active zones are present. Absence of vesicle circulation is evident by proximal nascent DCV delivery, limited impact of retrograde transport and older distal DCVs. Traffic studies show that DCV axonal transport and synaptic capture are not scaled for extensive innervation, thus limiting distal delivery. Activity-induced synaptic endocytosis and synaptic neuropeptide release are also reduced distally. We propose that limits in organelle transport and synaptic capture compromise distal synapse maintenance and function in extensive axonal arbors, thereby affecting development, plasticity and vulnerability to neurodegenerative disease. © 2017. Published by The Company of Biologists Ltd.

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

    International Nuclear Information System (INIS)

    Corsi, P.; D'Aprile, A.; Nico, B.; Costa, G.L.; Assennato, G.

    2007-01-01

    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

  11. Readily releasable pool of synaptic vesicles measured at single synaptic contacts.

    Science.gov (United States)

    Trigo, Federico F; Sakaba, Takeshi; Ogden, David; Marty, Alain

    2012-10-30

    To distinguish between different models of vesicular release in brain synapses, it is necessary to know the number of vesicles of transmitter that can be released immediately at individual synapses by a high-calcium stimulus, the readily releasable pool (RRP). We used direct stimulation by calcium uncaging at identified, single-site inhibitory synapses to investigate the statistics of vesicular release and the size of the RRP. Vesicular release, detected as quantal responses in the postsynaptic neuron, showed an unexpected stochastic variation in the number of quanta from stimulus to stimulus at high intracellular calcium, with a mean of 1.9 per stimulus and a maximum of three or four. The results provide direct measurement of the RRP at single synaptic sites. They are consistent with models in which release proceeds from a small number of vesicle docking sites with an average occupancy around 0.7.

  12. Mannotriose regulates learning and memory signal transduction in the hippocampus

    Institute of Scientific and Technical Information of China (English)

    Lina Zhang; Weiwei Dai; Xueli Zhang; Zhangbin Gong; Guoqin Jin

    2013-01-01

    Rehmannia is a commonly used Chinese herb, which improves learning and memory. However, the crucial components of the signal transduction pathway associated with this effect remain elusive. Pri-mary hippocampal neurons were cultured in vitro, insulted with high-concentration (1 × 10-4 mol/L) cor-ticosterone, and treated with 1 × 10-4 mol/L mannotriose. Thiazolyl blue tetrazolium bromide assay and western blot analysis showed that hippocampal neuron survival rates and protein levels of glucocorti-coid receptor, serum and glucocorticoid-regulated protein kinase, and brain-derived neurotrophic factor were al dramatical y decreased after high-concentration corticosterone-induced injury. This effect was reversed by mannotriose, to a similar level as RU38486 and donepezil. Our findings indicate that mannotriose could protect hippocampal neurons from high-concentration corticosterone-induced injury. The mechanism by which this occurred was associated with levels of glucocorticoid receptor protein, serum and glucocorticoid-regulated protein kinase, and brain-derived neurotrophic factor.

  13. The interleukin-4 receptor: signal transduction by a hematopoietin receptor.

    Science.gov (United States)

    Keegan, A D; Pierce, J H

    1994-02-01

    Over the last several years, the receptors for numerous cytokines have been molecularly characterized. Analysis of their amino acid sequences shows that some of these receptors bear certain motifs in their extracellular domains that define a family of receptors called the Hematopoietin receptor superfamily. Significant advances in characterizing the structure, function, and mechanisms of signal transduction have been made for several members of this family. The purpose of this review is to discuss the recent advances made for one of the family members, the interleukin (IL) 4 receptor. Other receptor systems have recently been reviewed elsewhere. The IL-4 receptor consists of, at the minimum, the cloned 140 kDa IL-4-binding chain with the potential for associating with other chains. The IL-4 receptor transduces its signal by activating a tyrosine kinase that phosphorylates cellular substrates, including the receptor itself, and the 170 kDa substrate called 4PS. Phosphorylated 4PS interacts with the SH2 domain of the enzyme PI-3'-kinase and increases its enzymatic activity. These early events in the IL-4 receptor initiated signaling pathway may trigger a series of signals that will ultimately lead to an IL-4 specific biologic outcome.

  14. Fenspiride and membrane transduction signals in rat alveolar macrophages.

    Science.gov (United States)

    Féray, J C; Mohammadi, K; Taouil, K; Brunet, J; Garay, R P; Hannaert, P

    1997-07-15

    Fenspiride inhibits the calcium signal evoked by the inflammatory peptide formyl-Met-Leu-Phe (fMLP) in peritoneal macrophages, but at concentrations (approximately 1 mM) far above the therapeutic range (approximately 1 microM). Here, in rat alveolar macrophages, high fenspiride concentrations (1 mM) were required to inhibit the calcium signals evoked by the calcium agonist Bay K8644 or by ionomycin. Moreover, fenspiride (1 mM) was a poor inhibitor of the cell membrane depolarization induced by gramicidine D. By contrast, fenspiride blocked Na+-H+ antiport activation by (i) fMLP with an IC50 = 3.1 +/- 1.9 nM and (ii) PMA (phorbol 12-myristate 13-acetate) with an IC50 = 9.2 +/- 3.1 nM. Finally, protein kinase C (PKC) activity of macrophage homogenate was not significantly modified by 10 or 100 microM fenspiride (at 100 microM: 2.57 +/- 1.60 vs. 2.80 +/- 1.71 pmol/10(6) cells/min). In conclusion, fenspiride inhibits fMLP- and PMA-induced pH signals in rat alveolar macrophages, probably by acting distally on the PKC transduction signal. This pH antagonistic action may be relevant for the antiinflammatory mechanism of fenspiride and requires further investigation.

  15. Structural basis for energy transduction by respiratory alternative complex III.

    Science.gov (United States)

    Sousa, Joana S; Calisto, Filipa; Langer, Julian D; Mills, Deryck J; Refojo, Patrícia N; Teixeira, Miguel; Kühlbrandt, Werner; Vonck, Janet; Pereira, Manuela M

    2018-04-30

    Electron transfer in respiratory chains generates the electrochemical potential that serves as energy source for the cell. Prokaryotes can use a wide range of electron donors and acceptors and may have alternative complexes performing the same catalytic reactions as the mitochondrial complexes. This is the case for the alternative complex III (ACIII), a quinol:cytochrome c/HiPIP oxidoreductase. In order to understand the catalytic mechanism of this respiratory enzyme, we determined the structure of ACIII from Rhodothermus marinus at 3.9 Å resolution by single-particle cryo-electron microscopy. ACIII presents a so-far unique structure, for which we establish the arrangement of the cofactors (four iron-sulfur clusters and six c-type hemes) and propose the location of the quinol-binding site and the presence of two putative proton pathways in the membrane. Altogether, this structure provides insights into a mechanism for energy transduction and introduces ACIII as a redox-driven proton pump.

  16. Signal transduction in cells of the immune system in microgravity

    Directory of Open Access Journals (Sweden)

    Huber Kathrin

    2008-10-01

    Full Text Available Abstract Life on Earth developed in the presence and under the constant influence of gravity. Gravity has been present during the entire evolution, from the first organic molecule to mammals and humans. Modern research revealed clearly that gravity is important, probably indispensable for the function of living systems, from unicellular organisms to men. Thus, gravity research is no more or less a fundamental question about the conditions of life on Earth. Since the first space missions and supported thereafter by a multitude of space and ground-based experiments, it is well known that immune cell function is severely suppressed in microgravity, which renders the cells of the immune system an ideal model organism to investigate the influence of gravity on the cellular and molecular level. Here we review the current knowledge about the question, if and how cellular signal transduction depends on the existence of gravity, with special focus on cells of the immune system. Since immune cell function is fundamental to keep the organism under imnological surveillance during the defence against pathogens, to investigate the effects and possible molecular mechanisms of altered gravity is indispensable for long-term space flights to Earth Moon or Mars. Thus, understanding the impact of gravity on cellular functions on Earth will provide not only important informations about the development of life on Earth, but also for therapeutic and preventive strategies to cope successfully with medical problems during space exploration.

  17. Signal transduction by the platelet-derived growth factor receptor

    International Nuclear Information System (INIS)

    Williams, L.T.; Escobedo, J.A.; Keating, M.T.; Coughlin, S.R.

    1988-01-01

    The mitogenic effects of platelet-derived growth factor (PDGF) are mediated by the PDGF receptor. The mouse PDGF receptor was recently purified on the basis of its ability to become tyrosine phosphorylated in response to the A-B human platelet form of PDGF, and the receptor amino acid sequence was determined from a full-length cDNA clone. Both the human and mouse receptor cDNA sequences have been expressed in Chinese hamster ovary fibroblast (CHO) cells that normally lack PDGF receptors. This paper summarizes recent results using this system to study signal transduction by the PDGF receptor. Some of the findings show that the KI domain of the PDGF receptor plays an important role in the stimulation of DNA synthesis by PDGF. Surprisingly, the kinase insert region is not essential for PDGF stimulation of PtdIns turnover, pH change, increase in cellular calcium, and receptor autophosphorylation. In addition, PDGF stimulates a conformational change in the receptor

  18. Metformin selectively targets redox control of complex I energy transduction

    Directory of Open Access Journals (Sweden)

    Amy R. Cameron

    2018-04-01

    Full Text Available Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled. Keywords: Diabetes, Metformin, Mitochondria, NADH, NAD+

  19. Phosphoproteomics-based systems analysis of signal transduction networks

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    Hiroko eKozuka-Hata

    2012-01-01

    Full Text Available Signal transduction systems coordinate complex cellular information to regulate biological events such as cell proliferation and differentiation. Although the accumulating evidence on widespread association of signaling molecules has revealed essential contribution of phosphorylation-dependent interaction networks to cellular regulation, their dynamic behavior is mostly yet to be analyzed. Recent technological advances regarding mass spectrometry-based quantitative proteomics have enabled us to describe the comprehensive status of phosphorylated molecules in a time-resolved manner. Computational analyses based on the phosphoproteome dynamics accelerate generation of novel methodologies for mathematical analysis of cellular signaling. Phosphoproteomics-based numerical modeling can be used to evaluate regulatory network elements from a statistical point of view. Integration with transcriptome dynamics also uncovers regulatory hubs at the transcriptional level. These omics-based computational methodologies, which have firstly been applied to representative signaling systems such as the epidermal growth factor receptor pathway, have now opened up a gate for systems analysis of signaling networks involved in immune response and cancer.

  20. Signal transduction around thymic stromal lymphopoietin (TSLP in atopic asthma

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    Kuepper Michael

    2008-08-01

    Full Text Available Abstract Thymic stromal lymphopoietin (TSLP, a novel interleukin-7-like cytokine, triggers dendritic cell-mediated inflammatory responses ultimately executed by T helper cells of the Th2 subtype. TSLP emerged as a central player in the development of allergic symptoms, especially in the airways, and is a prime regulatory cytokine at the interface of virus- or antigen-exposed epithelial cells and dendritic cells (DCs. DCs activated by epithelium-derived TSLP can promote naïve CD4+ T cells to adopt a Th2 phenotype, which in turn recruite eosinophilic and basophilic granulocytes as well as mast cells into the airway mucosa. These different cells secrete inflammatory cytokines and chemokines operative in inducing an allergic inflammation and atopic asthma. TSLP is, thus, involved in the control of both an innate and an adaptive immune response. Since TSLP links contact of allergen with the airway epithelium to the onset and maintainance of the asthmatic syndrome, defining the signal transduction underlying TSLP expression and function is of profound interest for a better understandimg of the disease and for the development of new therapeutics.

  1. Defect in radiation signal transduction in ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Lavin, M.F.

    1994-01-01

    Exposure of mammalian cells to ionizing radiation causes a delay in progression through the cycle at several checkpoints. Cells from patients with ataxia-telangiectasia (A-T) ignore these checkpoint controls postirradiation. The tumour suppressor gene product p53 plays a key role at the G 1 /S checkpoint preventing the progression of cells into S phase. The induction of p53 by radiation is reduced and/or delayed in A-T cells, which appears to account for the failure of delay at the G 1 /S checkpoint. We have investigated further this defect in radiation signal transduction in A-T. While the p53 response was defective after radiation, agents that interfered with cell cycle progression such as mimosine, aphidicolin and deprivation of serum led to a normal p53 response in A-T cells. None of these agents caused breaks in DNA, as determined by pulse-field gel electrophoresis, in order to elicit the response. Since this pathway is mediated by protein kinases, we investigated the activity of several of these enzymes in control and A-T cells. Ca +2 -dependent and -independent protein kinase C activities were increased by radiation to the same extent in the two cell types, a variety of serine/threonine protein kinase activities were approximately the same and anti-tyrosine antibodies failed to reveal any differences in protein phosphorylation between A-T and control cells. (author)

  2. Signal transduction in mitogenesis: Further evidence for multiple pathways

    International Nuclear Information System (INIS)

    Rozengurt, E.; Erusalimsky, J.; Mehmet, H.; Morris, C.; Nanberg, E.; Sinnett-Smith, J.

    1988-01-01

    Growth factors are implicated in a wide variety of physiological and pathological processes, including embryogenesis, hematopoiesis, would healing, immune responses, atherosclerosis, and neoplasia. An important link between growth factors and their receptors and oncogene products has also been established. Thus, the elucidation of the mechanism of action of growth factors has emerged as one of the fundamental problems in biology and may prove crucial for understanding the unrestrained proliferation of cancer cells. A new and intriguing development is the discovery that neuropeptides localized in neural and neuroendocrine cells of mammalian tissue can also act as growth factors for cells in culture. Furthermore, indirect evidence is accumulating that the mitogenic effects of neuropeptides may be relevant for a variety of long-term biological processes, including development and oncogenesis. In this context, the peptides of the bombesin family are of particular significance. These peptides are potent mitogens for Swiss 3T3 cells and may act as autocrine growth factors for small cell lung cancer. Here, the authors summarize their recent studies using bombesin-like peptides for elucidating the signal transduction pathways leading to mitogenesis and compare these pathways with those elicited by other growth factors

  3. Synaptic potentiation onto habenula neurons in learned helplessness model of depression

    Science.gov (United States)

    Li, Bo; Piriz, Joaquin; Mirrione, Martine; Chung, ChiHye; Proulx, Christophe D.; Schulz, Daniela; Henn, Fritz; Malinow, Roberto

    2010-01-01

    The cellular basis of depressive disorders is poorly understood1. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (i.e. disappointment or anticipation of a negative outcome)2, 3, 4. LHb neurons project to and modulate dopamine-rich regions such as the ventral-tegmental area (VTA)2, 5 that control reward-seeking behavior6 and participate in depressive disorders7. Here we show in two learned helplessness models of depression that excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal’s helplessness behavior and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective on depressed patients8, 9, dramatically suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behavior in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression. PMID:21350486

  4. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression.

    Science.gov (United States)

    Li, Bo; Piriz, Joaquin; Mirrione, Martine; Chung, ChiHye; Proulx, Christophe D; Schulz, Daniela; Henn, Fritz; Malinow, Roberto

    2011-02-24

    The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

  5. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression

    International Nuclear Information System (INIS)

    Li, B.; Schulz, D.; Piriz, J.; Mirrione, M.; Chung, C.H.; Proulx, C.D.; Schulz, D.; Henn, F.; Malinow, R.

    2011-01-01

    The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

  6. The Histone H3K27 Demethylase UTX Regulates Synaptic Plasticity and Cognitive Behaviors in Mice

    Directory of Open Access Journals (Sweden)

    Gang-Bin Tang

    2017-08-01

    Full Text Available Histone demethylase UTX mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3 to establish a mechanistic switch to activate large sets of genes. Mutation of Utx has recently been shown to be associated with Kabuki syndrome, a rare congenital anomaly syndrome with dementia. However, its biological function in the brain is largely unknown. Here, we observe that deletion of Utx results in increased anxiety-like behaviors and impaired spatial learning and memory in mice. Loss of Utx in the hippocampus leads to reduced long-term potentiation and amplitude of miniature excitatory postsynaptic current, aberrant dendrite development and defective synapse formation. Transcriptional profiling reveals that Utx regulates a subset of genes that are involved in the regulation of dendritic morphology, synaptic transmission, and cognition. Specifically, Utx deletion disrupts expression of neurotransmitter 5-hydroxytryptamine receptor 5B (Htr5b. Restoration of Htr5b expression in newborn hippocampal neurons rescues the defects of neuronal morphology by Utx ablation. Therefore, we provide evidence that Utx plays a critical role in modulating synaptic transmission and cognitive behaviors. Utx cKO mouse models like ours provide a valuable means to study the underlying mechanisms of the etiology of Kabuki syndrome.

  7. Synaptic Plasticity in Cardiac Innervation and Its Potential Role in Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Jesse L. Ashton

    2018-03-01

    Full Text Available Synaptic plasticity is defined as the ability of synapses to change their strength of transmission. Plasticity of synaptic connections in the brain is a major focus of neuroscience research, as it is the primary mechanism underpinning learning and memory. Beyond the brain however, plasticity in peripheral neurons is less well understood, particularly in the neurons innervating the heart. The atria receive rich innervation from the autonomic branch of the peripheral nervous system. Sympathetic neurons are clustered in stellate and cervical ganglia alongside the spinal cord and extend fibers to the heart directly innervating the myocardium. These neurons are major drivers of hyperactive sympathetic activity observed in heart disease, ventricular arrhythmias, and sudden cardiac death. Both pre- and postsynaptic changes have been observed to occur at synapses formed by sympathetic ganglion neurons, suggesting that plasticity at sympathetic neuro-cardiac synapses is a major contributor to arrhythmias. Less is known about the plasticity in parasympathetic neurons located in clusters on the heart surface. These neuronal clusters, termed ganglionated plexi, or “little brains,” can independently modulate neural control of the heart and stimulation that enhances their excitability can induce arrhythmia such as atrial fibrillation. The ability of these neurons to alter parasympathetic activity suggests that plasticity may indeed occur at the synapses formed on and by ganglionated plexi neurons. Such changes may not only fine-tune autonomic innervation of the heart, but could also be a source of maladaptive plasticity during atrial fibrillation.

  8. Exogenous ciliary neurotrophic factor (CNTF) reduces synaptic depression during repetitive stimulation.

    Science.gov (United States)

    Garcia, Neus; Santafé, Manel M; Tomàs, Marta; Priego, Mercedes; Obis, Teresa; Lanuza, Maria A; Besalduch, Nuria; Tomàs, Josep

    2012-09-01

    It has been shown that ciliary neurotrophic factor (CNTF) has trophic and maintenance effects on several types of peripheral and central neurons, glia, and cells outside the nervous system. Both CNTF and its receptor, CNTF-Rα, are expressed in the muscle. We use confocal immunocytochemistry to show that the trophic cytokine and its receptor are present in the pre- and post-synaptic sites of the neuromuscular junctions (NMJs). Applied CNTF (7.5-200 ng/ml, 60 min-3 h) does not acutely affect spontaneous potentials (size or frequency) or quantal content of the evoked acetylcholine release from post-natal (in weak or strong axonal inputs on dually innervated end plates or in the most mature singly innervated synapses at P6) or adult (P30) NMJ of Levator auris longus muscle of the mice. However, CNTF reduces roughly 50% the depression produced by repetitive stimulation (40 Hz, 2 min) on the adult NMJs. Our findings indicate that, unlike neurotrophins, exogenous CNTF does not acutely modulate transmitter release locally at the mammalian neuromuscular synapse but can protect mature end plates from activity-induced synaptic depression. © 2012 Peripheral Nerve Society.

  9. Signaling in Parasitic Nematodes: Physicochemical Communication Between Host and Parasite and Endogenous Molecular Transduction Pathways Governing Worm Development and Survival.

    Science.gov (United States)

    Lok, James B

    2016-12-01

    Signaling or communication between host and parasite may occur over relatively long ranges to enable host finding and acquisition by infective parasitic nematode larvae. Innate behaviors in infective larvae transmitted from the soil that enhance the likelihood of host contact, such as negative geotaxis and hypermotility, are likely mediated by mechanoreception and neuromuscular signaling. Host cues such as vibration of the substratum, elevated temperature, exhaled CO 2 , and other volatile odorants are perceived by mechanosensory and chemosensory neurons of the amphidial complex. Beyond this, the molecular systems that transduce these external cues within the worm are unknown at this time. Overall, the signal transduction mechanisms that regulate switching between dauer and continuous reproductive development in Caenorhabditis elegans , and doubtless other free-living nematodes, have provided a useful framework for testing hypotheses about how the morphogenesis and development of infective parasitic nematode larvae and the lifespan of adult parasites are regulated. In C. elegans , four major signal transduction pathways, G protein-coupled receptor signaling, insulin/insulin-like growth factor signaling, TGFβ-like signaling and steroid-nuclear hormone receptor signaling govern the switch between dauer and continuous development and regulate adult lifespan. Parasitic nematodes appear to have conserved the functions of G-protein-coupled signaling, insulin-like signaling and steroid-nuclear hormone receptor signaling to regulate larval development before and during the infective process. By contrast, TGFβ-like signaling appears to have been adapted for some other function, perhaps modulation of the host immune response. Of the three signal transduction pathways that appear to regulate development in parasitic nematodes, steroid-nuclear hormone signaling is the most straightforward to manipulate with administered small molecules and may form the basis of new

  10. Disruption of Microtubules Post-Virus Entry Enhances Adeno-Associated Virus Vector Transduction

    Science.gov (United States)

    Xiao, Ping-Jie; Mitchell, Angela M.; Huang, Lu; Li, Chengwen; Samulski, R. Jude

    2016-01-01

    Perinuclear retention of viral particles is a poorly understood phenomenon observed during many virus infections. In this study, we investigated whether perinuclear accumulation acts as a barrier to limit recombinant adeno-associated virus (rAAV) transduction. After nocodazole treatment to disrupt microtubules at microtubule-organization center (MT-MTOC) after virus entry, we observed higher rAAV transduction. To elucidate the role of MT-MTOC in rAAV infection and study its underlying mechanisms, we demonstrated that rAAV's perinuclear localization was retained by MT-MTOC with fluorescent analysis, and enhanced rAAV transduction from MT-MTOC disruption was dependent on the rAAV capsid's nuclear import signals. Interestingly, after knocking down RhoA or inhibiting its downstream effectors (ROCK and Actin), MT-MTOC disruption failed to increase rAAV transduction or nuclear entry. These data suggest that enhancement of rAAV transduction is the result of increased trafficking to the nucleus via the RhoA-ROCK-Actin pathway. Ten-fold higher rAAV transduction was also observed by disrupting MT-MTOC in brain, liver, and tumor in vivo. In summary, this study indicates that virus perinuclear accumulation at MT-MTOC is a barrier-limiting parameter for effective rAAV transduction and defines a novel defense mechanism by which host cells restrain viral invasion. PMID:26942476

  11. Microfluidic Transduction Harnesses Mass Transport Principles to Enhance Gene Transfer Efficiency.

    Science.gov (United States)

    Tran, Reginald; Myers, David R; Denning, Gabriela; Shields, Jordan E; Lytle, Allison M; Alrowais, Hommood; Qiu, Yongzhi; Sakurai, Yumiko; Li, William C; Brand, Oliver; Le Doux, Joseph M; Spencer, H Trent; Doering, Christopher B; Lam, Wilbur A

    2017-10-04

    Ex vivo gene therapy using lentiviral vectors (LVs) is a proven approach to treat and potentially cure many hematologic disorders and malignancies but remains stymied by cumbersome, cost-prohibitive, and scale-limited production processes that cannot meet the demands of current clinical protocols for widespread clinical utilization. However, limitations in LV manufacture coupled with inefficient transduction protocols requiring significant excess amounts of vector currently limit widespread implementation. Herein, we describe a microfluidic, mass transport-based approach that overcomes the diffusion limitations of current transduction platforms to enhance LV gene transfer kinetics and efficiency. This novel ex vivo LV transduction platform is flexible in design, easy to use, scalable, and compatible with standard cell transduction reagents and LV preparations. Using hematopoietic cell lines, primary human T cells, primary hematopoietic stem and progenitor cells (HSPCs) of both murine (Sca-1 + ) and human (CD34 + ) origin, microfluidic transduction using clinically processed LVs occurs up to 5-fold faster and requires as little as one-twentieth of LV. As an in vivo validation of the microfluidic-based transduction technology, HSPC gene therapy was performed in hemophilia A mice using limiting amounts of LV. Compared to the standard static well-based transduction protocols, only animals transplanted with microfluidic-transduced cells displayed clotting levels restored to normal. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  12. Beyond labels: A review of the application of quantum dots as integrated components of assays, bioprobes, and biosensors utilizing optical transduction

    Energy Technology Data Exchange (ETDEWEB)

    Algar, W. Russ; Tavares, Anthony J. [Chemical Sensors Group, Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario L5L 1C6 (Canada); Krull, Ulrich J., E-mail: ulrich.krull@utoronto.ca [Chemical Sensors Group, Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario L5L 1C6 (Canada)

    2010-07-12

    A comprehensive review of the development of assays, bioprobes, and biosensors using quantum dots (QDs) as integrated components is presented. In contrast to a QD that is selectively introduced as a label, an integrated QD is one that is present in a system throughout a bioanalysis, and simultaneously has a role in transduction and as a scaffold for biorecognition. Through a diverse array of coatings and bioconjugation strategies, it is possible to use QDs as a scaffold for biorecognition events. The modulation of QD luminescence provides the opportunity for the transduction of these events via fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), charge transfer quenching, and electrochemiluminescence (ECL). An overview of the basic concepts and principles underlying the use of QDs with each of these transduction methods is provided, along with many examples of their application in biological sensing. The latter include: the detection of small molecules using enzyme-linked methods, or using aptamers as affinity probes; the detection of proteins via immunoassays or aptamers; nucleic acid hybridization assays; and assays for protease or nuclease activity. Strategies for multiplexed detection are highlighted among these examples. Although the majority of developments to date have been in vitro, QD-based methods for ex vivo biological sensing are emerging. Some special attention is given to the development of solid-phase assays, which offer certain advantages over their solution-phase counterparts.

  13. Synaptic proteins and receptors defects in autism spectrum disorders

    Directory of Open Access Journals (Sweden)

    Jianling eChen

    2014-09-01

    Full Text Available Recent studies have found that hundreds of genetic variants, including common and rare variants, rare and de novo mutations, and common polymorphisms have contributed to the occurrence of autism spectrum disorders (ASDs. The mutations in a number of genes such as neurexin, neuroligin, postsynaptic density protein 95 (PSD-95, SH3 and multiple ankyrin repeat domains 3 (SHANK3, synapsin, gephyrin, cadherin (CDH and protocadherin (PCDH, thousand-and-one-amino acid 2 kinase (TAOK2, and contactin (CNTN, have been shown to play important roles in the development and function of synapses. In addition, synaptic receptors, such as gamma-aminobutyric acid (GABA receptors and glutamate receptors, have also been associated with ASDs. This review will primarily focus on the defects of synaptic proteins and receptors associated with ASDs and their roles in the pathogenesis of ASDs via synaptic pathways.

  14. Interregional synaptic maps among engram cells underlie memory formation.

    Science.gov (United States)

    Choi, Jun-Hyeok; Sim, Su-Eon; Kim, Ji-Il; Choi, Dong Il; Oh, Jihae; Ye, Sanghyun; Lee, Jaehyun; Kim, TaeHyun; Ko, Hyoung-Gon; Lim, Chae-Seok; Kaang, Bong-Kiun

    2018-04-27

    Memory resides in engram cells distributed across the brain. However, the site-specific substrate within these engram cells remains theoretical, even though it is generally accepted that synaptic plasticity encodes memories. We developed the dual-eGRASP (green fluorescent protein reconstitution across synaptic partners) technique to examine synapses between engram cells to identify the specific neuronal site for memory storage. We found an increased number and size of spines on CA1 engram cells receiving input from CA3 engram cells. In contextual fear conditioning, this enhanced connectivity between engram cells encoded memory strength. CA3 engram to CA1 engram projections strongly occluded long-term potentiation. These results indicate that enhanced structural and functional connectivity between engram cells across two directly connected brain regions forms the synaptic correlate for memory formation. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  15. Integrated neuron circuit for implementing neuromorphic system with synaptic device

    Science.gov (United States)

    Lee, Jeong-Jun; Park, Jungjin; Kwon, Min-Woo; Hwang, Sungmin; Kim, Hyungjin; Park, Byung-Gook

    2018-02-01

    In this paper, we propose and fabricate Integrate & Fire neuron circuit for implementing neuromorphic system. Overall operation of the circuit is verified by measuring discrete devices and the output characteristics of the circuit. Since the neuron circuit shows asymmetric output characteristic that can drive synaptic device with Spike-Timing-Dependent-Plasticity (STDP) characteristic, the autonomous weight update process is also verified by connecting the synaptic device and the neuron circuit. The timing difference of the pre-neuron and the post-neuron induce autonomous weight change of the synaptic device. Unlike 2-terminal devices, which is frequently used to implement neuromorphic system, proposed scheme of the system enables autonomous weight update and simple configuration by using 4-terminal synapse device and appropriate neuron circuit. Weight update process in the multi-layer neuron-synapse connection ensures implementation of the hardware-based artificial intelligence, based on Spiking-Neural- Network (SNN).

  16. PRRT2: from Paroxysmal Disorders to Regulation of Synaptic Function.

    Science.gov (United States)

    Valtorta, Flavia; Benfenati, Fabio; Zara, Federico; Meldolesi, Jacopo

    2016-10-01

    In the past few years, proline-rich transmembrane protein (PRRT)2 has been identified as the causative gene for several paroxysmal neurological disorders. Recently, an important role of PRRT2 in synapse development and function has emerged. Knock down of the protein strongly impairs the formation of synaptic contacts and neurotransmitter release. At the nerve terminal, PRRT2 endows synaptic vesicle exocytosis with Ca 2+ sensitivity by interacting with proteins of the fusion complex and with the Ca 2+ sensors synaptotagmins (Syts). In the postsynaptic compartment, PRRT2 interacts with glutamate receptors. The study of PRRT2 and of its mutations may help in refining our knowledge of the process of synaptic transmission and elucidating the pathogenetic mechanisms leading to derangement of network function in paroxysmal disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Synaptic clustering within dendrites: an emerging theory of memory formation

    Science.gov (United States)

    Kastellakis, George; Cai, Denise J.; Mednick, Sara C.; Silva, Alcino J.; Poirazi, Panayiota

    2015-01-01

    It is generally accepted that complex memories are stored in distributed representations throughout the brain, however the mechanisms underlying these representations are not understood. Here, we review recent findings regarding the subcellular mechanisms implicated in memory formation, which provide evidence for a dendrite-centered theory of memory. Plasticity-related phenomena which affect synaptic properties, such as synaptic tagging and capture, synaptic clustering, branch strength potentiation and spinogenesis provide the foundation for a model of memory storage that relies heavily on processes operating at the dendrite level. The emerging picture suggests that clusters of functionally related synapses may serve as key computational and memory storage units in the brain. We discuss both experimental evidence and theoretical models that support this hypothesis and explore its advantages for neuronal function. PMID:25576663

  18. Defective glycinergic synaptic transmission in zebrafish motility mutants

    Directory of Open Access Journals (Sweden)

    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.

  19. Precise synaptic efficacy alignment suggests potentiation dominated learning

    Directory of Open Access Journals (Sweden)

    Christoph eHartmann

    2016-01-01

    Full Text Available 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 in the morning than they are after sleep depriviation.In conclusion, we show that synaptic normalization in conjunction with

  20. Emergence of Functional Specificity in Balanced Networks with Synaptic Plasticity.

    Directory of Open Access Journals (Sweden)

    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

  1. Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants

    Science.gov (United States)

    Hirata, Hiromi; Carta, Eloisa; Yamanaka, Iori; Harvey, Robert J.; Kuwada, John Y.

    2009-01-01

    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. PMID:20161699

  2. Hardwiring of fine synaptic layers in the zebrafish visual pathway

    Directory of Open Access Journals (Sweden)

    Taylor Michael R

    2008-12-01

    Full Text Available Abstract Background Neuronal connections are often arranged in layers, which are divided into sublaminae harboring synapses with similar response properties. It is still debated how fine-grained synaptic layering is established during development. Here we investigated two stratified areas of the zebrafish visual pathway, the inner plexiform layer (IPL of the retina and the neuropil of the optic tectum, and determined if activity is required for their organization. Results The IPL of 5-day-old zebrafish larvae is composed of at least nine sublaminae, comprising the connections between different types of amacrine, bipolar, and ganglion cells (ACs, BCs, GCs. These sublaminae were distinguished by their expression of cell type-specific transgenic fluorescent reporters and immunohistochemical markers, including protein kinase Cβ (PKC, parvalbumin (Parv, zrf3, and choline acetyltransferase (ChAT. In the tectum, four retinal input layers abut a laminated array of neurites of tectal cells, which differentially express PKC and Parv. We investigated whether these patterns were affected by experimental disruptions of retinal activity in developing fish. Neither elimination of light inputs by dark rearing, nor a D, L-amino-phosphono-butyrate-induced reduction in the retinal response to light onset (but not offset altered IPL or tectal lamination. Moreover, thorough elimination of chemical synaptic transmission with Botulinum toxin B left laminar synaptic arrays intact. Conclusion Our results call into question a role for activity-dependent mechanisms – instructive light signals, balanced on and off BC activity, Hebbian plasticity, or a permissive role for synaptic transmission – in the synaptic stratification we examined. We propose that genetically encoded cues are sufficient to target groups of neurites to synaptic layers in this vertebrate visual system.

  3. Graph Regularized Meta-path Based Transductive Regression in Heterogeneous Information Network.

    Science.gov (United States)

    Wan, Mengting; Ouyang, Yunbo; Kaplan, Lance; Han, Jiawei

    2015-01-01

    A number of real-world networks are heterogeneous information networks, which are composed of different types of nodes and links. Numerical prediction in heterogeneous information networks is a challenging but significant area because network based information for unlabeled objects is usually limited to make precise estimations. In this paper, we consider a graph regularized meta-path based transductive regression model ( Grempt ), which combines the principal philosophies of typical graph-based transductive classification methods and transductive regression models designed for homogeneous networks. The computation of our method is time and space efficient and the precision of our model can be verified by numerical experiments.

  4. Synaptic model for spontaneous activity in developing networks

    DEFF Research Database (Denmark)

    Lerchner, Alexander; Rinzel, J.

    2005-01-01

    Spontaneous rhythmic activity occurs in many developing neural networks. The activity in these hyperexcitable networks is comprised of recurring "episodes" consisting of "cycles" of high activity that alternate with "silent phases" with little or no activity. We introduce a new model of synaptic...... dynamics that takes into account that only a fraction of the vesicles stored in a synaptic terminal is readily available for release. We show that our model can reproduce spontaneous rhythmic activity with the same general features as observed in experiments, including a positive correlation between...

  5. Kalirin Binds the NR2B Subunit of the NMDA Receptor, Altering Its Synaptic Localization and Function

    KAUST Repository

    Kiraly, D. D.

    2011-08-31

    The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins, including PSD-95, DISC-1, AF-6, and Arf6. Mice genetically lacking Kal7 (Kal7KO) exhibit deficient hippocampal long-term potentiation (LTP) as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7KO mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7KO animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7KO mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.

  6. Kalirin Binds the NR2B Subunit of the NMDA Receptor, Altering Its Synaptic Localization and Function

    KAUST Repository

    Kiraly, D. D.; Lemtiri-Chlieh, Fouad; Levine, E. S.; Mains, R. E.; Eipper, B. A.

    2011-01-01

    The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins, including PSD-95, DISC-1, AF-6, and Arf6. Mice genetically lacking Kal7 (Kal7KO) exhibit deficient hippocampal long-term potentiation (LTP) as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7KO mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7KO animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7KO mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.

  7. Cryptochromes and Hormone Signal Transduction under Near-Zero Magnetic Fields: New Clues to Magnetic Field Effects in a Rice Planthopper.

    Directory of Open Access Journals (Sweden)

    Gui-Jun Wan

    Full Text Available Although there are considerable reports of magnetic field effects (MFE on organisms, very little is known so far about the MFE-related signal transduction pathways. Here we establish a manipulative near-zero magnetic field (NZMF to investigate the potential signal transduction pathways involved in MFE. We show that exposure of migratory white-backed planthopper, Sogatella furcifera, to the NZMF results in delayed egg and nymphal development, increased frequency of brachypterous females, and reduced longevity of macropterous female adults. To understand the changes in gene expression underlying these phenotypes, we examined the temporal patterns of gene expression of (i CRY1 and CRY2 as putative magnetosensors, (ii JHAMT, FAMeT and JHEH in the juvenile hormone pathway, (iii CYP307A1 in the ecdysone pathway, and (iv reproduction-related Vitellogenin (Vg. The significantly altered gene expression of CRY1 and CRY2 under the NZMF suggest their developmental stage-specific patterns and potential upstream location in magnetic response. Gene expression patterns of JHAMT, JHEH and CYP307A1 were consistent with the NZMF-triggered delay in nymphal development, higher proportion of brachypterous female adults, and the shortened longevity of macropterous female adults, which show feasible links between hormone signal transduction and phenotypic MFE. By conducting manipulative NZMF experiments, our study suggests an important role of the geomagnetic field (GMF in modulating development and physiology of insects, provides new insights into the complexity of MFE-magnetosensitivity interactions, and represents an initial but crucial step forward in understanding the molecular basis of cryptochromes and hormone signal transduction involved in MFE.

  8. Interaction between protein kinase C and protein kinase A can modulate transmitter release at the rat neuromuscular synapse.

    Science.gov (United States)

    Santafé, M M; Garcia, N; Lanuza, M A; Tomàs, M; Tomàs, J

    2009-02-15

    We used intracellular recording to investigate the functional interaction between protein kinase C (PKC) and protein kinase A (PKA) signal transduction cascades in the control of transmitter release in the neuromuscular synapses from adult rats. Our results indicate that: 1) PKA and PKC are independently involved in asynchronous release. 2) Evoked acetylcholine (ACh) release is enhanced with the PKA agonist Sp-8-BrcAMP and the PKC agonist phorbol ester (PMA). 3) PKA has a constitutive role in promoting a component of normal evoked transmitter release because, when the kinase is inhibited with H-89, the release diminishes. However, the PKC inhibitor calphostin C (CaC) does not affect ACh release. 4) PKA regulates neurotransmission without PKC involvement because, after PMA or CaC modulation of the PKC activity, coupling to the ACh release of PKA can normally be stimulated with Sp-8-BrcAMP or inhibited with H-89. 5) After PKA inhibition with H-89, PKC stimulation with PMA (or inhibition with CaC) does not lead to any change in evoked ACh release. However, in PKA-stimulated preparations with Sp-8-BrcAMP, PKC becomes tonically active, thus potentiating a component of release that can now be blocked with CaC. In normal conditions, therefore, PKA was able to modulate ACh release independently of PKC activity, whereas PKA stimulation caused the PKC coupling to evoked release. In contrast, PKA inhibition prevent PKC stimulation (with the phorbol ester) and coupling to ACh output. There was therefore some dependence of PKC on PKA activity in the fine control of the neuromuscular synaptic functionalism and ACh release.

  9. Glia co-culture with neurons in microfluidic platforms promotes the formation and stabilization of synaptic contacts.

    Science.gov (United States)

    Shi, Mingjian; Majumdar, Devi; Gao, Yandong; Brewer, Bryson M; Goodwin, Cody R; McLean, John A; Li, Deyu; Webb, Donna J

    2013-08-07

    Two novel microfluidic cell culture schemes, a vertically-layered set-up and a four chamber set-up, were developed for co-culturing central nervous system (CNS) neurons and glia. The cell chambers in these devices were separated by pressure-enabled valve barriers, which permitted us to control communication between the two cell types. The unique design of these devices facilitated the co-culture of glia with neurons in close proximity (∼50-100 μm), differential transfection of neuronal populations, and dynamic visualization of neuronal interactions, such as the development of synapses. With these co-culture devices, initial synaptic contact between neurons transfected with different fluorescent markers, such as green fluorescent protein (GFP) and mCherry-synaptophysin, was imaged using high-resolution fluorescence microscopy. The presence of glial cells had a profound influence on synapses by increasing the number and stability of synaptic contacts. Interestingly, as determined by liquid chromatography-ion mobility-mass spectrometry, neuron-glia co-cultures produced elevated levels of soluble factors compared to that secreted by individual neuron or glia cultures, suggesting a potential mechanism by which neuron-glia interactions could modulate synaptic function. Collectively, these results show that communication between neurons and glia is critical for the formation and stability of synapses and point to the importance of developing neuron-glia co-culture systems such as the microfluidic platforms described in this study.

  10. Corticosterone rapidly increases thorns of CA3 neurons via synaptic/extranuclear glucocorticoid receptor in rat hippocampus

    Directory of Open Access Journals (Sweden)

    Miyuki eYoshiya

    2013-11-01

    Full Text Available Modulation of synapses under acute stress is attracting much attention. Exposure to acute stress induces corticosterone (CORT secretion from the adrenal cortex, resulting in rapid increase of CORT levels in plasma and the hippocampus. We tried to test whether rapid CORT effects involve activation of essential kinases as non-genomic processes.We demonstrated rapid effects (~ 1 h of CORT on the density of thorns, by imaging Lucifer Yellow-injected neurons in adult male rat hippocampal slices. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. The application of CORT at 100, 500 and 1000 nM induced a rapid increase in the density of thorns in the stratum lucidum of CA3 pyramidal neurons. Co-administration of RU486, an antagonist of glucocorticoid receptor (GR, abolished the effect of CORT. Blocking a single kinase, including MAPK, PKA or PKC, suppressed CORT-induced enhancement of thorn-genesis. On the other hand, GSK-3β was not involved in the signaling of thorn-genesis. Blocking AMPA receptors suppressed the CORT effect. Expression of CA3 synaptic/extranuclear GR was demonstrated by immunogold electron microscopic analysis. From these results, stress levels of CORT (100-1000 nM might drive the rapid thorn-genesis via synaptic/extranuclear GR and multiple kinase pathways, although a role of nuclear GRs cannot be completely excluded.

  11. Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy.

    Science.gov (United States)

    Bhaskaran, Muthu D; Smith, Bret N

    2010-06-01

    Temporal lobe epilepsy (TLE) is a condition characterized by an imbalance between excitation and inhibition in the temporal lobe. Hallmarks of this change are axon sprouting and accompanying synaptic reorganization in the temporal lobe. Synthetic and endogenous cannabinoids have variable therapeutic potential in treating intractable temporal lobe epilepsy, in part because cannabinoid ligands can bind multiple receptor types. This study utilized in vitro electrophysiological methods to examine the effect of transient receptor potential vanilloid type 1 (TRPV1) activation in dentate gyrus granule cells in a murine model of TLE. Capsaicin, a selective TRPV1 agonist had no measurable effect on overall synaptic input to granule cells in control animals, but significantly enhanced spontaneous and miniature EPSC frequency in mice with TLE. Exogenous application of anandamide, an endogenous cannabinoid that acts at both TRPV1 and cannabinoid type 1 receptors (CB1R), also enhanced glutamate release in the presence of a CB1R antagonist. Anandamide reduced the EPSC frequency when TRPV1 were blocked with capsazepine. Western blot analysis of TRPV1 receptor indicated protein expression was significantly greater in the dentate gyrus of mice with TLE compared with control mice. This study indicates that a prominent cannabinoid agonist can increase excitatory circuit activity in the synaptically reorganized dentate gyrus of mice with TLE by activating TRPV1 receptors, and suggests caution in designing anticonvulsant therapy based on modulating the endocannabinoid system. Copyright (c) 2009 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Sarah X. Luo

    2016-12-01

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

  13. Synaptic excitation in spinal motoneurons alternates with synaptic inhibition and is balanced by outward rectification during rhythmic motor network activity

    DEFF Research Database (Denmark)

    Guzulaitis, Robertas; Hounsgaard, Jorn

    2017-01-01

    channels. Intrinsic outward rectification facilitates spiking by focusing synaptic depolarization near threshold for action potentials. By direct recording of synaptic currents, we also show that motoneurons are activated by out-of-phase peaks in excitation and inhibition during network activity, whereas......Regular firing in spinal motoneurons of red-eared turtles (Trachemys scripta elegans, either sex) evoked by steady depolarization at rest is replaced by irregular firing during functional network activity. The transition caused by increased input conductance and synaptic fluctuations in membrane...... potential was suggested to originate from intense concurrent inhibition and excitation. We show that the conductance increase in motoneurons during functional network activity is mainly caused by intrinsic outward rectification near threshold for action potentials by activation of voltage and Ca2+ gated K...

  14. Proteolytic Remodeling of Perineuronal Nets: Effects on Synaptic Plasticity and Neuronal Population Dynamics

    Directory of Open Access Journals (Sweden)

    P. Lorenzo Bozzelli

    2018-01-01

    Full Text Available The perineuronal net (PNN represents a lattice-like structure that is prominently expressed along the soma and proximal dendrites of parvalbumin- (PV- positive interneurons in varied brain regions including the cortex and hippocampus. It is thus apposed to sites at which PV neurons receive synaptic input. Emerging evidence suggests that changes in PNN integrity may affect glutamatergic input to PV interneurons, a population that is critical for the expression of synchronous neuronal population discharges that occur with gamma oscillations and sharp-wave ripples. The present review is focused on the composition of PNNs, posttranslation modulation of PNN components by sulfation and proteolysis, PNN alterations in disease, and potential effects of PNN remodeling on neuronal plasticity at the single-cell and population level.

  15. Fast voltage-sensitive dye imaging of excitatory and inhibitory synaptic transmission in the rat granular retrosplenial cortex.

    Science.gov (United States)

    Nixima, Ken'ichi; Okanoya, Kazuo; Ichinohe, Noritaka; Kurotani, Tohru

    2017-09-01

    Rodent granular retrosplenial cortex (GRS) has dense connections between the anterior thalamic nuclei (ATN) and hippocampal formation. GRS superficial pyramidal neurons exhibit distinctive late spiking (LS) firing property and form patchy clusters with prominent apical dendritic bundles. The aim of this study was to investigate spatiotemporal dynamics of signal transduction in the GRS induced by ATN afferent stimulation by using fast voltage-sensitive dye imaging in rat brain slices. In coronal slices, layer 1a stimulation, which presumably activated thalamic fibers, evoked propagation of excitatory synaptic signals from layers 2-4 to layers 5-6 in a direction perpendicular to the layer axis, followed by transverse signal propagation within each layer. In the presence of ionotropic glutamate receptor antagonists, inhibitory responses were observed in superficial layers, induced by direct activation of inhibitory interneurons in layer 1. In horizontal slices, excitatory signals in deep layers propagated transversely mainly from posterior to anterior via superficial layers. Cortical inhibitory responses upon layer 1a stimulation in horizontal slices were weaker than those in the coronal slices. Observed differences between coronal and horizontal planes suggest anisotropy of the intracortical circuitry. In conclusion, ATN inputs are processed differently in coronal and horizontal planes of the GRS and then conveyed to other cortical areas. In both planes, GRS superficial layers play an important role in signal propagation, which suggests that superficial neuronal cascade is crucial in the integration of multiple information sources. NEW & NOTEWORTHY Superficial neurons in the rat granular retrosplenial cortex (GRS) show distinctive late-spiking (LS) firing property. However, little is known about spatiotemporal dynamics of signal transduction in the GRS. We demonstrated LS neuron network relaying thalamic inputs to deep layers and anisotropic distribution of

  16. Signal transduction through the IL-4 and insulin receptor families.

    Science.gov (United States)

    Wang, L M; Keegan, A; Frankel, M; Paul, W E; Pierce, J H

    1995-07-01

    Activation of tyrosine kinase-containing receptors and intracellular tyrosine kinases by ligand stimulation is known to be crucial for mediating initial and subsequent events involved in mitogenic signal transduction. Receptors for insulin and insulin-like growth factor 1 (IGF-1) contain cytoplasmic tyrosine kinase domains that undergo autophosphorylation upon ligand stimulation. Activation of these receptors also leads to pronounced and rapid tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells of connective tissue origin. A related substrate, designated 4PS, is similarly phosphorylated by insulin and IGF-1 stimulation in many hematopoietic cell types. IRS-1 and 4PS possess a number of tyrosine phosphorylation sites that are within motifs that bind specific SH2-containing molecules known to be involved in mitogenic signaling such as PI-3 kinase, SHPTP-2 (Syp) and Grb-2. Thus, they appear to act as docking substrates for a variety of signaling molecules. The majority of hematopoietic cytokines bind to receptors that do not possess intrinsic kinase activity, and these receptors have been collectively termed as members of the hematopoietin receptor superfamily. Despite their lack of tyrosine kinase domains, stimulation of these receptors has been demonstrated to activate intracellular kinases leading to tyrosine phosphorylation of multiple substrates. Recent evidence has demonstrated that activation of different members of the Janus family of tyrosine kinases is involved in mediating tyrosine phosphorylation events by specific cytokines. Stimulation of the interleukin 4 (IL-4) receptor, a member of the hematopoietin receptor superfamily, is thought to result in activation of Jak1, Jak3, and/or Fes tyrosine kinases.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Computational study of noise in a large signal transduction network

    Directory of Open Access Journals (Sweden)

    Ruohonen Keijo

    2011-06-01

    Full Text Available Abstract Background Biochemical systems are inherently noisy due to the discrete reaction events that occur in a random manner. Although noise is often perceived as a disturbing factor, the system might actually benefit from it. In order to understand the role of noise better, its quality must be studied in a quantitative manner. Computational analysis and modeling play an essential role in this demanding endeavor. Results We implemented a large nonlinear signal transduction network combining protein kinase C, mitogen-activated protein kinase, phospholipase A2, and β isoform of phospholipase C networks. We simulated the network in 300 different cellular volumes using the exact Gillespie stochastic simulation algorithm and analyzed the results in both the time and frequency domain. In order to perform simulations in a reasonable time, we used modern parallel computing techniques. The analysis revealed that time and frequency domain characteristics depend on the system volume. The simulation results also indicated that there are several kinds of noise processes in the network, all of them representing different kinds of low-frequency fluctuations. In the simulations, the power of noise decreased on all frequencies when the system volume was increased. Conclusions We concluded that basic frequency domain techniques can be applied to the analysis of simulation results produced by the Gillespie stochastic simulation algorithm. This approach is suited not only to the study of fluctuations but also to the study of pure noise processes. Noise seems to have an important role in biochemical systems and its properties can be numerically studied by simulating the reacting system in different cellular volumes. Parallel computing techniques make it possible to run massive simulations in hundreds of volumes and, as a result, accurate statistics can be obtained from computational studies.

  18. Transduction-like gene transfer in the methanogen Methanococcus voltae

    Science.gov (United States)

    Bertani, G.

    1999-01-01

    Strain PS of Methanococcus voltae (a methanogenic, anaerobic archaebacterium) was shown to generate spontaneously 4.4-kbp chromosomal DNA fragments that are fully protected from DNase and that, upon contact with a cell, transform it genetically. This activity, here called VTA (voltae transfer agent), affects all markers tested: three different auxotrophies (histidine, purine, and cobalamin) and resistance to BES (2-bromoethanesulfonate, an inhibitor of methanogenesis). VTA was most effectively prepared by culture filtration. This process disrupted a fraction of the M. voltae cells (which have only an S-layer covering their cytoplasmic membrane). VTA was rapidly inactivated upon storage. VTA particles were present in cultures at concentrations of approximately two per cell. Gene transfer activity varied from a minimum of 2 x 10(-5) (BES resistance) to a maximum of 10(-3) (histidine independence) per donor cell. Very little VTA was found free in culture supernatants. The phenomenon is functionally similar to generalized transduction, but there is no evidence, for the time being, of intrinsically viral (i.e., containing a complete viral genome) particles. Consideration of VTA DNA size makes the existence of such viral particles unlikely. If they exist, they must be relatively few in number;perhaps they differ from VTA particles in size and other properties and thus escaped detection. Digestion of VTA DNA with the AluI restriction enzyme suggests that it is a random sample of the bacterial DNA, except for a 0.9-kbp sequence which is amplified relative to the rest of the bacterial chromosome. A VTA-sized DNA fraction was demonstrated in a few other isolates of M. voltae.

  19. Transduction on Directed Graphs via Absorbing Random Walks.

    Science.gov (United States)

    De, Jaydeep; Zhang, Xiaowei; Lin, Feng; Cheng, Li

    2017-08-11

    In this paper we consider the problem of graph-based transductive classification, and we are particularly interested in the directed graph scenario which is a natural form for many real world applications.Different from existing research efforts that either only deal with undirected graphs or circumvent directionality by means of symmetrization, we propose a novel random walk approach on directed graphs using absorbing Markov chains, which can be regarded as maximizing the accumulated expected number of visits from the unlabeled transient states. Our algorithm is simple, easy to implement, and works with large-scale graphs on binary, multiclass, and multi-label prediction problems. Moreover, it is capable of preserving the graph structure even when the input graph is sparse and changes over time, as well as retaining weak signals presented in the directed edges. We present its intimate connections to a number of existing methods, including graph kernels, graph Laplacian based methods, and interestingly, spanning forest of graphs. Its computational complexity and the generalization error are also studied. Empirically our algorithm is systematically evaluated on a wide range of applications, where it has shown to perform competitively comparing to a suite of state-of-the-art methods. In particular, our algorithm is shown to work exceptionally well with large sparse directed graphs with e.g. millions of nodes and tens of millions of edges, where it significantly outperforms other state-of-the-art methods. In the dynamic graph setting involving insertion or deletion of nodes and edge-weight changes over time, it also allows efficient online updates that produce the same results as of the batch update counterparts.

  20. Radiation-induced adaptive response and intracellular signal transduction pathways

    International Nuclear Information System (INIS)

    Tachibana, Akira

    2009-01-01

    As an essential biological function, cells can sense the radiation even at low dose and respond to it, and which is one of bases of the radiation-induced adaptive response (AR) where effects caused by high dose radiation are reduced by prior exposure to low dose radiation (LDR). Here described are studies of AR in well established m5S cells on the intracellular signal transduction that involves sensing of LDR and transmitting of its signal within the cell network. The first signal for AR yielded by LDR on the cell membrane is exactly unknown though hydrogen peroxide and phorbol ester (PMA) can reportedly cause AR. As PMA activates protein kinase C (PKC) and its inhibitors suppress AR, participation of PKC in AR has been suggested and supported by studies showing PKCα activation by LDR. In addition, p38 mitogen-activated protein kinase (MAPK) is shown to participate in AR by those facts that the enzyme is activated by LDR, a p38 MAPK inhibitor suppresses AR, and PKC inhibitors suppress the enzyme activation, which also suggesting that the signaling from PKC to p38 MAPK can become operative by LDR. However, the possible reverse signaling is also suggested, and thus the activation of positive feedback mechanism is postulated in PKC/p38 MAPK/phospholipase δ1/ PKC pathway. Cells introduced with siRNA against Prkca gene (coding PKCs) produce reduced amount of the enzyme, particularly, of PKCα. In those cells, AR by 5 Gy X-ray is not observed and thereby PKCα is involved in AR. The signaling in AR is only partly elucidated at present as above, and more detailed studies including identification of more PKC subtypes and signaling to DNA repair system are considered necessary. (K.T.)

  1. Second-chance signal transduction explains cooperative flagellar switching.

    Science.gov (United States)

    Zot, Henry G; Hasbun, Javier E; Minh, Nguyen Van

    2012-01-01

    The reversal of flagellar motion (switching) results from the interaction between a switch complex of the flagellar rotor and a torque-generating stationary unit, or stator (motor unit). To explain the steeply cooperative ligand-induced switching, present models propose allosteric interactions between subunits of the rotor, but do not address the possibility of a reaction that stimulates a bidirectional motor unit to reverse direction of torque. During flagellar motion, the binding of a ligand-bound switch complex at the dwell site could excite a motor unit. The probability that another switch complex of the rotor, moving according to steady-state rotation, will reach the same dwell site before that motor unit returns to ground state will be determined by the independent decay rate of the excited-state motor unit. Here, we derive an analytical expression for the energy coupling between a switch complex and a motor unit of the stator complex of a flagellum, and demonstrate that this model accounts for the cooperative switching response without the need for allosteric interactions. The analytical result can be reproduced by simulation when (1) the motion of the rotor delivers a subsequent ligand-bound switch to the excited motor unit, thereby providing the excited motor unit with a second chance to remain excited, and (2) the outputs from multiple independent motor units are constrained to a single all-or-none event. In this proposed model, a motor unit and switch complex represent the components of a mathematically defined signal transduction mechanism in which energy coupling is driven by steady-state and is regulated by stochastic ligand binding. Mathematical derivation of the model shows the analytical function to be a general form of the Hill equation (Hill AV (1910) The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 40: iv-vii).

  2. Spike Pattern Structure Influences Synaptic Efficacy Variability Under STDP and Synaptic Homeostasis. I: Spike Generating Models on Converging Motifs

    Directory of Open Access Journals (Sweden)

    Zedong eBi

    2016-02-01

    Full Text Available In neural systems, synaptic plasticity is usually driven by spike trains. Due to the inherent noises of neurons and synapses as well as the randomness of connection details, spike trains typically exhibit variability such as spatial randomness and temporal stochasticity, resulting in variability of synaptic changes under plasticity, which we call efficacy variability. How the variability of spike trains influences the efficacy variability of synapses remains unclear. In this paper, we try to understand this influence under pair-wise additive spike-timing dependent plasticity (STDP when the mean strength of plastic synapses into a neuron is bounded (synaptic homeostasis. Specifically, we systematically study, analytically and numerically, how four aspects of statistical features, i.e. synchronous firing, burstiness/regularity, heterogeneity of rates and heterogeneity of cross-correlations, as well as their interactions influence the efficacy variability in converging motifs (simple networks in which one neuron receives from many other neurons. Neurons (including the post-synaptic neuron in a converging motif generate spikes according to statistical models with tunable parameters. In this way, we can explicitly control the statistics of the spike patterns, and investigate their influence onto the efficacy variability, without worrying about the feedback from synaptic changes onto the dynamics of the post-synaptic neuron. We separate efficacy variability into two parts: the drift part (DriftV induced by the heterogeneity of change rates of different synapses, and the diffusion part (DiffV induced by weight diffusion caused by stochasticity of spike trains. Our main findings are: (1 synchronous firing and burstiness tend to increase DiffV, (2 heterogeneity of rates induces DriftV when potentiation and depression in STDP are not balanced, and (3 heterogeneity of cross-correlations induces DriftV together with heterogeneity of rates. We anticipate our

  3. Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism.

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    Fruzsina Soltész

    Full Text Available Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such "synaptogenic" therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load on electrophysiological (EEG markers of synaptic activity and their structural (MRI correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met. Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN; and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early

  4. Plasticity resembling spike-timing dependent synaptic plasticity: the evidence in human cortex

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    Florian Müller-Dahlhaus

    2010-07-01

    Full Text Available Spike-timing dependent plasticity (STDP has been studied extensively in a variety of animal models during the past decade but whether it can be studied at the systems level of the human cortex has been a matter of debate. Only recently newly developed non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS have made it possible to induce and assess timing dependent plasticity in conscious human subjects. This review will present a critical synopsis of these experiments, which suggest that several of the principal characteristics and molecular mechanisms of TMS-induced plasticity correspond to those of STDP as studied at a cellular level. TMS combined with a second phasic stimulation modality can induce bidirectional long-lasting changes in the excitability of the stimulated cortex, whose polarity depends on the order of the associated stimulus-evoked events within a critical time window of tens of milliseconds. Pharmacological evidence suggests an NMDA receptor mediated form of synaptic plasticity. Studies in human motor cortex demonstrated that motor learning significantly modulates TMS-induced timing dependent plasticity, and, conversely, may be modulated bidirectionally by prior TMS-induced plasticity, providing circumstantial evidence that long-term potentiation-like mechanisms may be involved in motor learning. In summary, convergent evidence is being accumulated for the contention that it is now possible to induce STDP-like changes in the intact human central nervous system by means of TMS to study and interfere with synaptic plasticity in neural circuits in the context of behaviour such as learning and memory.

  5. Multidrug resistance and retroviral transduction potential in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Theilade, M D; Gram, G J; Jensen, P B

    1999-01-01

    Multidrug resistance (MDR) remains a major problem in the successful treatment of small cell lung cancer (SCLC). New treatment strategies are needed, such as gene therapy specifically targeting the MDR cells in the tumor. Retroviral LacZ gene-containing vectors that were either pseudotyped...... for the gibbon ape leukemia virus (GALV-1) receptor or had specificity for the amphotropic murine leukemia virus (MLV-A) receptor were used for transduction of five SCLC cell lines differing by a range of MDR mechanisms. Transduction efficiencies in these cell lines were compared by calculating the percentage...... of blue colonies after X-Gal staining of the cells grown in soft agar. All examined SCLC cell lines were transducible with either vector. Transduction efficiencies varied from 5.7% to 33.5% independent of the presence of MDR. These results indicate that MDR does not severely impair transduction of SCLC...

  6. Efficient, Broadband and Wide-Angle Hot-Electron Transduction using Metal-Semiconductor Hyperbolic Metamaterials

    KAUST Repository

    Sakhdari, Maryam; Hajizadegan, Mehdi; Farhat, Mohamed; Chen, Pai-Yen

    2016-01-01

    Hot-electron devices are emerging as promising candidates for the transduction of optical radiation into electrical current, as they enable photodetection and solar/infrared energy harvesting at sub-bandgap wavelengths. Nevertheless, poor

  7. [Cellular adhesion signal transduction network of tumor necrosis factor-alpha induced hepatocellular carcinoma cells].

    Science.gov (United States)

    Zheng, Yongchang; Du, Shunda; Xu, Haifeng; Xu, Yiyao; Zhao, Haitao; Chi, Tianyi; Lu, Xin; Sang, Xinting; Mao, Yilei

    2014-11-18

    To systemically explore the cellular adhesion signal transduction network of tumor necrosis factor-alpha (TNF-α)-induced hepatocellular carcinoma cells with bioinformatics tools. Published microarray dataset of TNF-α-induced HepG2, human transcription factor database HTRI and human protein-protein interaction database HPRD were used to construct and analyze the signal transduction network. In the signal transduction network, MYC and SP1 were the key nodes of signaling transduction. Several genes from the network were closely related with cellular adhesion.Epidermal growth factor receptor (EGFR) is a possible key gene of effectively regulating cellular adhesion during the induction of TNF-α. EGFR is a possible key gene for TNF-α-induced metastasis of hepatocellular carcinoma.

  8. A Ca2+-based computational model for NDMA receptor-dependent synaptic plasticity at individual post-synaptic spines in the hippocampus

    Directory of Open Access Journals (Sweden)

    Owen Rackham

    2010-07-01

    Full Text Available Associative synaptic plasticity is synapse specific and requires coincident activity in presynaptic and postsynaptic neurons to activate NMDA receptors (NMDARs. The resultant Ca2+ influx is the critical trigger for the induction of synaptic plasticity. Given its centrality for the induction of synaptic plasticity, a model for NMDAR activation incorporating the timing of presynaptic glutamate release and postsynaptic depolarization by back-propagating action potentials could potentially predict the pre- and post-synaptic spike patterns required to induce synaptic plasticity. We have developed such a model by incorporating currently available data on the timecourse and amplitude of the postsynaptic membrane potential within individual spines. We couple this with data on the kinetics of synaptic NMDARs and then use the model to predict the continuous spine [Ca2+] in response to regular or irregular pre- and post-synaptic spike patterns. We then incorporate experimental data from synaptic plasticity induction protocols by regular activity patterns to couple the predicted local peak [Ca2+] to changes in synaptic strength. We find that our model accurately describes [Ca2+] in dendritic spines resulting from NMDAR activation during presynaptic and postsynaptic activity when compared to previous experimental observations. The model also replicates the experimentally determined plasticity outcome of regular and irregular spike patterns when applied to a single synapse. This model could therefore be used to predict the induction of synaptic plasticity under a variety of experimental conditions and spike patterns.

  9. Cell surface receptors for signal transduction and ligand transport: a design principles study.

    Directory of Open Access Journals (Sweden)

    Harish Shankaran

    2007-06-01

    Full Text Available Receptors constitute the interface of cells to their external environment. These molecules bind specific ligands involved in multiple processes, such as signal transduction and nutrient transport. Although a variety of cell surface receptors undergo endocytosis, the systems-level design principles that govern the evolution of receptor trafficking dynamics are far from fully understood. We have constructed a generalized mathematical model of receptor-ligand binding and internalization to understand how receptor internalization dynamics encodes receptor function and regulation. A given signaling or transport receptor system represents a particular implementation of this module with a specific set of kinetic parameters. Parametric analysis of the response of receptor systems to ligand inputs reveals that receptor systems can be characterized as being: i avidity-controlled where the response control depends primarily on the extracellular ligand capture efficiency, ii consumption-controlled where the ability to internalize surface-bound ligand is the primary control parameter, and iii dual-sensitivity where both the avidity and consumption parameters are important. We show that the transferrin and low-density lipoprotein receptors are avidity-controlled, the vitellogenin receptor is consumption-controlled, and the epidermal growth factor receptor is a dual-sensitivity receptor. Significantly, we show that ligand-induced endocytosis is a mechanism to enhance the accuracy of signaling receptors rather than merely serving to attenuate signaling. Our analysis reveals that the location of a receptor system in the avidity-consumption parameter space can be used to understand both its function and its regulation.

  10. Highly efficient transduction of human plasmacytoid dendritic cells without phenotypic and functional maturation

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    Plumas Joel

    2009-01-01

    Full Text Available Abstract Background Gene modified dendritic cells (DC are able to modulate DC functions and induce therapeutic immunity or tolerance in an antigen-specific manner. Among the different DC subsets, plasmacytoid DC (pDC are well known for their ability to recognize and respond to a variety of viruses by secreting high levels of type I interferon. Methods We analyzed here, the transduction efficiency of a pDC cell line, GEN2.2, and of pDC derived from CD34+ progenitors, using lentiviral vectors (LV pseudotyped with different envelope glycoproteins such as the vesicular stomatitis virus envelope (VSVG, the gibbon ape leukaemia virus envelope (GaLV or the feline endogenous virus envelope (RD114. At the same time, we evaluated transgene expression (E-GFP reporter gene under the control of different promoters. Results We found that efficient gene transfer into pDC can be achieved with VSVG-pseudotyped lentiviral vectors (LV under the control of phoshoglycerate kinase (PGK and elongation factor-1 (EF1α promoters (28% to 90% of E-GFP+ cells, respectively in the absence of phenotypic and functional maturation. Surprisingly, promoters (desmin or synthetic C5–12 described as muscle-specific and which drive gene expression in single strand AAV vectors in gene therapy protocols were very highly active in pDC using VSVG-LV. Conclusion Taken together, our results indicate that LV vectors can serve to design pDC-based vaccines in humans, and they are also useful in vitro to evaluate the immunogenicity of the vector preparations, and the specificity and safety of given promoters used in gene therapy protocols.

  11. Thoracic spinal cord and cervical vagosympathetic neuromodulation obtund nodose sensory transduction of myocardial ischemia.

    Science.gov (United States)

    Salavatian, Siamak; Beaumont, Eric; Gibbons, David; Hammer, Matthew; Hoover, Donald B; Armour, J Andrew; Ardell, Jeffrey L

    2017-12-01

    Autonomic regulation therapy involving either vagus nerve stimulation (VNS) or spinal cord stimulation (SCS) represents emerging bioelectronic therapies for heart disease. The objective of this study was to determine if VNS and/or SCS modulate primary cardiac afferent sensory transduction of the ischemic myocardium. Using extracellular recordings in 19 anesthetized canines, of 88 neurons evaluated, 36 ventricular-related nodose ganglia sensory neurons were identified by their functional activity responses to epicardial touch, chemical activation of their sensory neurites (epicardial veratridine) and great vessel (descending aorta or inferior vena cava) occlusion. Neural responses to 1min left anterior descending (LAD) coronary artery occlusion (CAO) were then evaluated. These interventions were then studied following either: i) SCS [T1-T3 spinal level; 50Hz, 90% motor threshold] or ii) cervical VNS [15-20Hz; 1.2× threshold]. LAD occlusion activated 66% of identified nodose ventricular sensory neurons (0.33±0.08-0.79±0.20Hz; baseline to CAO; p<0.002). Basal activity of cardiac-related nodose neurons was differentially reduced by VNS (0.31±0.11 to 0.05±0.02Hz; p<0.05) as compared to SCS (0.36±0.12 to 0.28±0.14, p=0.59), with their activity response to transient LAD CAO being suppressed by either SCS (0.85±0.39-0.11±0.04Hz; p<0.03) or VNS (0.75±0.27-0.12±0.05Hz; p<0.04). VNS did not alter evoked neural responses of cardiac-related nodose neurons to great vessel occlusion. Both VNS and SCS obtund ventricular ischemia induced enhancement of nodose afferent neuronal inputs to the medulla. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Investigation of the charge effect on the electrochemical transduction in a quinone-based DNA sensor

    DEFF Research Database (Denmark)

    Reisberg, S.; Piro, B.; Noel, V.

    2008-01-01

    To elucidate the mechanism involved in the electrochemical transduction process of a conducting polymer-based DNA sensor, peptide nucleic acids (PNA) were used. PNA are DNA analogues having similar hybridization properties but are neutral. This allows to discriminate the electrostatic effect of D...... strands from the steric hindrance generated on the bioelectrode upon hybridization. It can be concluded that DNA conformational changes are determinant in the transduction process and that the electrostatic effect is negligible....

  13. Cavity opto-electromechanical system combining strong electrical actuation with ultrasensitive transduction

    OpenAIRE

    McRae, Terry G.; Lee, Kwan H.; Harris, Glen I.; Knittel, Joachim; Bowen, Warwick P.

    2010-01-01

    A cavity opto-electromechanical system is reported which combines the ultrasensitive transduction of cavity optomechanical systems with the electrical actuation of nanoelectromechanical systems. Ultrasensitive mechanical transduction is achieved via opto-mechanical coupling. Electrical gradient forces as large as 0.40 $\\mu$N are realized, facilitating strong actuation with ultralow dissipation. A scanning probe microscope is implemented, capable of characterizing the mechanical modes. The int...

  14. Sleep and protein synthesis-dependent synaptic plasticity: impacts of sleep loss and stress

    Science.gov (United States)

    Grønli, Janne; Soulé, Jonathan; Bramham, Clive R.

    2014-01-01

    Sleep has been ascribed a critical role in cognitive functioning. Several lines of evidence implicate sleep in the consolidation of synaptic plasticity and long-term memory. Stress disrupts sleep while impairing synaptic plasticity and cognitive performance. Here, we discuss evidence linking sleep to mechanisms of protein synthesis-dependent synaptic plasticity and synaptic scaling. We then consider how disruption of sleep by acute and chronic stress may impair these mechanisms and degrade sleep function. PMID:24478645

  15. Polymer-electrolyte-gated nanowire synaptic transistors for neuromorphic applications

    Science.gov (United States)

    Zou, Can; Sun, Jia; Gou, Guangyang; Kong, Ling-An; Qian, Chuan; Dai, Guozhang; Yang, Junliang; Guo, Guang-hua

    2017-09-01

    Polymer-electrolytes are formed by dissolving a salt in polymer instead of water, the conducting mechanism involves the segmental motion-assisted diffusion of ion in the polymer matrix. Here, we report on the fabrication of tin oxide (SnO2) nanowire synaptic transistors using polymer-electrolyte gating. A thin layer of poly(ethylene oxide) and lithium perchlorate (PEO/LiClO4) was deposited on top of the devices, which was used to boost device performances. A voltage spike applied on the in-plane gate attracts ions toward the polymer-electrolyte/SnO2 nanowire interface and the ions are gradually returned after the pulse is removed, which can induce a dynamic excitatory postsynaptic current in the nanowire channel. The SnO2 synaptic transistors exhibit the behavior of short-term plasticity like the paired-pulse facilitation and self-adaptation, which is related to the electric double-effect regulation. In addition, the synaptic logic functions and the logical function transformation are also discussed. Such single SnO2 nanowire-based synaptic transistors are of great importance for future neuromorphic devices.

  16. The Predominance of Electric Transport in Synaptic Transmission

    OpenAIRE

    Hamid Reza Noori

    2008-01-01

    The quantitative description of the motion of neurotransmitters in the synaptic cleft appears to be one of the most difficult problems in the modeling of synapses. Here we show in contradiction to the common view, that this process is merely governed by electric transport than diffusion forces.

  17. Synaptically evoked glutamate transporter currents in Spinal Dorsal Horn Astrocytes

    Directory of Open Access Journals (Sweden)

    Dougherty Patrick M

    2009-07-01

    Full Text Available Abstract Background Removing and sequestering synaptically released glutamate from the extracellular space is carried out by specific plasma membrane transporters that are primarily located in astrocytes. Glial glutamate transporter function can be monitored by recording the currents that are produced by co-transportation of Na+ ions with the uptake of glutamate. The goal of this study was to characterize glutamate transporter function in astrocytes of the spinal cord dorsal horn in real time by recording synaptically evoked glutamate transporter currents. Results Whole-cell patch clamp recordings were obtained from astrocytes in the spinal substantia gelatinosa (SG area in spinal slices of young adult rats. Glutamate transporter currents were evoked in these cells by electrical stimulation at the spinal dorsal root entry zone in the presence of bicuculline, strychnine, DNQX and D-AP5. Transporter currents were abolished when synaptic transmission was blocked by TTX or Cd2+. Pharmacological studies identified two subtypes of glutamate transporters in spinal astrocytes, GLAST and GLT-1. Glutamate transporter currents were graded with stimulus intensity, reaching peak responses at 4 to 5 times activation threshold, but were reduced following low-frequency (0.1 – 1 Hz repetitive stimulation. Conclusion These results suggest that glutamate transporters of spinal astrocytes could be activated by synaptic activation, and recording glutamate transporter currents may provide a means of examining the real time physiological responses of glial cells in spinal sensory processing, sensitization, hyperalgesia and chronic pain.

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

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    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.

  19. Inflammation Subverts Hippocampal Synaptic Plasticity in Experimental Multiple Sclerosis

    Science.gov (United States)

    Mandolesi, Georgia; Piccinin, Sonia; Berretta, Nicola; Pignatelli, Marco; Feligioni, Marco; Musella, Alessandra; Gentile, Antonietta; Mori, Francesco; Bernardi, Giorgio; Nicoletti, Ferdinando; Mercuri, Nicola B.; Centonze, Diego

    2013-01-01

    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. PMID:23355887

  20. High bandwidth synaptic communication and frequency tracking in human neocortex

    NARCIS (Netherlands)

    Testa-Silva, Guilherme; Verhoog, Matthijs B; Linaro, Daniele; de Kock, Christiaan P J; Baayen, Johannes C; Meredith, Rhiannon M; De Zeeuw, Chris I; Giugliano, Michele; Mansvelder, Huibert D

    2014-01-01

    Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from

  1. High bandwidth synaptic communication and frequency tracking in human neocortex.

    NARCIS (Netherlands)

    Testa-Silva, G.; Verhoog, M.B.; Linaro, D.; de Kock, C.P.J.; Baayen, J.C.; Meredith, R.M.; Zeeuw, C.I.; Giugliano, M.; Mansvelder, H.D.

    2014-01-01

    Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from

  2. High Bandwidth Synaptic Communication and Frequency Tracking in Human Neocortex

    NARCIS (Netherlands)

    G. Testa-Silva (Guilherme); M.B. Verhoog (Matthijs); D. Linaro (Daniele); C.P.J. de Kock (Christiaan); J.C. Baayen; R.M. Meredith (Rhiannon); C.I. de Zeeuw (Chris); M. Giugliano (Michele); H.D. Mansvelder (Huibert)

    2014-01-01

    textabstractNeuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we

  3. Intense synaptic activity enhances temporal resolution in spinal motoneurons.

    Directory of Open Access Journals (Sweden)

    Rune W Berg

    Full Text Available In neurons, spike timing is determined by integration of synaptic potentials in delicate concert with intrinsic properties. Although the integration time is functionally crucial, it remains elusive during network activity. While mechanisms of rapid processing are well documented in sensory systems, agility in motor systems has received little attention. Here we analyze how intense synaptic activity affects integration time in spinal motoneurons during functional motor activity and report a 10-fold decrease. As a result, action potentials can only be predicted from the membrane potential within 10 ms of their occurrence and detected for less than 10 ms after their occurrence. Being shorter than the average inter-spike interval, the AHP has little effect on integration time and spike timing, which instead is entirely determined by fluctuations in membrane potential caused by the barrage of inhibitory and excitatory synaptic activity. By shortening the effective integration time, this intense synaptic input may serve to facilitate the generation of rapid changes in movements.

  4. Control of synaptic plasticity in deep cortical networks

    NARCIS (Netherlands)

    Roelfsema, Pieter R.; Holtmaat, Anthony

    2018-01-01

    Humans and many other animals have an enormous capacity to learn about sensory stimuli and to master new skills. However, many of the mechanisms that enable us to learn remain to be understood. One of the greatest challenges of systems neuroscience is to explain how synaptic connections change to

  5. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction.

    NARCIS (Netherlands)

    van Huijstee, A.N.; Mansvelder, H.D.

    2015-01-01

    Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) 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

  6. Synaptic activity regulates AMPA receptor trafficking through different recycling pathways

    Science.gov (United States)

    Zheng, Ning; Jeyifous, Okunola; Munro, Charlotte; Montgomery, Johanna M; Green, William N

    2015-01-01

    Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. In this study, we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites. DOI: http://dx.doi.org/10.7554/eLife.06878.001 PMID:25970033

  7. Inhibitory Synaptic Plasticity - Spike timing dependence and putative network function.

    Directory of Open Access Journals (Sweden)

    Tim P Vogels

    2013-07-01

    Full Text Available While the plasticity of excitatory synaptic connections in the brain has been widely studied, the plasticity of inhibitory connections is much less understood. Here, we present recent experimental and theoretical □ndings concerning the rules of spike timing-dependent inhibitory plasticity and their putative network function. This is a summary of a workshop at the COSYNE conference 2012.

  8. Irregular persistent activity induced by synaptic excitatory feedback

    Directory of Open Access Journals (Sweden)

    Francesca Barbieri

    2007-11-01

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

  9. Polyploidization without mitosis improves in vivo liver transduction with lentiviral vectors.

    Science.gov (United States)

    Pichard, Virginie; Couton, Dominique; Desdouets, Chantal; Ferry, Nicolas

    2013-02-01

    Lentiviral vectors are efficient gene delivery vehicles for therapeutic and research applications. In contrast to oncoretroviral vectors, they are able to infect most nonproliferating cells. In the liver, induction of cell proliferation dramatically improved hepatocyte transduction using all types of retroviral vectors. However, the precise relationship between hepatocyte division and transduction efficiency has not been determined yet. Here we compared gene transfer efficiency in the liver after in vivo injection of recombinant lentiviral or Moloney murine leukemia viral (MoMuLV) vectors in hepatectomized rats treated or not with retrorsine, an alkaloid that blocks hepatocyte division and induces megalocytosis. Partial hepatectomy alone resulted in a similar increase in hepatocyte transduction using either vector. In retrorsine-treated and partially hepatectomized rats, transduction with MoMuLV vectors dropped dramatically. In contrast, we observed that retrorsine treatment combined with partial hepatectomy increased lentiviral transduction to higher levels than hepatectomy alone. Analysis of nuclear ploidy in single cells showed that a high level of transduction was associated with polyploidization. In conclusion, endoreplication could be exploited to improve the efficiency of liver-directed lentiviral gene therapy.

  10. Evidence that membrane transduction of oligoarginine does not require vesicle formation

    International Nuclear Information System (INIS)

    Zaro, Jennica L.; Shen Weichiang

    2005-01-01

    The involvement of vesicular formation processes in the membrane transduction and nuclear transport of oligoarginine is currently a subject of controversy. In this report, a novel quantitative method which allows for the selective measurement of membrane transduction excluding concurrent endocytosis was used to determine the effects of temperature, endosomal acidification, endosomolysis, and several known inhibitors of endocytic pathways on the internalization of oligoarginine. The results show that, unlike endocytosis, transduction of oligoarginine was not affected by incubation at 16 deg. C as compared to the 37 deg. C control, and was only partially inhibited at 4 deg. C incubation. Additionally, membrane transduction was not inhibited to the same extent as endocytosis following treatment with ammonium chloride, hypertonic medium, amiloride, or filipin. The endosomolytic activity of oligoarginine was investigated by examining the leakage of FITC-dextran into the cytosolic compartment, which was not higher in the presence of oligoarginine. Furthermore, ammonium chloride showed no effect on the nuclear transport of oligoarginine. The data presented in this report indicate that membrane transduction is likely to occur at the plasma membrane without the formation of membrane vesicles, and the nuclear localization involves membrane transduction, rather than endocytosis of oligoarginine

  11. Optogenetic Examination of Prefrontal-Amygdala Synaptic Development.

    Science.gov (United States)

    Arruda-Carvalho, Maithe; Wu, Wan-Chen; Cummings, Kirstie A; Clem, Roger L

    2017-03-15

    A brain network comprising the medial prefrontal cortex (mPFC) and amygdala plays important roles in developmentally regulated cognitive and emotional processes. However, very little is known about the maturation of mPFC-amygdala circuitry. We conducted anatomical tracing of mPFC projections and optogenetic interrogation of their synaptic connections with neurons in the basolateral amygdala (BLA) at neonatal to adult developmental stages in mice. Results indicate that mPFC-BLA projections exhibit delayed emergence relative to other mPFC pathways and establish synaptic transmission with BLA excitatory and inhibitory neurons in late infancy, events that coincide with a massive increase in overall synaptic drive. During subsequent adolescence, mPFC-BLA circuits are further modified by excitatory synaptic strengthening as well as a transient surge in feedforward inhibition. The latter was correlated with increased spontaneous inhibitory currents in excitatory neurons, suggesting that mPFC-BLA circuit maturation culminates in a period of exuberant GABAergic transmission. These findings establish a time course for the onset and refinement of mPFC-BLA transmission and point to potential sensitive periods in the development of this critical network. SIGNIFICANCE STATEMENT Human mPFC-amygdala functional connectivity is developmentally regulated and figures prominently in numerous psychiatric disorders with a high incidence of adolescent onset. However, it remains unclear when synaptic connections between these structures emerge or how their properties change with age. Our work establishes developmental windows and cellular substrates for synapse maturation in this pathway involving both excitatory and inhibitory circuits. The engagement of these substrates by early life experience may support the ontogeny of fundamental behaviors but could also lead to inappropriate circuit refinement and psychopathology in adverse situations. Copyright © 2017 the authors 0270-6474/17/372976-10$15.00/0.

  12. Synaptic dysfunction in amygdala in intellectual disorder models.

    Science.gov (United States)

    Aincy, Marianne; Meziane, Hamid; Herault, Yann; Humeau, Yann

    2018-06-08

    The amygdala is a part of the limbic circuit that has been extensively studied in terms of synaptic connectivity, plasticity and cellular organization since decades (Ehrlich et al., 2009; Ledoux, 2000; Maren, 2001). Amygdala sub-nuclei, including lateral, basolateral and central amygdala appear now as "hubs" providing in parallel and in series neuronal processing enabling the animal to elicit freezing or escaping behavior in response to external threats. In rodents, these behaviors are easily observed and quantified following associative fear conditioning. Thus, studies on amygdala circuit in association with threat/fear behavior became very popular in laboratories and are often used among other behavioral tests to evaluate learning abilities of mouse models for various neuropsychiatric conditions including genetically encoded intellectual disabilities (ID). Yet, more than 100 human X-linked genes - and several hundreds of autosomal genes - have been associated with ID in humans. These mutations introduced in mice can generate social deficits, anxiety dysregulations and fear learning impairments (McNaughton et al., 2008; Houbaert et al., 2013; Jayachandran et al., 2014; Zhang et al., 2015). Noteworthy, a significant proportion of the coded ID gene products are synaptic proteins. It is postulated that the loss of function of these proteins could destabilize neuronal circuits by global changes of the balance between inhibitory and excitatory drives onto neurons. However, whereas amygdala related behavioral deficits are commonly observed in ID models, the role of most of these ID-genes in synaptic function and plasticity in the amygdala are only sparsely studied. We will here discuss some of the concepts that emerged from amygdala-targeted studies examining the role of syndromic and non-syndromic ID genes in fear-related behaviors and/or synaptic function. Along describing these cases, we will discuss how synaptic deficits observed in amygdala circuits could impact

  13. Full Piezoelectric Multilayer-Stacked Hybrid Actuation/Transduction Systems

    Science.gov (United States)

    Su, Ji; Jiang, Xiaoning; Zu, Tian-Bing

    2011-01-01

    The Stacked HYBATS (Hybrid Actuation/Transduction system) demonstrates significantly enhanced electromechanical performance by using the cooperative contributions of the electromechanical responses of multilayer, stacked negative strain components and positive strain components. Both experimental and theoretical studies indicate that, for Stacked HYBATS, the displacement is over three times that of a same-sized conventional flextensional actuator/transducer. The coupled resonance mode between positive strain and negative strain components of Stacked HYBATS is much stronger than the resonance of a single element actuation only when the effective lengths of the two kinds of elements match each other. Compared with the previously invented hybrid actuation system (HYBAS), the multilayer Stacked HYBATS can be designed to provide high mechanical load capability, low voltage driving, and a highly effective piezoelectric constant. The negative strain component will contract, and the positive strain component will expand in the length directions when an electric field is applied on the device. The interaction between the two elements makes an enhanced motion along the Z direction for Stacked-HYBATS. In order to dominate the dynamic length of Stacked-HYBATS by the negative strain component, the area of the cross-section for the negative strain component will be much larger than the total cross-section areas of the two positive strain components. The transverse strain is negative and longitudinal strain positive in inorganic materials, such as ceramics/single crystals. Different piezoelectric multilayer stack configurations can make a piezoelectric ceramic/single-crystal multilayer stack exhibit negative strain or positive strain at a certain direction without increasing the applied voltage. The difference of this innovation from the HYBAS is that all the elements can be made from one-of-a-kind materials. Stacked HYBATS can provide an extremely effective piezoelectric

  14. The dynamic basis of energy transduction in enzymes.

    Science.gov (United States)

    Somogyi, B; Welch, G R; Damjanovich, S

    1984-09-06

    The most important idea underlying our treatment herein is the unity of the enzyme molecule and the medium. Appreciation of this relationship is vital, if enzymology is to graduate from its present reductionistic status to a more holistic posture. Enzymes are biological entities firstly, and isolated objects of physicochemical analysis secondly. Perhaps the most crucial 'biological lesson', particularly apropos of enzymes in intermediary metabolism, concerns the 'cytosociology' of enzyme action in vivo [94,128]. The natural habitat of many enzymes in the living cell is far different from that in bulk aqueous solution in vitro. In order to obtain a real grasp of the nature of enzyme function, one must ultimately couch enzymology in concepts emerging from contemporary cell biology [95]. Notwithstanding, analysis precedes synthesis; and one must needs begin with the individual enzyme molecule. The trenchant efforts of the physical chemist and the organic chemist have produced a wealth of information on the nature of the binding and catalytic events at the enzyme active site. While it is not yet possible to explain precisely the complete sequence of events in the catalytic process, nevertheless, the basic mechanisms by which enzymes effect catalysis (i.e., reduce activation energy) now seem apparent [81,129]. The new frontier is to be found, in exploring the dynamic role of the protein matrix [17]. Not only does the protein provide the 3-D scaffolding for active-site processes, but, more importantly, it serves as the local solvent for the bound chemical subsystem. Thus, the dynamical aspects of enzyme catalysis (for thermally based systems) must arise from the fluctuational properties of the protein molecule. This notion is the common denominator in all of the models in subsection IIC. It is the anisotropic nature of this fluctuational behavior, which would characterize the energy-transduction phenomenon leading to localized catalytic events at the active-site. In

  15. Signal transduction, receptors, mediators and genes: younger than ever - the 13th meeting of the Signal Transduction Society focused on aging and immunology

    Directory of Open Access Journals (Sweden)

    Klotz Lars-Oliver

    2010-02-01

    Full Text Available Abstract The 13th meeting of the Signal Transduction Society was held in Weimar, from October 28 to 30, 2009. Special focus of the 2009 conference was "Aging and Senescence", which was co-organized by the SFB 728 "Environmentally-Induced Aging Processes" of the University of Düsseldorf and the study group 'Signal Transduction' of the German Society for Cell Biology (DGZ. In addition, several other areas of signal transduction research were covered and supported by different consortia associated with the Signal Transduction Society including the long-term associated study groups of the German Society for Immunology and the Society for Biochemistry and Molecular Biology, and for instance the SFB/Transregio 52 "Transcriptional Programming of Individual T Cell Subsets" located in Würzburg, Mainz and Berlin. The different research areas that were introduced by outstanding keynote speakers attracted more than 250 scientists, showing the timeliness and relevance of the interdisciplinary concept and exchange of knowledge during the three days of the scientific program. This report gives an overview of the presentations of the conference.

  16. Odor-Specific Habituation Arises from Interaction of Afferent Synaptic Adaptation and Intrinsic Synaptic Potentiation in Olfactory Cortex

    Science.gov (United States)

    Linster, Christiane; Menon, Alka V.; Singh, Christopher Y.; Wilson, Donald A.

    2009-01-01

    Segmentation of target odorants from background odorants is a fundamental computational requirement for the olfactory system and is thought to be behaviorally mediated by olfactory habituation memory. Data from our laboratory have shown that odor-specific adaptation in piriform neurons, mediated at least partially by synaptic adaptation between…

  17. Network features and pathway analyses of a signal transduction cascade

    Directory of Open Access Journals (Sweden)

    Ryoji Yanashima

    2009-05-01

    Full Text Available The scale-free and small-world network models reflect the functional units of networks. However, when we investigated the network properties of a signaling pathway using these models, no significant differences were found between the original undirected graphs and the graphs in which inactive proteins were eliminated from the gene expression data. We analyzed signaling networks by focusing on those pathways that best reflected cellular function. Therefore, our analysis of pathways started from the ligands and progressed to transcription factors and cytoskeletal proteins. We employed the Python module to assess the target network. This involved comparing the original and restricted signaling cascades as a directed graph using microarray gene expression profiles of late onset Alzheimer's disease. The most commonly used method of shortest-path analysis neglects to consider the influences of alternative pathways that can affect the activation of transcription factors or cytoskeletal proteins. We therefore introduced included k-shortest paths and k-cycles in our network analysis using the Python modules, which allowed us to attain a reasonable computational time and identify k-shortest paths. This technique reflected results found in vivo and identified pathways not found when shortest path or degree analysis was applied. Our module enabled us to comprehensively analyse the characteristics of biomolecular networks and also enabled analysis of the effects of diseases considering the feedback loop and feedforward loop control structures as an alternative path.

  18. A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism.

    Science.gov (United States)

    Wang, B; Liu, Y; Huang, L; Chen, J; Li, J J; Wang, R; Kim, E; Chen, Y; Justicia, C; Sakata, K; Chen, H; Planas, A; Ostrom, R S; Li, W; Yang, G; McDonald, M P; Chen, R; Heck, D H; Liao, F-F

    2017-07-01

    Induction of neuroprotective heat-shock proteins via pharmacological Hsp90 inhibitors is currently being investigated as a potential treatment for neurodegenerative diseases. Two major hurdles for therapeutic use of Hsp90 inhibitors are systemic toxicity and limited central nervous system permeability. We demonstrate here that chronic treatment with a proprietary Hsp90 inhibitor compound (OS47720) not only elicits a heat-shock-like response but also offers synaptic protection in symptomatic Tg2576 mice, a model of Alzheimer's disease, without noticeable systemic toxicity. Despite a short half-life of OS47720 in mouse brain, a single intraperitoneal injection induces rapid and long-lasting (>3 days) nuclear activation of the heat-shock factor, HSF1. Mechanistic study indicates that the remedial effects of OS47720 depend upon HSF1 activation and the subsequent HSF1-mediated transcriptional events on synaptic genes. Taken together, this work reveals a novel role of HSF1 in synaptic function and memory, which likely occurs through modulation of the synaptic transcriptome.

  19. Alteration of synaptic activity-regulating genes underlying functional improvement by long-term exposure to an enriched environment in the adult brain.

    Science.gov (United States)

    Lee, Min-Young; Yu, Ji Hea; Kim, Ji Yeon; Seo, Jung Hwa; Park, Eun Sook; Kim, Chul Hoon; Kim, Hyongbum; Cho, Sung-Rae

    2013-01-01

    Housing animals in an enriched environment (EE) enhances behavioral function. However, the mechanism underlying this EE-mediated functional improvement and the resultant changes in gene expression have yet to be elucidated. We attempted to investigate the underlying mechanisms associated with long-term exposure to an EE by evaluating gene expression patterns. We housed 6-week-old CD-1 (ICR) mice in standard cages or an EE comprising a running wheel, novel objects, and social interaction for 2 months. Motor and cognitive performances were evaluated using the rotarod test and passive avoidance test, and gene expression profile was investigated in the cerebral hemispheres using microarray and gene set enrichment analysis (GSEA). In behavioral assessment, an EE significantly enhanced rotarod performance and short-term working memory. Microarray analysis revealed that genes associated with neuronal activity were significantly altered by an EE. GSEA showed that genes involved in synaptic transmission and postsynaptic signal transduction were globally upregulated, whereas those associated with reuptake by presynaptic neurotransmitter transporters were downregulated. In particular, both microarray and GSEA demonstrated that EE exposure increased opioid signaling, acetylcholine release cycle, and postsynaptic neurotransmitter receptors but decreased Na+ / Cl- -dependent neurotransmitter transporters, including dopamine transporter Slc6a3 in the brain. Western blotting confirmed that SLC6A3, DARPP32 (PPP1R1B), and P2RY12 were largely altered in a region-specific manner. An EE enhanced motor and cognitive function through the alteration of synaptic activity-regulating genes, improving the efficient use of neurotransmitters and synaptic plasticity by the upregulation of genes associated with postsynaptic receptor activity and downregulation of presynaptic reuptake by neurotransmitter transporters.

  20. Gene transfer to pre-hematopoietic and committed hematopoietic precursors in the early mouse Yolk Sac: a comparative study between in situ electroporation and retroviral transduction

    Directory of Open Access Journals (Sweden)

    Lécluse Yann

    2007-07-01

    Full Text Available Abstract Background Hematopoietic development in vertebrate embryos results from the sequential contribution of two pools of precursors independently generated. While intra-embryonic precursors harbour the features of hematopoietic stem cells (HSC, precursors formed earlier in the yolk sac (YS display limited differentiation and self-renewal potentials. The mechanisms leading to the generation of the precursors in both sites are still largely unknown, as are the molecular basis underlying their different potential. A possible approach to assess the role of candidate genes is to transfer or modulate their expression/activity in both sites. We thus designed and compared transduction protocols to target either native extra-embryonic precursors, or hematopoietic precursors. Results One transduction protocol involves transient modification of gene expression through in situ electroporation of the prospective blood islands, which allows the evolution of transfected mesodermal cells in their "normal" environment, upon organ culture. Following in situ electroporation of a GFP reporter construct into the YS cavity of embryos at post-streak (mesodermal/pre-hematopoietic precursors or early somite (hematopoietic precursors stages, high GFP expression levels as well as a good preservation of cell viability is observed in YS explants. Moreover, the erythro-myeloid progeny typical of the YS arises from GFP+ mesodermal cells or hematopoietic precursors, even if the number of targeted precursors is low. The second approach, based on retroviral transduction allows a very efficient transduction of large precursor numbers, but may only be used to target 8 dpc YS hematopoietic precursors. Again, transduced cells generate a progeny quantitatively and qualitatively similar to that of control YS. Conclusion We thus provide two protocols whose combination may allow a thorough study of both early and late events of hematopoietic development in the murine YS. In situ

  1. Single Amino Acid Modification of Adeno-Associated Virus Capsid Changes Transduction and Humoral Immune Profiles

    Science.gov (United States)

    Diprimio, Nina; Bowles, Dawn E.; Hirsch, Matthew L.; Monahan, Paul E.; Asokan, Aravind; Rabinowitz, Joseph; Agbandje-McKenna, Mavis

    2012-01-01

    Adeno-associated virus (AAV) vectors have the potential to promote long-term gene expression. Unfortunately, humoral immunity restricts patient treatment and in addition provides an obstacle to the potential option of vector readministration. In this study, we describe a comprehensive characterization of the neutralizing antibody (NAb) response to AAV type 1 (AAV1) through AAV5 both in vitro and in vivo. These results demonstrated that NAbs generated from one AAV type are unable to neutralize the transduction of other types. We extended this observation by demonstrating that a rationally engineered, muscle-tropic AAV2 mutant containing 5 amino acid substitutions from AAV1 displayed a NAb profile different from those of parental AAV2 and AAV1. Here we found that a single insertion of Thr from AAV1 into AAV2 capsid at residue 265 preserved high muscle transduction, while also changing the immune profile. To better understand the role of Thr insertion at position 265, we replaced all 20 amino acids and evaluated both muscle transduction and the NAb response. Of these variants, 8 mutants induced higher muscle transduction than AAV2. Additionally, three classes of capsid NAb immune profile were defined based on the ability to inhibit transduction from AAV2 or mutants. While no relationship was found between transduction, amino acid properties, and NAb titer or its cross-reactivity, these studies map a critical capsid motif involved in all steps of AAV infectivity. Our results suggest that AAV types can be utilized not only as templates to generate mutants with enhanced transduction efficiency but also as substrates for repeat administration. PMID:22593151

  2. Agrin and synaptic laminin are required to maintain adult neuromuscular junctions.

    Directory of Open Access Journals (Sweden)

    Melanie A Samuel

    Full Text Available As synapses form and mature the synaptic partners produce organizing molecules that regulate each other's differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ, these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Here, we used mutant mice to ask whether these organizers are also required for synaptic maintenance. Deletion of agrin from a subset of adult motor neurons resulted in the loss of acetylcholine receptors and other components of the postsynaptic apparatus and synaptic cleft. Nerve terminals also atrophied and eventually withdrew from muscle fibers. On the other hand, mice lacking the presynaptic organizer laminin-α4 retained most of the synaptic cleft components but exhibited synaptic alterations reminiscent of those observed in aged animals. Although we detected no marked decrease in laminin or agrin levels at aged NMJs, we observed alterations in the distribution and organization of these synaptic cleft components suggesting that such changes could contribute to age-related synaptic disassembly. Together, these results demonstrate that pre- and post-synaptic organizers actively function to maintain the structure and function of adult NMJs.

  3. Preparation of synaptic plasma membrane and postsynaptic density proteins using a discontinuous sucrose gradient.

    Science.gov (United States)

    Bermejo, Marie Kristel; Milenkovic, Marija; Salahpour, Ali; Ramsey, Amy J

    2014-09-03

    Neuronal subcellular fractionation techniques allow the quantification of proteins that are trafficked to and from the synapse. As originally described in the late 1960's, proteins associated with the synaptic plasma membrane can be isolated by ultracentrifugation on a sucrose density gradient. Once synaptic membranes are isolated, the macromolecular complex known as the post-synaptic density can be subsequently isolated due to its detergent insolubility. The techniques used to isolate synaptic plasma membranes and post-synaptic density proteins remain essentially the same after 40 years, and are widely used in current neuroscience research. This article details the fractionation of proteins associated with the synaptic plasma membrane and post-synaptic density using a discontinuous sucrose gradient. Resulting protein preparations are suitable for western blotting or 2D DIGE analysis.

  4. Two Classes of Secreted Synaptic Organizers in the Central Nervous System.

    Science.gov (United States)

    Yuzaki, Michisuke

    2018-02-10

    Research in the last two decades has identified many synaptic organizers in the central nervous system that directly regulate the assembly of pre- and/or postsynaptic molecules, such as synaptic vesicles, active zone proteins, and neurotransmitter receptors. They are classified into secreted factors and cell adhesion molecules, such as neurexins and neuroligins. Certain secreted factors are termed extracellular scaffolding proteins (ESPs) because they are components of the synaptic extracellular matrix and serve as a scaffold at the synaptic cleft. These include Lgi1, Cbln1, neuronal pentraxins, Hevin, thrombospondins, and glypicans. Diffusible secreted factors, such as Wnts, fibroblast growth factors, and semaphorins, tend to act from a distance. In contrast, ESPs remain at the synaptic cleft and often help synaptic adhesion and/or accumulation of postsynaptic receptors. Many fundamental questions remain about when, how, and why various synaptic organizers establish and modify the vast numbers of connections during development and throughout life.

  5. Learning with three factors: modulating Hebbian plasticity with errors.

    Science.gov (United States)

    Kuśmierz, Łukasz; Isomura, Takuya; Toyoizumi, Taro

    2017-10-01

    Synaptic plasticity is a central theme in neuroscience. A framework of three-factor learning rules provides a powerful abstraction, helping to navigate through the abundance of models of synaptic plasticity. It is well-known that the dopamine modulation of learning is related to reward, but theoretical models predict other functional roles of the modulatory third factor; it may encode errors for supervised learning, summary statistics of the population activity for unsupervised learning or attentional feedback. Specialized structures may be needed in order to generate and propagate third factors in the neural network. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Does autophagy work in synaptic plasticity and memory?

    Science.gov (United States)

    Shehata, Mohammad; Inokuchi, Kaoru

    2014-01-01

    Many studies have reported the roles played by regulated proteolysis in neural plasticity and memory. Within this context, most of the research focused on the ubiquitin-proteasome system and the endosome-lysosome system while giving lesser consideration to another major protein degradation system, namely, autophagy. Although autophagy intersects with many of the pathways known to underlie synaptic plasticity and memory, only few reports related autophagy to synaptic remodeling. These pathways include PI3K-mTOR pathway and endosome-dependent proteolysis. In this review, we will discuss several lines of evidence supporting a physiological role of autophagy in memory processes, and the possible mechanistic scenarios for how autophagy could fulfill this function.

  7. Synaptic Bistability Due to Nucleation and Evaporation of Receptor Clusters

    KAUST Repository

    Burlakov, V. M.

    2012-01-10

    We introduce a bistability mechanism for long-term synaptic plasticity based on switching between two metastable states that contain significantly different numbers of synaptic receptors. One state is characterized by a two-dimensional gas of mobile interacting receptors and is stabilized against clustering by a high nucleation barrier. The other state contains a receptor gas in equilibrium with a large cluster of immobile receptors, which is stabilized by the turnover rate of receptors into and out of the synapse. Transitions between the two states can be initiated by either an increase (potentiation) or a decrease (depotentiation) of the net receptor flux into the synapse. This changes the saturation level of the receptor gas and triggers nucleation or evaporation of receptor clusters. © 2012 American Physical Society.

  8. Synaptic communication between neurons and NG2+ cells.

    Science.gov (United States)

    Paukert, Martin; Bergles, Dwight E

    2006-10-01

    Chemical synaptic transmission provides the basis for much of the rapid signaling that occurs within neuronal networks. However, recent studies have provided compelling evidence that synapses are not used exclusively for communication between neurons. Physiological and anatomical studies indicate that a distinct class of glia known as NG2(+) cells also forms direct synaptic junctions with both glutamatergic and GABAergic neurons. Glutamatergic signaling can influence intracellular Ca(2+) levels in NG2(+) cells by activating Ca(2+) permeable AMPA receptors, and these inputs can be potentiated through high frequency stimulation. Although the significance of this highly differentiated form of communication remains to be established, these neuro-glia synapses might enable neurons to influence rapidly the behavior of this ubiquitous class of glial progenitors.

  9. Emulating short-term synaptic dynamics with memristive devices

    Science.gov (United States)

    Berdan, Radu; Vasilaki, Eleni; Khiat, Ali; Indiveri, Giacomo; Serb, Alexandru; Prodromakis, Themistoklis

    2016-01-01

    Neuromorphic architectures offer great promise for achieving computation capacities beyond conventional Von Neumann machines. The essential elements for achieving this vision are highly scalable synaptic mimics that do not undermine biological fidelity. Here we demonstrate that single solid-state TiO2 memristors can exhibit non-associative plasticity phenomena observed in biological synapses, supported by their metastable memory state transition properties. We show that, contrary to conventional uses of solid-state memory, the existence of rate-limiting volatility is a key feature for capturing short-term synaptic dynamics. We also show how the temporal dynamics of our prototypes can be exploited to implement spatio-temporal computation, demonstrating the memristors full potential for building biophysically realistic neural processing systems.

  10. Short-term synaptic plasticity and heterogeneity in neural systems

    Science.gov (United States)

    Mejias, J. F.; Kappen, H. J.; Longtin, A.; Torres, J. J.

    2013-01-01

    We review some recent results on neural dynamics and information processing which arise when considering several biophysical factors of interest, in particular, short-term synaptic plasticity and neural heterogeneity. The inclusion of short-term synaptic plasticity leads to enhanced long-term memory capacities, a higher robustness of memory to noise, and irregularity in the duration of the so-called up cortical states. On the other hand, considering some level of neural heterogeneity in neuron models allows neural systems to optimize information transmission in rate coding and temporal coding, two strategies commonly used by neurons to codify information in many brain areas. In all these studies, analytical approximations can be made to explain the underlying dynamics of these neural systems.

  11. Random synaptic feedback weights support error backpropagation for deep learning

    Science.gov (United States)

    Lillicrap, Timothy P.; Cownden, Daniel; Tweed, Douglas B.; Akerman, Colin J.

    2016-01-01

    The brain processes information through multiple layers of neurons. This deep architecture is representationally powerful, but complicates learning because it is difficult to identify the responsible neurons when a mistake is made. In machine learning, the backpropagation algorithm assigns blame by multiplying error signals with all the synaptic weights on each neuron's axon and further downstream. However, this involves a precise, symmetric backward connectivity pattern, which is thought to be impossible in the brain. Here we demonstrate that this strong architectural constraint is not required for effective error propagation. We present a surprisingly simple mechanism that assigns blame by multiplying errors by even random synaptic weights. This mechanism can transmit teaching signals across multiple layers of neurons and performs as effectively as backpropagation on a variety of tasks. Our results help reopen questions about how the brain could use error signals and dispel long-held assumptions about algorithmic constraints on learning. PMID:27824044

  12. Irregular activity arises as a natural consequence of synaptic inhibition

    International Nuclear Information System (INIS)

    Terman, D.; Rubin, J. E.; Diekman, C. O.

    2013-01-01

    Irregular neuronal activity is observed in a variety of brain regions and states. This work illustrates a novel mechanism by which irregular activity naturally emerges in two-cell neuronal networks featuring coupling by synaptic inhibition. We introduce a one-dimensional map that captures the irregular activity occurring in our simulations of conductance-based differential equations and mathematically analyze the instability of fixed points corresponding to synchronous and antiphase spiking for this map. We find that the irregular solutions that arise exhibit expansion, contraction, and folding in phase space, as expected in chaotic dynamics. Our analysis shows that these features are produced from the interplay of synaptic inhibition with sodium, potassium, and leak currents in a conductance-based framework and provides precise conditions on parameters that ensure that irregular activity will occur. In particular, the temporal details of spiking dynamics must be present for a model to exhibit this irregularity mechanism and must be considered analytically to capture these effects

  13. Irregular activity arises as a natural consequence of synaptic inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Terman, D., E-mail: terman@math.ohio-state.edu [Department of Mathematics, The Ohio State University, Columbus, Ohio 43210 (United States); Rubin, J. E., E-mail: jonrubin@pitt.edu [Department of Mathematics, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 (United States); Diekman, C. O., E-mail: diekman@njit.edu [Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, New Jersey 07102 (United States)

    2013-12-15

    Irregular neuronal activity is observed in a variety of brain regions and states. This work illustrates a novel mechanism by which irregular activity naturally emerges in two-cell neuronal networks featuring coupling by synaptic inhibition. We introduce a one-dimensional map that captures the irregular activity occurring in our simulations of conductance-based differential equations and mathematically analyze the instability of fixed points corresponding to synchronous and antiphase spiking for this map. We find that the irregular solutions that arise exhibit expansion, contraction, and folding in phase space, as expected in chaotic dynamics. Our analysis shows that these features are produced from the interplay of synaptic inhibition with sodium, potassium, and leak currents in a conductance-based framework and provides precise conditions on parameters that ensure that irregular activity will occur. In particular, the temporal details of spiking dynamics must be present for a model to exhibit this irregularity mechanism and must be considered analytically to capture these effects.

  14. Inhibition of hippocampal synaptic transmission by impairment of Ral function

    DEFF Research Database (Denmark)

    Owe-Larsson, Björn; Chaves-Olarte, Esteban; Chauhan, Ashok

    2005-01-01

    Large clostridial cytotoxins and protein overexpression were used to probe for involvement of Ras-related GTPases (guanosine triphosphate) in synaptic transmission in cultured rat hippocampal neurons. The toxins TcdA-10463 (inactivates Rho, Rac, Cdc42, Rap) and TcsL-1522 (inactivates Ral, Rac, Ras......, R-Ras, Rap) both inhibited autaptic responses. In a proportion of the neurons (25%, TcdA-10463; 54%, TcsL-1522), the inhibition was associated with a shift from activity-dependent depression to facilitation, indicating that the synaptic release probability was reduced. Overexpression of a dominant...... negative Ral mutant, Ral A28N, caused a strong inhibition of autaptic responses, which was associated with a shift to facilitation in a majority (80%) of the neurons. These results indicate that Ral, along with at least one other non-Rab GTPase, participates in presynaptic regulation in hippocampal neurons....

  15. Stochastic learning in oxide binary synaptic device for neuromorphic computing.

    Science.gov (United States)

    Yu, Shimeng; Gao, Bin; Fang, Zheng; Yu, Hongyu; Kang, Jinfeng; Wong, H-S Philip

    2013-01-01

    Hardware implementation of neuromorphic computing is attractive as a computing paradigm beyond the conventional digital computing. In this work, we show that the SET (off-to-on) transition of metal oxide resistive switching memory becomes probabilistic under a weak programming condition. The switching variability of the binary synaptic device implements a stochastic learning rule. Such stochastic SET transition was statistically measured and modeled for a simulation of a winner-take-all network for competitive learning. The simulation illustrates that with such stochastic learning, the orientation classification function of input patterns can be effectively realized. The system performance metrics were compared between the conventional approach using the analog synapse and the approach in this work that employs the binary synapse utilizing the stochastic learning. The feasibility of using binary synapse in the neurormorphic computing may relax the constraints to engineer continuous multilevel intermediate states and widens the material choice for the synaptic device design.

  16. MRP-1/CD9 gene transduction regulates the actin cytoskeleton through the downregulation of WAVE2.

    Science.gov (United States)

    Huang, C-L; Ueno, M; Liu, D; Masuya, D; Nakano, J; Yokomise, H; Nakagawa, T; Miyake, M

    2006-10-19

    Motility-related protein-1 (MRP-1/CD9) is involved in cell motility. We studied the change in the actin cytoskeleton, and the expression of actin-related protein (Arp) 2 and Arp3 and the Wiskott-Aldrich syndrome protein (WASP) family according to MRP-1/CD9 gene transduction into HT1080 cells. The frequency of cells with lamellipodia was significantly lower in MRP-1/CD9-transfected HT1080 cells than in control HT1080 cells (PMRP-1/CD9 gene transduction affected the subcellular localization of Arp2 and Arp3 proteins. Furthermore, MRP-1/CD9 gene transduction induced a downregulation of WAVE2 expression (PMRP-1/CD9 monoclonal antibody inhibited downregulation of WAVE2 in MRP-1/CD9-transfected HT1080 cells (PMRP-1/CD9 gene transduction. Furthermore, downregulation of WAVE2 by transfection of WAVE2-specific small interfering RNA (siRNA) mimicked the morphological effects of MRP-1/CD9 gene transduction and suppressed cell motility. However, transfection of each siRNA for Wnt1, Wnt2b1 or Wnt5a did not affect WAVE2 expression. Transfection of WAVE2-specific siRNA also did not affect expressions of these Wnts. These results indicate that MRP-1/CD9 regulates the actin cytoskeleton by downregulating of the WAVE2, through the Wnt-independent signal pathway.

  17. Effects of the TAT peptide orientation and relative location on the protein transduction efficiency.

    Science.gov (United States)

    Guo, Qingguo; Zhao, Guojie; Hao, Fengjin; Guan, Yifu

    2012-05-01

    To understand the protein transduction domain (PTD)-mediated protein transduction behavior and to explore its potential in delivering biopharmaceutic drugs, we prepared four TAT-EGFP conjugates: TAT(+)-EGFP, TAT(-)-EGFP, EGFP-TAT(+) and EGFP-TAT(-), where TAT(+) and TAT(-) represent the original and the reversed TAT sequence, respectively. These four TAT-EGFP conjugates were incubated with HeLa and PC12 cells for in vitro study as well as injected intraperitoneally to mice for in vivo study. Flow cytometric results showed that four TAT-EGFP conjugates were able to traverse HeLa and PC12 cells with almost equal transduction efficiency. The in vivo study showed that the TAT-EGFP conjugates could be delivered into different organs of mice with different transduction capabilities. Bioinformatic analyses and CD spectroscopic data revealed that the TAT peptide has no defined secondary structure, and conjugating the TAT peptide to the EGFP cargo protein would not alter the native structure and the function of the EGFP protein. These results conclude that the sequence orientation, the spatial structure, and the relative location of the TAT peptide have much less effect on the TAT-mediated protein transduction. Thus, the TAT-fused conjugates could be constructed in more convenient and flexible formats for a wide range of biopharmaceutical applications. © 2011 John Wiley & Sons A/S.

  18. Discovery of intramolecular signal transduction network based on a new protein dynamics model of energy dissipation.

    Directory of Open Access Journals (Sweden)

    Cheng-Wei Ma

    Full Text Available A novel approach to reveal intramolecular signal transduction network is proposed in this work. To this end, a new algorithm of network construction is developed, which is based on a new protein dynamics model of energy dissipation. A key feature of this approach is that direction information is specified after inferring protein residue-residue interaction network involved in the process of signal transduction. This enables fundamental analysis of the regulation hierarchy and identification of regulation hubs of the signaling network. A well-studied allosteric enzyme, E. coli aspartokinase III, is used as a model system to demonstrate the new method. Comparison with experimental results shows that the new approach is able to predict all the sites that have been experimentally proved to desensitize allosteric regulation of the enzyme. In addition, the signal transduction network shows a clear preference for specific structural regions, secondary structural types and residue conservation. Occurrence of super-hubs in the network indicates that allosteric regulation tends to gather residues with high connection ability to collectively facilitate the signaling process. Furthermore, a new parameter of propagation coefficient is defined to determine the propagation capability of residues within a signal transduction network. In conclusion, the new approach is useful for fundamental understanding of the process of intramolecular signal transduction and thus has significant impact on rational design of novel allosteric proteins.

  19. Rapid lentiviral transduction preserves the engraftment potential of Fanca(-/-) hematopoietic stem cells.

    Science.gov (United States)

    Müller, Lars U W; Milsom, Michael D; Kim, Mi-Ok; Schambach, Axel; Schuesler, Todd; Williams, David A

    2008-06-01

    Fanconi anemia (FA) is a rare recessive syndrome, characterized by congenital anomalies, bone marrow failure, and predisposition to cancer. Two earlier clinical trials utilizing gamma-retroviral vectors for the transduction of autologous FA hematopoietic stem cells (HSCs) required extensive in vitro manipulation and failed to achieve detectable long-term engraftment of transduced HSCs. As a strategy for minimizing ex vivo manipulation, we investigated the use of a "rapid" lentiviral transduction protocol in a murine Fanca(-/-) model. Importantly, while this and most murine models of FA fail to completely mimic the human hematopoietic phenotype, we observed a high incidence of HSC transplant engraftment failure and low donor chimerism after conventional transduction (CT) of Fanca(-/-) donor cells. In contrast, rapid transduction (RT) of Fanca(-/-) HSCs preserved engraftment to the level achieved in wild-type cells, resulting in long-term multilineage engraftment of gene-modified cells. We also demonstrate the correction of the characteristic hypersensitivity of FA cells against the cross-linking agent mitomycin C (MMC), and provide evidence for the advantage of using pharmacoselection as a means of further increasing gene-modified cells after RT. Collectively, these data support the use of rapid lentiviral transduction for gene therapy in FA.

  20. VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis

    Directory of Open Access Journals (Sweden)

    Gareth W. Fearnley

    2016-05-01

    Full Text Available Vascular endothelial growth factor A (VEGF-A binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A–VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor–ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145 promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes.

  1. VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis.

    Science.gov (United States)

    Fearnley, Gareth W; Smith, Gina A; Abdul-Zani, Izma; Yuldasheva, Nadira; Mughal, Nadeem A; Homer-Vanniasinkam, Shervanthi; Kearney, Mark T; Zachary, Ian C; Tomlinson, Darren C; Harrison, Michael A; Wheatcroft, Stephen B; Ponnambalam, Sreenivasan

    2016-05-15

    Vascular endothelial growth factor A (VEGF-A) binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A-VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor-ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145) promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes. © 2016. Published by The Company of Biologists Ltd.

  2. Loss of catecholaminergic neuromodulation of persistent forms of hippocampal synaptic plasticity with increasing age

    Directory of Open Access Journals (Sweden)

    Hannah Twarkowski

    2016-09-01

    Full Text Available Neuromodulation by means of the catecholaminergic system is a key component of motivation-driven learning and behaviorally modulated hippocampal synaptic plasticity. In particular, dopamine acting on D1/D5 receptors and noradrenaline acting on beta-adrenergic receptors exert a very potent regulation of forms of hippocampal synaptic plasticity that last for very long-periods of time (>24h, and occur in conjunction with novel spatial learning. Antagonism of these receptors not only prevents long-term potentiation (LTP and long-term depression (LTD, but prevents the memory of the spatial event that, under normal circumstances, leads to the perpetuation of these plasticity forms. Spatial learning behavior that normally comes easily to rats, such as object-place learning and spatial reference learning, becomes increasingly impaired with aging. Middle-aged animals display aging-related deficits of specific, but not all, components of spatial learning, and one possibility is that this initial manifestation of decrements in learning ability that become manifest in middle-age relate to changes in motivation, attention and/or the regulation by neuromodulatory systems of these behavioral states.Here, we compared the regulation by dopaminergic D1/D5 and beta-adrenergic receptors of persistent LTP in young (2-4 month old and middle-aged (8-14 month old rats. We observed in young rats, that weak potentiation that typically lasts for ca. 2h could be strengthened into persistent (>24h LTP by pharmacological activation of either D1/D5 or beta-adrenergic receptors. By contrast, no such facilitation occurred in middle-aged rats. This difference was not related to an ostensible learning deficit: a facilitation of weak potentiation into LTP by spatial learning was possible both in young and middle-aged rats. It was also not directly linked to deficits in LTP: strong afferent stimulation resulted in equivalent LTP in both age groups. We postulate that this change in

  3. Convergent synaptic and circuit substrates underlying autism genetic risks.

    Science.gov (United States)

    McGee, Aaron; Li, Guohui; Lu, Zhongming; Qiu, Shenfeng

    2014-02-01

    There has been a surge of diagnosis of autism spectrum disorders (ASD) over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.

  4. Quercetin targets cysteine string protein (CSPalpha and impairs synaptic transmission.

    Directory of Open Access Journals (Sweden)

    Fenglian Xu

    2010-06-01

    Full Text Available Cysteine string protein (CSPalpha is a synaptic vesicle protein that displays unique anti-neurodegenerative properties. CSPalpha is a member of the conserved J protein family, also called the Hsp40 (heat shock protein of 40 kDa protein family, whose importance in protein folding has been recognized for many years. Deletion of the CSPalpha in mice results in knockout mice that are normal for the first 2-3 weeks of life followed by an unexplained presynaptic neurodegeneration and premature death. How CSPalpha prevents neurodegeneration is currently not known. As a neuroprotective synaptic vesicle protein, CSPalpha represents a promising therapeutic target for the prevention of neurodegenerative disorders.Here, we demonstrate that the flavonoid quercetin promotes formation of stable CSPalpha-CSPalpha dimers and that quercetin-induced dimerization is dependent on the unique cysteine string region. Furthermore, in primary cultures of Lymnaea neurons, quercetin induction of CSPalpha dimers correlates with an inhibition of synapse formation and synaptic transmission suggesting that quercetin interfers with CSPalpha function. Quercetin's action on CSPalpha is concentration dependent and does not promote dimerization of other synaptic proteins or other J protein family members and reduces the assembly of CSPalpha:Hsc70 units (70kDa heat shock cognate protein.Quercetin is a plant derived flavonoid and popular nutritional supplement proposed to prevent memory loss and altitude sickness among other ailments, although its precise mechanism(s of action has been unclear. In view of the therapeutic promise of upregulation of CSPalpha and the undesired consequences of CSPalpha dysfunction, our data establish an essential proof of principle that pharmaceutical agents can selectively target the neuroprotective J protein CSPalpha.

  5. Presynaptic Active Zone Density during Development and Synaptic Plasticity.

    Science.gov (United States)

    Clarke, Gwenaëlle L; Chen, Jie; Nishimune, Hiroshi

    2012-01-01

    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.

  6. Mechanisms of Synaptic Alterations in a Neuroinflammation Model of Autism

    Science.gov (United States)

    2015-10-01

    inhibitory presynaptic input in the cortex of MIA offspring To determine if the altered number, shape and dynamic proper- ties of spines are...affects synaptic function in the cortex . We performed whole-cell voltage -clamp recordings from layer 2 pyramidal neurons in the somatosensory cortex ...highly dynamic struc- tures with new spines forming and others disappearing on a time scale of minutes (Dailey and Smith, 1996; Dunaevsky et al., 1999

  7. Dynamic learning and memory, synaptic plasticity and neurogenesis: an update

    Czech Academy of Sciences Publication Activity Database

    Stuchlík, Aleš

    2014-01-01

    Roč. 8, APR 1 (2014), s. 106 ISSN 1662-5153 R&D Projects: GA ČR(CZ) GA14-03627S Grant - others:Rada Programu interní podpory projektů mezinárodní spolupráce AV ČR(CZ) M200111204 Institutional support: RVO:67985823 Keywords : learning * memory * synaptic plasticity * neurogenesis Subject RIV: FH - Neurology Impact factor: 3.270, year: 2014

  8. Robust Short-Term Memory without Synaptic Learning

    OpenAIRE

    Johnson, Samuel; Marro, J.; Torres, Joaquin J.

    2013-01-01

    Short-term memory in the brain cannot in general be explained the way long-term memory can ??? as a gradual modification of synaptic weights ??? since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining inf...

  9. Synaptic metaplasticity underlies tetanic potentiation in Lymnaea: a novel paradigm.

    Directory of Open Access Journals (Sweden)

    Anita Mehta

    Full Text Available We present a mathematical model that explains and interprets a novel form of short-term potentiation, which was found to be use-, but not time-dependent, in experiments done on Lymnaea neurons. The high degree of potentiation is explained using a model of synaptic metaplasticity, while the use-dependence (which is critically reliant on the presence of kinase in the experiment is explained using a model of a stochastic and bistable biological switch.

  10. Two Aspects of ASIC Function: Synaptic Plasticity and Neuronal Injury.

    Science.gov (United States)

    Huang, Yan; Jiang, Nan; Li, Jun; Ji, Yong-Hua; Xiong, Zhi-Gang; Zha, Xiang-ming

    2015-01-01

    Extracellular brain pH fluctuates in both physiological and disease conditions. The main postsynaptic proton receptor is the acid-sensing ion channels (ASICs). During the past decade, much progress has been made on protons, ASICs, and neurological disease. This review summarizes the recent progress on synaptic role of protons and our current understanding of how ASICs contribute to various types of neuronal injury in the brain. PMID:25582290

  11. ERK pathway activation bidirectionally affects visual recognition memory and synaptic plasticity in the perirhinal cortex

    Directory of Open Access Journals (Sweden)

    Davide eSilingardi

    2011-12-01

    Full Text Available ERK 1,2 pathway mediates experience-dependent gene transcription in neurons and several studies have identified its pivotal role in experience-dependent synaptic plasticity and in forms of long term memory involving hippocampus, amygdala or striatum. The perirhinal cortex (PRHC plays an essential role in familiarity-based object recognition memory. It is still unknown whether ERK activation in PRHC is necessary for recognition memory consolidation. Most important, it is unknown whether by modulating the gain of the ERK pathway it is possible to bidirectionally affect visual recognition memory and PRHC synaptic plasticity.We have first pharmacologically blocked ERK activation in the PRHC of adult mice and found that this was sufficient to impair long term recognition memory in a familiarity-based task, the Object Recognition Task (ORT. We have then tested performance in the ORT in Ras-GRF1 knock-out (KO mice, which exhibit a reduced activation of ERK by neuronal activity, and in ERK1 KO mice, which have an increased activation of ERK2 and exhibit enhanced striatal plasticity and striatal mediated memory. We found that Ras-GRF1 KO mice have normal short-term memory but display a long term memory deficit; memory reconsolidation is also impaired. On the contrary, ERK1 KO mice exhibit a better performance than WT mice at 72 hour retention interval, suggesting a longer lasting recognition memory. In parallel with behavioural data, LTD was strongly reduced and LTP was significantly smaller in PRHC slices from Ras-GRF1 KO than in WT mice while enhanced LTP and LTD were found in PRHC slices from ERK1 KO mice.

  12. Synaptic properties of SOM- and CCK-expressing cells in dentate gyrus interneuron networks.

    Science.gov (United States)

    Savanthrapadian, Shakuntala; Meyer, Thomas; Elgueta, Claudio; Booker, Sam A; Vida, Imre; Bartos, Marlene

    2014-06-11

    Hippocampal GABAergic cells are highly heterogeneous, but the functional significance of this diversity is not fully understood. By using paired recordings of synaptically connected interneurons in slice preparations of the rat and mouse dentate gyrus (DG), we show that morphologically identified interneurons form complex neuronal networks. Synaptic inhibitory interactions exist between cholecystokinin (CCK)-expressing hilar commissural associational path (HICAP) cells and among somatostatin (SOM)-containing hilar perforant path-associated (HIPP) interneurons. Moreover, both interneuron types inhibit parvalbumin (PV)-expressing perisomatic inhibitory basket cells (BCs), whereas BCs and HICAPs rarely target HIPP cells. HICAP and HIPP cells produce slow, weak, and unreliable inhibition onto postsynaptic interneurons. The time course of inhibitory signaling is defined by the identity of the presynaptic and postsynaptic cell. It is the slowest for HIPP-HIPP, intermediately slow for HICAP-HICAP, but fast for BC-BC synapses. GABA release at interneuron-interneuron synapses also shows cell type-specific short-term dynamics, ranging from multiple-pulse facilitation at HICAP-HICAP, biphasic modulation at HIPP-HIPP to depression at BC-BC synapses. Although dendritic inhibition at HICAP-BC and HIPP-BC synapses appears weak and slow, channelrhodopsin 2-mediated excitation of SOM terminals demonstrates that they effectively control the activity of target interneurons. They markedly reduce the discharge probability but sharpen the temporal precision of action potential generation. Thus, dendritic inhibition seems to play an important role in determining the activity pattern of GABAergic interneuron populations and thereby the flow of information through the DG circuitry. Copyright © 2014 the authors 0270-6474/14/348197-13$15.00/0.

  13. Novel Mutations in Synaptic Transmission Genes Suppress Neuronal Hyperexcitation in Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Katherine A. McCulloch

    2017-07-01

    Full Text Available Acetylcholine (ACh receptors (AChR regulate neural circuit activity in multiple contexts. In humans, mutations in ionotropic acetylcholine receptor (iAChR genes can cause neurological disorders, including myasthenia gravis and epilepsy. In Caenorhabditis elegans, iAChRs play multiple roles in the locomotor circuit. The cholinergic motor neurons express an ACR-2-containing pentameric AChR (ACR-2R comprised of ACR-2, ACR-3, ACR-12, UNC-38, and UNC-63 subunits. A gain-of-function mutation in the non-α subunit gene acr-2 [acr-2(gf] causes defective locomotion as well as spontaneous convulsions. Previous studies of genetic suppressors of acr-2(gf have provided insights into ACR-2R composition and assembly. Here, to further understand how the ACR-2R regulates neuronal activity, we expanded the suppressor screen for acr-2(gf-induced convulsions. The majority of these suppressor mutations affect genes that play critical roles in synaptic transmission, including two novel mutations in the vesicular ACh transporter unc-17. In addition, we identified a role for a conserved major facilitator superfamily domain (MFSD protein, mfsd-6, in regulating neural circuit activity. We further defined a role for the sphingosine (SPH kinase (Sphk sphk-1 in cholinergic neuron activity, independent of previously known signaling pathways. Overall, the genes identified in our study suggest that optimal modulation of synaptic activity is balanced by the differential activities of multiple pathways, and the novel alleles provide valuable reagents to further dissect neuronal mechanisms regulating the locomotor circuit.

  14. Myocardial pre-synaptic sympathetic function correlates with glucose uptake in the failing human heart

    International Nuclear Information System (INIS)

    Mongillo, Marco; Leccisotti, Lucia; John, Anna S.; Pennell, Dudley J.; Camici, Paolo G.

    2007-01-01

    We have previously shown that the myocardium of patients with heart failure (HF) is insulin resistant. Chronic β-adrenergic stimulation has been implicated in insulin resistance in cultured cardiomyocytes in vitro, where sustained noradrenaline stimulation inhibited insulin-modulated glucose uptake. As the failing heart is characterized by increased sympathetic drive, we hypothesized that there is a correlation between pre-synaptic sympathetic function and insulin sensitivity in the myocardium of patients with HF. Eight patients (aged 67 ± 7 years) with coronary artery disease and left ventricular dysfunction (ejection fraction 44 ± 10%) underwent function and viability assessment with cardiovascular magnetic resonance. Myocardial glucose utilization (MGU) was measured using positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG). Pre-synaptic noradrenaline re-uptake was measured by calculating [ 11 C]meta-hydroxy-ephedrine (HED) volume of distribution (V d ) with PET. Two groups of healthy volunteers served as controls for the FDG (n = 8, aged 52 ± 4 years, p -1 .g -1 ) and dysfunctional (0.49 ± 0.14 μmol.min -1 .g -1 ) segments compared with controls (0.61 ± 0.7 μmol.min -1 .g -1 ; p d was reduced in dysfunctional segments of patients (38.9 ± 21.2 ml.g -1 ) compared with normal segments (52.2 ± 19.6 ml.g -1 ) and compared with controls (62.7 ± 11.3 ml.g -1 ). In patients, regional MGU was correlated with HED V d . The results of this study provide novel evidence of a correlation between cardiac sympathetic function and insulin sensitivity, which may represent one of the mechanisms contributing to insulin resistance in failing human hearts. (orig.)

  15. Neuron-astrocyte interaction enhance GABAergic synaptic transmission in a manner dependent on key metabolic enzymes.

    Directory of Open Access Journals (Sweden)

    Przemysław eKaczor

    2015-04-01

    Full Text Available GABA is the major inhibitory neurotransmitter in the adult brain and mechanisms of GABAergic inhibition have been intensely investigated in the past decades. Recent studies provided evidence for an important role of astrocytes in shaping GABAergic currents. One of the most obvious, but yet poorly understood, mechanisms of the cross-talk between GABAergic currents and astrocytes is metabolism including neurotransmitter homeostasis. In particular, how modulation of GABAergic currents by astrocytes depends on key enzymes involved in cellular metabolism remains largely unknown. To address this issue, we have considered two simple models of neuronal cultures: nominally astrocyte-free neuronal culture (NC and neuronal-astrocytic co-cultures (ANCC and miniature Inhibitory Postsynaptic Currents (mIPSCs were recorded in control conditions and in the presence of respective enzyme blockers. We report that enrichment of neuronal culture with astrocytes results in a marked increase in mIPSC frequency. This enhancement of GABAergic activity was accompanied by increased number of GAD65 and vGAT puncta, indicating that at least a part of the frequency enhancement was due to increased number of synaptic contacts. Inhibition of glutamine synthetase (with MSO strongly reduced mIPSC frequency in ANCC but had no effect in NC. Moreover, treatment of ANCC with inhibitor of glycogen phosphorylase (BAYU6751 or with selective inhibitor of astrocytic Krebs cycle,fluoroacetate, resulted in a marked reduction of mIPSC frequency in ANCC having no effect in NC. We conclude that GABAergic synaptic transmission strongly depends on neuron-astrocyte interaction in a manner dependent on key metabolic enzymes as well as on the Krebs cycle.

  16. Robust Short-Term Memory without Synaptic Learning

    Science.gov (United States)

    Johnson, Samuel; Marro, J.; Torres, Joaquín J.

    2013-01-01

    Short-term memory in the brain cannot in general be explained the way long-term memory can – as a gradual modification of synaptic weights – since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining information for a short time (a few seconds). The mechanism is robust to different network topologies and kinds of neural model. This could constitute a viable means available to the brain for sensory and/or short-term memory with no need of synaptic learning. Relevant phenomena described by neurobiology and psychology, such as local synchronization of synaptic inputs and power-law statistics of forgetting avalanches, emerge naturally from this mechanism, and we suggest possible experiments to test its viability in more biological settings. PMID:23349664

  17. Robust short-term memory without synaptic learning.

    Directory of Open Access Journals (Sweden)

    Samuel Johnson

    Full Text Available Short-term memory in the brain cannot in general be explained the way long-term memory can--as a gradual modification of synaptic weights--since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining information for a short time (a few seconds. The mechanism is robust to different network topologies and kinds of neural model. This could constitute a viable means available to the brain for sensory and/or short-term memory with no need of synaptic learning. Relevant phenomena described by neurobiology and psychology, such as local synchronization of synaptic inputs and power-law statistics of forgetting avalanches, emerge naturally from this mechanism, and we suggest possible experiments to test its viability in more biological settings.

  18. Robust short-term memory without synaptic learning.

    Science.gov (United States)

    Johnson, Samuel; Marro, J; Torres, Joaquín J

    2013-01-01

    Short-term memory in the brain cannot in general be explained the way long-term memory can--as a gradual modification of synaptic weights--since it takes place too quickly. Theories based on some form of cellular bistability, however, do not seem able to account for the fact that noisy neurons can collectively store information in a robust manner. We show how a sufficiently clustered network of simple model neurons can be instantly induced into metastable states capable of retaining information for a short time (a few seconds). The mechanism is robust to different network topologies and kinds of neural model. This could constitute a viable means available to the brain for sensory and/or short-term memory with no need of synaptic learning. Relevant phenomena described by neurobiology and psychology, such as local synchronization of synaptic inputs and power-law statistics of forgetting avalanches, emerge naturally from this mechanism, and we suggest possible experiments to test its viability in more biological settings.

  19. Evolution of the aging brain transcriptome and synaptic regulation.

    Directory of Open Access Journals (Sweden)

    Patrick M Loerch

    Full Text Available Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4. However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.

  20. Binocular Rivalry in a Competitive Neural Network with Synaptic Depression

    KAUST Repository

    Kilpatrick, Zachary P.

    2010-01-01

    We study binocular rivalry in a competitive neural network with synaptic depression. In particular, we consider two coupled hypercolums within primary visual cortex (V1), representing orientation selective cells responding to either left or right eye inputs. Coupling between hypercolumns is dominated by inhibition, especially for neurons with dissimilar orientation preferences. Within hypercolumns, recurrent connectivity is excitatory for similar orientations and inhibitory for different orientations. All synaptic connections are modifiable by local synaptic depression. When the hypercolumns are driven by orthogonal oriented stimuli, it is possible to induce oscillations that are representative of binocular rivalry. We first analyze the occurrence of oscillations in a space-clamped version of the model using a fast-slow analys is, taking advantage of the fact that depression evolves much slower than population activity. We th en analyze the onset of oscillations in the full spatially extended system by carrying out a piecewise smooth stability analysis of single (winner-take-all) and double (fusion) bumps within the network. Although our stability analysis takes into account only instabilities associated with real eigenvalues, it identifies points of instability that are consistent with what is found numerically. In particular, we show that, in regions of parameter space where double bumps are unstable and no single bumps exist, binocular rivalry can arise as a slow alternation between either population supporting a bump. © 2010 Society for Industrial and Applied Mathematics.

  1. Structural Components of Synaptic Plasticity and Memory Consolidation

    Science.gov (United States)

    Bailey, Craig H.; Kandel, Eric R.; Harris, Kristen M.

    2015-01-01

    Consolidation of implicit memory in the invertebrate Aplysia and explicit memory in the mammalian hippocampus are associated with remodeling and growth of preexisting synapses and the formation of new synapses. Here, we compare and contrast structural components of the synaptic plasticity that underlies these two distinct forms of memory. In both cases, the structural changes involve time-dependent processes. Thus, some modifications are transient and may contribute to early formative stages of long-term memory, whereas others are more stable, longer lasting, and likely to confer persistence to memory storage. In addition, we explore the possibility that trans-synaptic signaling mechanisms governing de novo synapse formation during development can be reused in the adult for the purposes of structural synaptic plasticity and memory storage. Finally, we discuss how these mechanisms set in motion structural rearrangements that prepare a synapse to strengthen the same memory and, perhaps, to allow it to take part in other memories as a basis for understanding how their anatomical representation results in the enhanced expression and storage of memories in the brain. PMID:26134321

  2. The evolutionary origin of the need to sleep: an inevitable consequence of synaptic neurotransmission?

    Science.gov (United States)

    Cantor, Robert S

    2015-01-01

    It is proposed that the evolutionary origin of the need to sleep is the removal of neurotransmitters (NTs) that escape reuptake and accumulate in brain interstitial fluid (ISF). Recent work suggests that the activity of ionotropic postsynaptic receptors, rapidly initiated by binding of NTs to extracellular sites, is modulated over longer times by adsorption of these NTs to the lipid bilayers in which the receptors are embedded. This bilayer-mediated mechanism is far less molecularly specific than binding, so bilayer adsorption of NTs that have diffused into synapses for other receptors would modulate their activity as well. Although NT