Science.gov

Sample records for potentiation synaptic transmission

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

    PubMed

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

    2016-01-01

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

  2. Recording long-term potentiation of synaptic transmission by three-dimensional multi-electrode arrays

    PubMed Central

    Kopanitsa, Maksym V; Afinowi, Nurudeen O; Grant, Seth GN

    2006-01-01

    Background Multi-electrode arrays (MEAs) have become popular tools for recording spontaneous and evoked electrical activity of excitable tissues. The majority of previous studies of synaptic transmission in brain slices employed MEAs with planar electrodes that had limited ability to detect signals coming from deeper, healthier layers of the slice. To overcome this limitation, we used three-dimensional (3D) MEAs with tip-shaped electrodes to probe plasticity of field excitatory synaptic potentials (fEPSPs) in the CA1 area of hippocampal slices of 129S5/SvEvBrd and C57BL/6J-TyrC-Brd mice. Results Using 3D MEAs, we were able to record larger fEPSPs compared to signals measured by planar MEAs. Several stimulation protocols were used to induce long-term potentiation (LTP) of synaptic responses in the CA1 area recorded following excitation of Schäffer collateral/commissural fibres. Either two trains of high frequency tetanic stimulation or three trains of theta-burst stimulation caused a persistent, pathway specific enhancement of fEPSPs that remained significantly elevated for at least 60 min. A third LTP induction protocol that comprised 150 pulses delivered at 5 Hz, evoked moderate LTP if excitation strength was increased to 1.5× of the baseline stimulus. In all cases, we observed a clear spatial plasticity gradient with maximum LTP levels detected in proximal apical dendrites of pyramidal neurones. No significant differences in the manifestation of LTP were observed between 129S5/SvEvBrd and C57BL/6J-TyrC-Brd mice with the three protocols used. All forms of plasticity were sensitive to inhibition of N-methyl-D-aspartate (NMDA) receptors. Conclusion Principal features of LTP (magnitude, pathway specificity, NMDA receptor dependence) recorded in the hippocampal slices using MEAs were very similar to those seen in conventional glass electrode experiments. Advantages of using MEAs are the ability to record from different regions of the slice and the ease of conducting

  3. Functional contributions of synaptically localized NR2B subunits of the NMDA receptor to synaptic transmission and long-term potentiation in the adult mouse CNS

    PubMed Central

    Miwa, Hideki; Fukaya, Masahiro; Watabe, Ayako M; Watanabe, Masahiko; Manabe, Toshiya

    2008-01-01

    The NMDA-type glutamate receptor is a heteromeric complex composed of the NR1 and at least one of the NR2 subunits. Switching from the NR2B to the NR2A subunit is thought to underlie functional alteration of the NMDA receptor during synaptic maturation, and it is generally believed that it results in preferential localization of NR2A subunits on the synaptic site and that of NR2B subunits on the extracellular site in the mature brain. It has also been proposed that activation of the NR2A and NR2B subunits results in long-term potentiation (LTP) and long-term depression (LTD), respectively. Furthermore, recent reports suggest that synaptic and extrasynaptic receptors may have distinct roles in synaptic plasticity as well as in gene expression associated with neuronal death. Here, we have investigated whether NR2B subunit-containing receptors are present and functional at mature synapses in the lateral nucleus of the amygdala (LA) and the CA1 region of the hippocampus, comparing their properties between the two brain regions. We have found, in contrast to the above hypotheses, that the NR2B subunit significantly contributes to synaptic transmission as well as LTP induction. Furthermore, its contribution is greater in the LA than in the CA1 region, and biophysical properties of NMDA receptors and the NR2B/NR2A ratio are different between the two brain regions. These results indicate that NR2B subunit-containing NMDA receptors accumulate on the synaptic site and are responsible for the unique properties of synaptic function and plasticity in the amygdala. PMID:18372311

  4. Brain-derived neurotrophic factor and nerve growth factor potentiate excitatory synaptic transmission in the rat visual cortex.

    PubMed Central

    Carmignoto, G; Pizzorusso, T; Tia, S; Vicini, S

    1997-01-01

    1. The effect of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) on excitatory synaptic transmission in the developing visual cortex was studied by whole-cell patch-clamp recordings from rat brain slices. 2. Both neurotrophins induced a rapid increase in the amplitude of impulse-evoked excitatory postsynaptic currents (EPSCs). BDNF also increased the frequency of spontaneous EPSCs. 3. Analysis of the currents revealed that alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated components contributing to the EPSC peak amplitude were equally potentiated by the neurotrophins. 4. When synaptic transmission was studied by minimal stimulation of intracortical afferents, neurotrophins induced a decrease in the occurrence of release failures. 5. A number of neurones were insensitive to the effects of the neurotrophins, possibly related to the considerable heterogeneity of neuronal types and to the uneven distribution of neurotrophin receptors in the visual cortex. 6. The probability of neurotransmitter release represents a rapidly modifiable synaptic feature by which neurotrophins can potentiate the efficacy of excitatory synaptic transmission in the visual cortex. PMID:9023775

  5. P2Y Receptors in Synaptic Transmission and Plasticity: Therapeutic Potential in Cognitive Dysfunction

    PubMed Central

    Guzman, Segundo J.; Gerevich, Zoltan

    2016-01-01

    ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer's disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states. PMID:27069691

  6. Changes in Synaptic Transmission and Long-term Potentiation Induction as a Possible Mechanism for Learning Disability in an Animal Model of Multiple Sclerosis

    PubMed Central

    2016-01-01

    Purpose: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. It has been shown that memory deficits is common in patients with MS. Recent studies using experimental autoimmune encephalomyelitis (EAE) as an animal model of MS have shown that indicated that EAE causes hippocampal-dependent impairment in learning and memory. Thus far, there have been no in vivo electrophysiological reports describing synaptic transmission in EAE animals. The aim of the present work is to evaluate the synaptic changes in the CA1 region of the hippocampus of EAE rats. Methods: To evaluate changes in synaptic transmission in the CA1 region of the hippocampus of EAE rats, field excitatory postsynaptic potentials (fEPSPs) from the stratum radiatum of CA1 neurons, were recorded following Schaffer collateral stimulation. Results: The results showed that EAE causes deficits in synaptic transmission and long-term potentiation (LTP) in the hippocampus. In addition, paired-pulse index with a 120 msec interstimulus interval was decreased in the EAE group. These findings indicate that EAE might induce suppression in synaptic transmission and LTP by increasing the inhibitory effect of GABAB receptors on the glutamate-mediated EPSP. Conclusions: In conclusion, influence of inflammation-triggered mechanisms on synaptic transmission may explain the negative effect of EAE on learning abilities in rats. PMID:27032554

  7. Fear Conditioning Potentiates Synaptic Transmission onto Long-Range Projection Neurons in the Lateral Subdivision of Central Amygdala

    PubMed Central

    Penzo, Mario A.; Robert, Vincent

    2014-01-01

    Recent studies indicate that the lateral subdivision of the central amygdala (CeL) is essential for fear learning. Specifically, fear conditioning induces cell-type-specific synaptic plasticity in CeL neurons that is required for the storage of fear memories. The CeL also controls fear expression by gating the activity of the medial subdivision of the central amygdala (CeM), the canonical amygdala output to areas that mediate defensive responses. In addition to the connection with CeM, the CeL sends long-range projections to innervate extra-amygdala areas. However, the long-range projection CeL neurons have not been well characterized, and their role in fear regulation is unknown. Here we show in mice that a subset of CeL neurons directly project to the midbrain periaqueductal gray (PAG) and the paraventricular nucleus of the thalamus, two brain areas implicated in defensive behavior. These long-range projection CeL neurons are predominantly somatostatin-positive (SOM+) neurons, which can directly inhibit PAG neurons, and some of which innervate both the PAG and paraventricular nucleus of the thalamus. Notably, fear conditioning potentiates excitatory synaptic transmission onto these long-range projection CeL neurons. Thus, our study identifies a subpopulation of SOM+ CeL neurons that may contribute to fear learning and regulate fear expression independent of CeM. PMID:24523533

  8. Synaptic Transmission Correlates of General Mental Ability

    ERIC Educational Resources Information Center

    McRorie, Margaret; Cooper, Colin

    2004-01-01

    Nerve conduction velocity (NCV) and efficiency of synaptic transmission are two possible biological mechanisms that may underpin intelligence. Direct assessments of NCV, without synaptic transmission, show few substantial or reliable correlations with cognitive abilities ["Intelligence" 16 (1992) 273]. We therefore assessed the latencies of…

  9. Prenatal Stress Enhances Excitatory Synaptic Transmission and Impairs Long-Term Potentiation in the Frontal Cortex of Adult Offspring Rats

    PubMed Central

    Sowa, Joanna; Bobula, Bartosz; Glombik, Katarzyna; Slusarczyk, Joanna; Basta-Kaim, Agnieszka; Hess, Grzegorz

    2015-01-01

    The effects of prenatal stress procedure were investigated in 3 months old male rats. Prenatally stressed rats showed depressive-like behavior in the forced swim test, including increased immobility, decreased mobility and decreased climbing. In ex vivo frontal cortex slices originating from prenatally stressed animals, the amplitude of extracellular field potentials (FPs) recorded in cortical layer II/III was larger, and the mean amplitude ratio of pharmacologically-isolated NMDA to the AMPA/kainate component of the field potential—smaller than in control preparations. Prenatal stress also resulted in a reduced magnitude of long-term potentiation (LTP). These effects were accompanied by an increase in the mean frequency, but not the mean amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in layer II/III pyramidal neurons. These data demonstrate that stress during pregnancy may lead not only to behavioral disturbances, but also impairs the glutamatergic transmission and long-term synaptic plasticity in the frontal cortex of the adult offspring. PMID:25749097

  10. Activin Controls Ethanol Potentiation of Inhibitory Synaptic Transmission Through GABAA Receptors and Concomitant Behavioral Sedation.

    PubMed

    Zheng, Fang; Puppel, Anne; Huber, Sabine E; Link, Andrea S; Eulenburg, Volker; van Brederode, Johannes F; Müller, Christian P; Alzheimer, Christian

    2016-07-01

    Activin, a member of the transforming growth factor-β family, exerts multiple functions in the nervous system. Originally identified as a neurotrophic and -protective agent, increasing evidence implicates activin also in the regulation of glutamatergic and GABAergic neurotransmission in brain regions associated with cognitive and affective functions. To explore how activin impacts on ethanol potentiation of GABA synapses and related behavioral paradigms, we used an established transgenic model of disrupted activin receptor signaling, in which mice express a dominant-negative activin receptor IB mutant (dnActRIB) under the control of the CaMKIIα promoter. Comparison of GABAA receptor currents in hippocampal neurons from dnActRIB mice and wild-type mice showed that all concentrations of ethanol tested (30-150 mM) produced much stronger potentiation of phasic inhibition in the mutant preparation. In dentate granule cells of dnActRIB mice, tonic GABA inhibition was more pronounced than in wild-type neurons, but remained insensitive to low ethanol (30 mM) in both preparations. The heightened ethanol sensitivity of phasic inhibition in mutant hippocampi resulted from both pre- and postsynaptic mechanisms, the latter probably involving PKCɛ. At the behavioral level, ethanol produced significantly stronger sedation in dnActRIB mice than in wild-type mice, but did not affect consumption of ethanol or escalation after withdrawal. We link the abnormal narcotic response of dnActRIB mice to ethanol to the excessive potentiation of inhibitory neurotransmission. Our study suggests that activin counteracts oversedation from ethanol by curtailing its augmenting effect at GABA synapses. PMID:26717882

  11. Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity

    PubMed Central

    Shin, Hyewon; van Riesen, Christoph; Whitcomb, Daniel; Warburton, Julia M.; Jo, Jihoon; Kim, Doyoun; Kim, Sun Gyun; Um, Seung Min; Kwon, Seok-kyu; Kim, Myoung-Hwan; Roh, Junyeop Daniel; Woo, Jooyeon; Jun, Heejung; Lee, Dongmin; Mah, Won; Kim, Hyun; Kaang, Bong-Kiun; Cho, Kwangwook; Rhee, Jeong-Seop; Choquet, Daniel; Kim, Eunjoon

    2016-01-01

    Summary Synaptic adhesion molecules regulate synapse development and plasticity through mechanisms including trans-synaptic adhesion and recruitment of diverse synaptic proteins. We report here that the immunoglobulin superfamily member 11 (IgSF11), a homophilic adhesion molecule preferentially expressed in the brain, is a novel and dual-binding partner of the postsynaptic scaffolding protein PSD-95 and AMPAR glutamate receptors (AMPARs). IgSF11 requires PSD-95 binding for its excitatory synaptic localization. In addition, IgSF11 stabilizes synaptic AMPARs, as shown by IgSF11 knockdown-induced suppression of AMPAR-mediated synaptic transmission and increased surface mobility of AMPARs, measured by high-throughput, single-molecule tracking. IgSF11 deletion in mice leads to suppression of AMPAR-mediated synaptic transmission in the dentate gyrus and long-term potentiation in the CA1 region of the hippocampus. IgSF11 does not regulate the functional characteristics of AMPARs, including desensitization, deactivation, or recovery. These results suggest that IgSF11 regulates excitatory synaptic transmission and plasticity through its tripartite interactions with PSD-95 and AMPARs. PMID:26595655

  12. Neuronal excitability: voltage-dependent currents and synaptic transmission.

    PubMed

    Rutecki, P A

    1992-04-01

    Neuronal membrane excitability and the synaptic connections among neurons produce behavior and cognition. The intracellular compartment of neurons is negatively charged relative to the extracellular space, and this charge, as well as current flow, is produced by ions. From the perspective of charged ions, the lipid bilayer of the neuronal membrane acts as a capacitor, and transmembrane glycoprotein pores or channels act as resistors. The open and closed states of ionic channels determine the membrane potential. At equilibrium, the lowest resistance or greatest permeability is for potassium, and the resting membrane potential is close to the equilibrium potential for potassium. When a channel is opened, permeable ions diffuse down their electrochemical gradients and the membrane potential is changed. Channels are gated (opened or closed) by voltage, neurotransmitters, and second messengers. The neuron integrates synaptic potentials produced by transmitter-gated channel activity and either generates a subthreshold potential, or a suprathreshold depolarization that generates an action potential or a burst of action potentials. Action potential generation is mediated by a large, brief sodium influx that is followed by activation of a voltage-dependent potassium eflux. The pattern of action potential firing is dependent on the interaction of a repertoire of voltage-dependent ion conductances. The action potential is the main signaling mechanism to activate synaptic transmission at axon terminals. Synaptic transmission is graded depending on the amount of calcium entering the presynaptic terminal. The number of action potentials, or the shape of the action potential, will determine the amount of calcium entering the terminal and the efficacy of synaptic transmission. Presynaptic ion channels may also be controlled by neurotransmitters or modulators and affect synaptic transmission by altering the amount of calcium influx. PMID:1375602

  13. Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission

    NASA Astrophysics Data System (ADS)

    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.

  14. Lateral regulation of synaptic transmission by astrocytes.

    PubMed

    Covelo, A; Araque, A

    2016-05-26

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

  15. Progesterone Regulation of Synaptic Transmission and Plasticity in Rodent Hippocampus

    ERIC Educational Resources Information Center

    Foy, Michael R.; Akopian, Garnik; Thompson, Richard F.

    2008-01-01

    Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the…

  16. Potentiation of Acetylcholine-Mediated Facilitation of Inhibitory Synaptic Transmission by an Azaindolizione Derivative, ZSET1446 (ST101), in the Rat Hippocampus.

    PubMed

    Takeda, Kentaro; Yamaguchi, Yoshimasa; Hino, Masataka; Kato, Fusao

    2016-02-01

    The integrity of the hippocampal network depends on the coordination of excitatory and inhibitory signaling, which are under dynamic control by various regulatory influences such as the cholinergic systems. ZSET1446 (ST101; spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) is a newly synthesized azaindolizinone derivative that significantly improves learning deficits in various types of Alzheimer disease (AD) models in rats. We examined the effect of ZSET1446 on the nicotinic acetylcholine (ACh) receptor (nAChR)-mediated regulation of synaptic transmission in hippocampal slices of rats. ZSET1446 significantly potentiated the facilitatory effect of nicotine and ACh on the frequency of spontaneous postsynaptic currents (sPSCs) recorded in CA1 pyramidal neurons with a maximum effect at 100 pM (tested range, 10 pM-1000 pM). The basal sPSC frequency without ACh was not affected. Such potentiation by ZSET1446 was observed in both the pharmacologic isolations of inhibitory and excitatory sPSCs and markedly reduced by blockade of either α7 or α4β2 nAChRs. ZSET1446 did not affect ACh-activated inward currents or depolarization of interneurons in the stratum radiatum and the lacunosum moleculare. These results indicate that ZSET1446 potentiates the nicotine-mediated enhancement of synaptic transmission in the hippocampal neurons without affecting nAChRs themselves, providing a novel possible mechanism of procognitive action that might improve learning deficits in clinical therapy. PMID:26578264

  17. proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus.

    PubMed

    Yang, Jianmin; Harte-Hargrove, Lauren C; Siao, Chia-Jen; Marinic, Tina; Clarke, Roshelle; Ma, Qian; Jing, Deqiang; Lafrancois, John J; Bath, Kevin G; Mark, Willie; Ballon, Douglas; Lee, Francis S; Scharfman, Helen E; Hempstead, Barbara L

    2014-05-01

    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 p75(NTR). 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 p75(NTR). 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. PMID:24746813

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

    SciTech Connect

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

    2011-08-01

    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 f

  19. Synaptic unreliability facilitates information transmission in balanced cortical populations

    NASA Astrophysics Data System (ADS)

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

    2015-06-01

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

  20. Porcupine controls hippocampal AMPAR levels, composition and synaptic transmission

    PubMed Central

    Erlenhardt, Nadine; Yu, Hong; Abiraman, Kavitha; Yamasaki, Tokiwa; Wadiche, Jacques I.; Tomita, Susumu; Bredt, David S.

    2016-01-01

    SUMMARY AMPAR (AMPAR) complexes contain auxiliary subunits that modulate receptor trafficking and gating. In addition to the transmembrane AMPAR regulatory proteins (TARPs) and cornichons (CNIH-2/3), recent proteomic studies identified a diverse array of additional AMPAR-associated transmembrane and secreted partners. We systematically surveyed these and found that PORCN and ABHD6 increase GluA1 levels in transfected cells. Knockdown of PORCN in rat hippocampal neurons, which express it in high amounts, selectively reduces levels of all tested AMPAR complex components. Regulation of AMPARs is independent of PORCN’s membrane-associated O-acyl transferase activity. PORCN knockdown in hippocampal neurons decreases AMPAR currents and accelerates desensitization, and leads to depletion of TARP γ-8 from AMPAR complexes. Conditional PORCN knockout mice also exhibit specific changes in AMPAR expression and gating that reduce basal synaptic transmission, but leave long-term potentiation intact. These studies define additional roles for PORCN in controlling synaptic transmission by regulating the level and composition of hippocampal AMPAR complexes. PMID:26776514

  1. Synaptic transmission at retinal ribbon synapses

    PubMed Central

    Heidelberger, Ruth; Thoreson, Wallace B.; Witkovsky, Paul

    2006-01-01

    The molecular organization of ribbon synapses in photoreceptors and ON bipolar cells is reviewed in relation to the process of neurotransmitter release. The interactions between ribbon synapse-associated proteins, synaptic vesicle fusion machinery and the voltage-gated calcium channels that gate transmitter release at ribbon synapses are discussed in relation to the process of synaptic vesicle exocytosis. We describe structural and mechanistic specializations that permit the ON bipolar cell to release transmitter at a much higher rate than the photoreceptor does, under in vivo conditions. We also consider the modulation of exocytosis at photoreceptor synapses, with an emphasis on the regulation of calcium channels. PMID:16027025

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

    PubMed Central

    Dobson, Katharine L.; Bellamy, Tomas C.

    2015-01-01

    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. PMID:26171253

  3. Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants

    PubMed Central

    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

  4. Insulin-Like Growth Factor I Produces an Antidepressant-Like Effect and Elicits N-Methyl-D-Aspartate Receptor Independent Long-Term Potentiation of Synaptic Transmission in Medial Prefrontal Cortex and Hippocampus

    PubMed Central

    Zhang, Xiao-lei; Colechio, Elizabeth M.; Ghoreishi-Haack, Nayereh; Gross, Amanda; Kroes, Roger A.; Stanton, Patric K.; Moskal, Joseph R.

    2016-01-01

    Background: Growth factors play an important role in regulating neurogenesis and synapse formation and may be involved in regulating the antidepressant response to conventional antidepressants. To date, Insulin-like growth factor I (IGFI) is the only growth factor that has shown antidepressant properties in human clinical trials. However, its mechanism of action remains unclear. Methods: The antidepressant-like effect of a single IV dose of IGFI was determined using a chronic unpredictable stress paradigm in the rat Porsolt, sucrose preference, novelty-induced hypophagia, and ultrasonic vocalization models. The dependence of the medial prefrontal cortex for these effects was determined by direct medial prefrontal cortex injection followed by Porsolt testing as well as IGFI receptor activation in the medial prefrontal cortex following an optimal IV antidepressant-like dose of IGFI. The effect of IGFI on synaptic transmission and long-term potentiation (LTP) of synaptic strength was assessed in the hippocampus and medial prefrontal cortex. The dependence of these effects on IGFI and AMPA receptor activation and protein synthesis were also determined. Results: IGFI produced a rapid-acting and long-lasting antidepressant-like effect in each of the depression models. These effects were blocked by IGFI and AMPA receptor antagonists, and medial prefrontal cortex was localized. IGFI robustly increased synaptic strength in the hippocampus and medial prefrontal cortex and these effects were IGFI receptor and protein synthesis-dependent but N-methyl-d-aspartate receptor independent. IGFI also robustly facilitated hippocampal metaplasticity 24 hours postdosing. Conclusions: These data support the conclusion that the antidepressant-like effects of IGFI are mediated by a persistent, LTP-like enhancement of synaptic strength requiring both IGFIR activation and ongoing protein synthesis. PMID:26374350

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-07-01

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

  7. Synaptic transmission deficits in Caenorhabditis elegans synaptobrevin mutants.

    PubMed

    Nonet, M L; Saifee, O; Zhao, H; Rand, J B; Wei, L

    1998-01-01

    Synaptobrevins are vesicle-associated proteins implicated in neurotransmitter release by both biochemical studies and perturbation experiments that use botulinum toxins. To test these models in vivo, we have isolated and characterized the first synaptobrevin mutants in metazoans and show that neurotransmission is severely disrupted in mutant animals. Mutants lacking snb-1 die just after completing embryogenesis. The dying animals retain some capability for movement, although they are extremely uncoordinated and incapable of feeding. We also have isolated and characterized several hypomorphic snb-1 mutants. Although fully viable, these mutants exhibit a variety of behavioral abnormalities that are consistent with a general defect in the efficacy of synaptic transmission. The viable mutants are resistant to the acetylcholinesterase inhibitor aldicarb, indicating that cholinergic transmission is impaired. Extracellular recordings from pharyngeal muscle also demonstrate severe defects in synaptic transmission in the mutants. The molecular lesions in the hypomorphic alleles reside on the hydrophobic face of a proposed amphipathic-helical region implicated biochemically in interacting with the t-SNAREs syntaxin and SNAP-25. Finally, we demonstrate that double mutants lacking both the v-SNAREs synaptotagmin and snb-1 are phenotypically similar to snb-1 mutants and less severe than syntaxin mutants. Our work demonstrates that synaptobrevin is essential for viability and is required for functional synaptic transmission. However, our analysis also suggests that transmitter release is not completely eliminated by removal of either one or both v-SNAREs. PMID:9412487

  8. What Is Transmitted in "Synaptic Transmission"?

    ERIC Educational Resources Information Center

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

    2010-01-01

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

  9. A novel synaptic plasticity rule explains homeostasis of neuromuscular transmission

    PubMed Central

    Ouanounou, Gilles; Baux, Gérard; Bal, Thierry

    2016-01-01

    Excitability differs among muscle fibers and undergoes continuous changes during development and growth, yet the neuromuscular synapse maintains a remarkable fidelity of execution. Here we show in two evolutionarily distant vertebrates (Xenopus laevis cell culture and mouse nerve-muscle ex-vivo) that the skeletal muscle cell constantly senses, through two identified calcium signals, synaptic events and their efficacy in eliciting spikes. These sensors trigger retrograde signal(s) that control presynaptic neurotransmitter release, resulting in synaptic potentiation or depression. In the absence of spikes, synaptic events trigger potentiation. Once the synapse is sufficiently strong to initiate spiking, the occurrence of these spikes activates a negative retrograde feedback. These opposing signals dynamically balance the synapse in order to continuously adjust neurotransmitter release to a level matching current muscle cell excitability. DOI: http://dx.doi.org/10.7554/eLife.12190.001 PMID:27138195

  10. Presynaptic clathrin levels are a limiting factor for synaptic transmission.

    PubMed

    López-Murcia, Francisco J; Royle, Stephen J; Llobet, Artur

    2014-06-18

    To maintain communication, neurons must recycle their synaptic vesicles with high efficiency. This process places a huge burden on the clathrin-mediated endocytic machinery, but the consequences of this are poorly understood. We found that the amount of clathrin in a presynaptic terminal is not fixed. During stimulation, clathrin moves out of synapses as a function of stimulus strength and neurotransmitter release probability, which, together with membrane coat formation, transiently reduces the available pool of free clathrin triskelia. Correlative functional and morphological experiments in cholinergic autapses established by superior cervical ganglion neurons in culture show that presynaptic terminal function is compromised if clathrin levels fall by 20% after clathrin heavy chain knock down using RNAi. Synaptic transmission is depressed due to a reduction of cytoplasmic and readily releasable pools of vesicles. However, synaptic depression reverts after dialysis of exogenous clathrin, thus compensating RNAi-induced depletion. Lowering clathrin levels also reduces quantal size, which occurs concomitantly with a decrease in the size of synaptic vesicles. Large dense-core vesicles are unaffected by clathrin knock down. Together, our results show that clathrin levels are a dynamic property of presynaptic terminals that can influence short-term plasticity in a stimulus-dependent manner. PMID:24948816

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

    PubMed Central

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

    2015-01-01

    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. PMID:26511387

  12. [EFFECT OF HYPOXIA ON SYNAPTIC TRANSMISSION BETWEEN RETINAL GANGLION CELLS AND SUPERIOR COLLICULUS NEURONS IN COCULTURE].

    PubMed

    Dumanska, G V; Rikhalsky, O V; Veselovsky, N S

    2015-01-01

    In this study we conducted a series of experiments to characterize the effect and define the mechanisms of hypoxia on synaptic transmission between retinal ganglion cells and superior colliculus (SC) neurons. Application of hypoxic solution leads to a long lasting potentiation (LTP) NMDA-mediated synaptic transmission. Analysis of the oxygen deficiency effect on the spontaneous and miniature postsynaptic currents (sPSC and mPSC respectively) revealed an increase in the frequency of their occurrence and the appearance of the second peak in the mPSC histogram distribution. The assessment of quantum and binomial parameters reflects the complex pre- and postsynaptic changes during the potentiation, independent of the release probability. Most likely this LTP can be caused by an increase in the total number of active synapses. Glutamatergic synaptic transmission mediated by non-NMDA activation receptor-channel complexes, responded to application of deoxygenated solution by the brief depression, which is the result of presynaptic dysfunction and associates with decrease in release probability and number of active zones. GABAergic synaptic transmission mediated by activation GABA(A)-receptor-channel complexes, responded to hypoxic action by long term depression (LTD). Analysis of sPSC and mPSC showed a significant decrease in the frequency of their occurrence and significant (P = 0.05) decrease in the quantum over a period of oxygen deficiency. In general, the effect of hypoxia-induced LTD of GABAergic synaptic transmission is based on complex changes of presynaptic (independent on the release probability) and postsynaptic (reduction sensitivity of receptors in postsynaptic membrane) mechanisms. PMID:27025053

  13. Cellular and molecular mechanisms of chemical synaptic transmission.

    PubMed

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

    1989-12-01

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

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

    PubMed Central

    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

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

    PubMed

    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

  16. Quercetin Targets Cysteine String Protein (CSPα) and Impairs Synaptic Transmission

    PubMed Central

    Xu, Fenglian; Proft, Juliane; Gibbs, Sarah; Winkfein, Bob; Johnson, Jadah N.; Syed, Naweed; Braun, Janice E. A.

    2010-01-01

    Background Cysteine string protein (CSPα) is a synaptic vesicle protein that displays unique anti-neurodegenerative properties. CSPα 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 CSPα 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 CSPα prevents neurodegeneration is currently not known. As a neuroprotective synaptic vesicle protein, CSPα represents a promising therapeutic target for the prevention of neurodegenerative disorders. Methodology/Principal Findings Here, we demonstrate that the flavonoid quercetin promotes formation of stable CSPα-CSPα dimers and that quercetin-induced dimerization is dependent on the unique cysteine string region. Furthermore, in primary cultures of Lymnaea neurons, quercetin induction of CSPα dimers correlates with an inhibition of synapse formation and synaptic transmission suggesting that quercetin interfers with CSPα function. Quercetin's action on CSPα is concentration dependent and does not promote dimerization of other synaptic proteins or other J protein family members and reduces the assembly of CSPα:Hsc70 units (70kDa heat shock cognate protein). Conclusions/Significance 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 CSPα and the undesired consequences of CSPα dysfunction, our data establish an essential proof of principle that pharmaceutical agents can selectively target the neuroprotective J protein CSPα. PMID:20548785

  17. Effect of VGLUT inhibitors on glutamatergic synaptic transmission in the rodent hippocampus and prefrontal cortex.

    PubMed

    Neale, S A; Copeland, C S; Salt, T E

    2014-07-01

    Vesicular glutamate transporters (VGLUTs) are known to be important in the uptake of glutamate into vesicles in the presynaptic terminal; thereby playing a role in synaptic function. VGLUT dysfunction has also been suggested in neurological and psychiatric disorders such as epilepsy and schizophrenia. A number of compounds have been identified as VGLUT inhibitors; however, little is known as to how these compounds affect synaptic transmission. We therefore investigated the effects of structurally unrelated VGLUT inhibitors on synaptic transmission in the rodent hippocampus and prefrontal cortex. In the CA1 and dentate gyrus regions of the in vitro slice preparation of mouse hippocampus, AMPA receptor-mediated field excitatory postsynaptic potentials (fEPSPs) were evoked in response to Schaffer collateral/commissural pathway stimulation. Application of the VGLUT inhibitors Rose Bengal (RB), Congo Red (CR) or Chicago Sky Blue 6B (CB) resulted in a concentration-related reduction of fEPSP amplitudes. RB (30μM) or CB (300μM) also depressed NMDA receptor-mediated responses in the CA1 region. The naturally occurring kynurenine Xanthurenic Acid (XA) is reported to be a VGLUT inhibitor. We found XA attenuated both AMPA and NMDA receptor-mediated synaptic transmission. The potency order of the VGLUT inhibitors was consistent with literature Ki values for VGLUT inhibition. Impaired glutamatergic neurotransmission is believed to contribute to schizophrenia, and VGLUTs have also been implicated in this disease. We therefore investigated the effect of VGLUT inhibition in the prefrontal cortex. Application of the VGLUT inhibitors RB or CB resulted in a concentration-dependent reduction in the amplitude of glutamate receptor-mediated fEPSPs recorded in layer V/VI in response to stimulation in the forceps minor. We conclude that VGLUT inhibitors can modulate glutamatergic synaptic transmission in the PFC and hippocampus. This could be important in the pathophysiology of nervous

  18. Peripherally restricted viral challenge elevates extracellular glutamate and enhances synaptic transmission in the hippocampus.

    PubMed

    Hunsberger, Holly C; Wang, Desheng; Petrisko, Tiffany J; Alhowail, Ahmad; Setti, Sharay E; Suppiramaniam, Vishnu; Konat, Gregory W; Reed, Miranda N

    2016-07-01

    Peripheral infections increase the propensity and severity of seizures in susceptible populations. We have previously shown that intraperitoneal injection of a viral mimic, polyinosinic-polycytidylic acid (PIC), elicits hypersusceptibility of mice to kainic acid (KA)-induced seizures. This study was undertaken to determine whether this seizure hypersusceptibility entails alterations in glutamate signaling. Female C57BL/6 mice were intraperitoneally injected with PIC, and after 24 h, glutamate homeostasis in the hippocampus was monitored using the enzyme-based microelectrode arrays. PIC challenge robustly increased the level of resting extracellular glutamate. While pre-synaptic potassium-evoked glutamate release was not affected, glutamate uptake was profoundly impaired and non-vesicular glutamate release was augmented, indicating functional alterations of astrocytes. Electrophysiological examination of hippocampal slices from PIC-challenged mice revealed a several fold increase in the basal synaptic transmission as compared to control slices. PIC challenge also increased the probability of pre-synaptic glutamate release as seen from a reduction of paired-pulse facilitation and synaptic plasticity as seen from an enhancement of long-term potentiation. Altogether, our results implicate a dysregulation of astrocytic glutamate metabolism and an alteration of excitatory synaptic transmission as the underlying mechanism for the development of hippocampal hyperexcitability, and consequently seizure hypersusceptibility following peripheral PIC challenge. Peripheral infections/inflammations enhance seizure susceptibility. Here, we explored the effect of peritoneal inflammation induced by a viral mimic on glutamate homeostasis and glutamatergic neurotransmission in the mouse hippocampus. We found that peritoneal inflammation elevated extracellular glutamate concentration and enhanced the probability of pre-synaptic glutamate release resulting in hyperexcitability of

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

    PubMed

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

    2016-09-01

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

  20. Statistical analysis of synaptic transmission: model discrimination and confidence limits.

    PubMed Central

    Stricker, C; Redman, S; Daley, D

    1994-01-01

    Procedures for discriminating between competing statistical models of synaptic transmission, and for providing confidence limits on the parameters of these models, have been developed. These procedures were tested against simulated data and were used to analyze the fluctuations in synaptic currents evoked in hippocampal neurones. All models were fitted to data using the Expectation-Maximization algorithm and a maximum likelihood criterion. Competing models were evaluated using the log-likelihood ratio (Wilks statistic). When the competing models were not nested, Monte Carlo sampling of the model used as the null hypothesis (H0) provided density functions against which H0 and the alternate model (H1) were tested. The statistic for the log-likelihood ratio was determined from the fit of H0 and H1 to these probability densities. This statistic was used to determine the significance level at which H0 could be rejected for the original data. When the competing models were nested, log-likelihood ratios and the chi 2 statistic were used to determine the confidence level for rejection. Once the model that provided the best statistical fit to the data was identified, many estimates for the model parameters were calculated by resampling the original data. Bootstrap techniques were then used to obtain the confidence limits of these parameters. PMID:7948672

  1. Age-dependent enhancement of inhibitory synaptic transmission in CA1 pyramidal neurons via GluR5 kainate receptors.

    PubMed

    Xu, Changqing; Cui, Changhai; Alkon, Daniel L

    2009-08-01

    Changes in hippocampal synaptic networks during aging may contribute to age-dependent compromise of cognitive functions such as learning and memory. Previous studies have demonstrated that GABAergic synaptic transmission exhibits age-dependent changes. To better understand such age-dependent changes of GABAergic synaptic inhibition, we performed whole-cell recordings from pyramidal cells in the CA1 area of acute hippocampal slices on aged (24-26 months old) and young (2-4 months old) Brown-Norway rats. We found that the frequency and amplitude of spontaneous inhibitory postsynaptic current (IPSCs) were significantly increased in aged rats, but the frequency and amplitude of mIPSCs were decreased. Furthermore, the regulation of GABAergic synaptic transmission by GluR5 containing kainate receptors was enhanced in aged rats, which was revealed by using LY382884 (a GluR5 kainate receptor antagonist) and ATPA (a GluR5 kainate receptor agonist). Moreover, we demonstrated that vesicular glutamate transporters are involved in the kainate receptor dependent regulation of sIPSCs. Taken together, these results suggest that GABAergic synaptic transmission is potentiated in aged rats, and GluR5 containing kainate receptors regulate the inhibitory synaptic transmission through endogenous glutamate. These alterations of GABAergic input with aging could contribute to age-dependent cognitive decline. PMID:19123252

  2. Modulation of GABA-mediated synaptic transmission by endogenous zinc in the immature rat hippocampus in vitro.

    PubMed Central

    Xie, X; Hider, R C; Smart, T G

    1994-01-01

    1. Intracellular recordings from postnatal 2- to 12-day-old (P2-12) rat hippocampal CA3 pyramidal neurones exhibited spontaneous synaptic potentials mediated by GABAA receptors. These potentials can be separated on the basis of amplitude into two classes which are referred to as small and large. 2. The large depolarizing potentials were reversibly inhibited by the Zn2+ chelator 1,2-diethyl-3-hydroxypyridin-4-one (CP94). The small inhibitory postsynaptic potentials. (IPSPs) were apparently unaffected. 3. Stimulation of the mossy fibre pathway evoked composite excitatory postsynaptic potentials (EPSPs) and IPSPs. Threshold stimulus-evoked synaptic potentials were mediated by GABAA receptors and were reversibly blocked by CP94. The responses evoked by suprathreshold stimulation and persisting in the presence of bicuculline or CP94 were partially inhibited by 2-amino-5-phosphonopropionic acid (AP5) and were completely blocked with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). 4. L-Histidine, which preferentially forms complexes with Cu2+ > Zn2+ > Fe2+ > Mn2+, inhibited both naturally occurring spontaneous and evoked GABAA-mediated large synaptic potentials without affecting the neuronal resting membrane properties. Exogenously applied Zn2+ induced large spontaneous synaptic potentials and prolonged the duration of the evoked potentials. These effects were reversibly blocked by histidine. 5. The metal chelating agent diethyldithiocarbamate had little effect on the large amplitude synaptic potentials. 6. The transition metal divalent cations Fe2+ and Mn2+ did not initiate large synaptic potentials in CA3 neurones; however, Cu2+ depolarized the membrane and enhanced both excitatory and inhibitory synaptic transmission, resulting in a transient increase in the frequency of the large amplitude events. In comparison, zinc increased the frequency of the large potentials and also induced such events in neurons (P4-21) where innate potentials were absent. The postsynaptic

  3. Regulation of Synaptic Transmission by RAB-3 and RAB-27 in Caenorhabditis elegans

    PubMed Central

    Mahoney, Timothy R.; Liu, Qiang; Itoh, Takashi; Luo, Shuo; Hadwiger, Gayla; Vincent, Rose; Wang, Zhao-Wen; Fukuda, Mitsunori

    2006-01-01

    Rab small GTPases are involved in the transport of vesicles between different membranous organelles. RAB-3 is an exocytic Rab that plays a modulatory role in synaptic transmission. Unexpectedly, mutations in the Caenorhabditis elegans RAB-3 exchange factor homologue, aex-3, cause a more severe synaptic transmission defect as well as a defecation defect not seen in rab-3 mutants. We hypothesized that AEX-3 may regulate a second Rab that regulates these processes with RAB-3. We found that AEX-3 regulates another exocytic Rab, RAB-27. Here, we show that C. elegans RAB-27 is localized to synapse-rich regions pan-neuronally and is also expressed in intestinal cells. We identify aex-6 alleles as containing mutations in rab-27. Interestingly, aex-6 mutants exhibit the same defecation defect as aex-3 mutants. aex-6; rab-3 double mutants have behavioral and pharmacological defects similar to aex-3 mutants. In addition, we demonstrate that RBF-1 (rabphilin) is an effector of RAB-27. Therefore, our work demonstrates that AEX-3 regulates both RAB-3 and RAB-27, that both RAB-3 and RAB-27 regulate synaptic transmission, and that RAB-27 potentially acts through its effector RBF-1 to promote soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) function. PMID:16571673

  4. NR2B-dependent cyclophilin D translocation suppresses the recovery of synaptic transmission after oxygen-glucose deprivation.

    PubMed

    Zhang, Zhihua; Wang, Yongfu; Yan, Shijun; Du, Fang; Yan, Shirley Shidu

    2015-10-01

    N-methyl d-aspartate receptor (NMDA) subunit 2B (NR2B)-containing NMDA receptors and mitochondrial protein cyclophilin D (CypD) are well characterized in mediating neuronal death after ischemia, respectively. However, whether and how NR2B and CypD work together in mediating synaptic injury after ischemia remains elusive. Using an ex vivo ischemia model of oxygen-glucose deprivation (OGD) in hippocampal slices, we identified a NR2B-dependent mechanism for CypD translocation onto the mitochondrial inner membrane. CypD depletion (CypD null mice) prevented OGD-induced impairment in synaptic transmission recovery. Overexpression of neuronal CypD mice (CypD+) exacerbated OGD-induced loss of synaptic transmission. Inhibition of CypD-dependent mitochondrial permeability transition pore (mPTP) opening by cyclosporine A (CSA) attenuated ischemia-induced synaptic perturbation in CypD+ and non-transgenic (non-Tg) mice. The treatment of antioxidant EUK134 to suppress mitochondrial oxidative stress rescued CypD-mediated synaptic dysfunction following OGD in CypD+ slices. Furthermore, OGD provoked the interaction of CypD with P53, which was enhanced in slices overexpressing CypD but was diminished in CypD-null slices. Inhibition of p53 using a specific inhibitor of p53 (pifithrin-μ) attenuated the CypD/p53 interaction following OGD, along with a restored synaptic transmission in both non-Tg and CypD+ hippocampal slices. Our results indicate that OGD-induced CypD translocation potentiates CypD/P53 interaction in a NR2B dependent manner, promoting oxidative stress and loss of synaptic transmission. We also evaluate a new ex vivo chronic OGD-induced ischemia model for studying the effect of oxidative stress on synaptic damage. PMID:26232180

  5. Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus.

    PubMed Central

    Lledo, P M; Tremblay, P; DeArmond, S J; Prusiner, S B; Nicoll, R A

    1996-01-01

    We recorded in the CA1 region from hippocampal slices of prion protein (PrP) gene knockout mice to investigate whether the loss of the normal form of prion protein (PrPC) affects neuronal excitability as well as synaptic transmission in the central nervous system. No deficit in synaptic inhibition was found using field potential recordings because (i) responses induced by stimulation in stratum radiatum consisted of a single population spike in PrP gene knockout mice similar to that recorded from control mice and (ii) the plot of field excitatory postsynaptic potential slope versus the population spike amplitude showed no difference between the two groups of mice. Intracellular recordings also failed to detect any difference in cell excitability and the reversal potential for inhibitory postsynaptic potentials. Analysis of the kinetics of inhibitory postsynaptic current revealed no modification. Finally, we examined whether synaptic plasticity was altered and found no difference in long-term potentiation between control and PrP gene knockout mice. On the basis of our findings, we propose that the loss of the normal form of prion protein does not alter the physiology of the CA1 region of the hippocampus. PMID:8637886

  6. Mice Deficient for Prion Protein Exhibit Normal Neuronal Excitability and Synaptic Transmission in the Hippocampus

    NASA Astrophysics Data System (ADS)

    Lledo, Pierre-Marie; Tremblay, Patrick; Dearmond, Stephen J.; Prusiner, Stanley B.; Nicoll, Roger A.

    1996-03-01

    We recorded in the CA1 region from hippocampal slices of prion protein (PrP) gene knockout mice to investigate whether the loss of the normal form of prion protein (PrPC) affects neuronal excitability as well as synaptic transmission in the central nervous system. No deficit in synaptic inhibition was found using field potential recordings because (i) responses induced by stimulation in stratum radiatum consisted of a single population spike in PrP gene knockout mice similar to that recorded from control mice and (ii) the plot of field excitatory postsynaptic potential slope versus the population spike amplitude showed no difference between the two groups of mice. Intracellular recordings also failed to detect any difference in cell excitability and the reversal potential for inhibitory postsynaptic potentials. Analysis of the kinetics of inhibitory postsynaptic current revealed no modification. Finally, we examined whether synaptic plasticity was altered and found no difference in long-term potentiation between control and PrP gene knockout mice. On the basis of our findings, we propose that the loss of the normal form of prion protein does not alter the physiology of the CA1 region of the hippocampus.

  7. Overexpression of Swedish mutant APP in aged astrocytes attenuates excitatory synaptic transmission.

    PubMed

    Katsurabayashi, Shutaro; Kawano, Hiroyuki; Ii, Miyuki; Nakano, Sachiko; Tatsumi, Chihiro; Kubota, Kaori; Takasaki, Kotaro; Mishima, Kenichi; Fujiwara, Michihiro; Iwasaki, Katsunori

    2016-01-01

    Amyloid precursor protein (APP), a type I transmembrane protein, has different aspects, namely, performs essential physiological functions and produces β-amyloid peptide (Aβ). Overexpression of neuronal APP is responsible for synaptic dysfunction. In the central nervous system, astrocytes - a major glial cell type - have an important role in the regulation of synaptic transmission. Although APP is expressed in astrocytes, it remains unclear whether astrocytic overexpression of mutant APP affects synaptic transmission. In this study, the effect of astrocytic overexpression of a mutant APP on the excitatory synaptic transmission was investigated using coculture system of the transgenic (Tg) cortical astrocytes that express the human APP695 polypeptide with the double mutation K670N + M671L found in a large Swedish family with early onset Alzheimer's disease, and wild-type hippocampal neuron. Significant secretion of Aβ 1-40 and 1-42 was observed in cultured cortical astrocytes from the Tg2576 transgenic mouse that genetically overexpresses Swedish mutant APP. Under the condition, Tg astrocytes did not affect excitatory synaptic transmission of cocultured wild-type neurons. However, aged Tg astrocytes cultured for 9 weeks elicited a significant decrease in excitatory synaptic transmission in cocultured neurons. Moreover, a reduction in the number of readily releasable synaptic vesicles accompanied a decrease in the number of excitatory synapses in neurons cocultured with aged Tg astrocytes. These observations indicate that astrocytic expression of the mutant APP is involved in the downregulation of synaptic transmission with age. PMID:26733247

  8. Developmental Exposure to Perchlorate Alters Synaptic Transmission in Hippocampus of the Adult Rat

    PubMed Central

    Gilbert, Mary E.; Sui, Li

    2008-01-01

    Background Perchlorate is an environmental contaminant that blocks iodine uptake into the thyroid gland and reduces thyroid hormones. This action of perchlorate raises significant concern over its effects on brain development. Objectives The purpose of this study was to evaluate neurologic function in rats after developmental exposure to perchlorate. Methods Pregnant rats were exposed to 0, 30, 300, or 1,000 ppm perchlorate in drinking water from gestational day 6 until weaning. Adult male offspring were evaluated on a series of behavioral tasks and neurophysiologic measures of synaptic function in the hippocampus. Results At the highest perchlorate dose, triiodothyronine (T3) and thyroxine (T4) were reduced in pups on postnatal day 21. T4 in dams was reduced relative to controls by 16%, 28%, and 60% in the 30-, 300-, and 1,000-ppm dose groups, respectively. Reductions in T4 were associated with increases in thyroid-stimulating hormone in the high-dose group. No changes were seen in serum T3. Perchlorate did not impair motor activity, spatial learning, or fear conditioning. However, significant reductions in baseline synaptic transmission were observed in hippocampal field potentials at all dose levels. Reductions in inhibitory function were evident at 300 and 1,000 ppm, and augmentations in long-term potentiation were observed in the population spike measure at the highest dose. Conclusions Dose-dependent deficits in hippocampal synaptic function were detectable with relatively minor perturbations of the thyroid axis, indicative of an irreversible impairment in synaptic transmission in response to developmental exposure to perchlorate. PMID:18560531

  9. Enhancement of synaptic transmission induced by BDNF in cultured cortical neurons

    NASA Astrophysics Data System (ADS)

    He, Jun; Gong, Hui; Zeng, Shaoqun; Li, Yanling; Luo, Qingming

    2005-03-01

    Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, BDNF has been reported to exert an acute potentiation of synaptic activity and are critically involved in long-term potentiation (LTP). We found that BDNF rapidly induced potentiation of synaptic activity and an increase in the intracellular Ca2+ concentration in cultured cortical neurons. Within minutes of BDNF application to cultured cortical neurons, spontaneous firing rate was dramatically increased as were the frequency and amplitude of excitatory spontaneous postsynaptic currents (EPSCs). Fura-2 recordings showed that BDNF acutely elicited an increase in intracellular calcium concentration ([Ca2+]c). This effect was partially dependent on [Ca2+]o; The BDNF-induced increase in [Ca2+]c can not be completely blocked by Ca2+-free solution. It was completely blocked by K252a and partially blocked by Cd2+ and TTX. The results demonstrate that BDNF can enhances synaptic transmission and that this effect is accompanied by a rise in [Ca2+]c that requires two route: the release of Ca2+ from intracellular calcium stores and influx of extracellular Ca2+ through voltage-dependent Ca2+ channels in cultured cortical neurons.

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

    NASA Technical Reports Server (NTRS)

    Cochran, S. L.

    1995-01-01

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

  11. TRPV1 receptors augment basal synaptic transmission in CA1 and CA3 pyramidal neurons in epilepsy.

    PubMed

    Saffarzadeh, F; Eslamizade, M J; Mousavi, S M M; Abraki, S B; Hadjighassem, M R; Gorji, A

    2016-02-01

    Temporal lobe epilepsy in human and animals is attributed to alterations in brain function especially hippocampus formation. Changes in synaptic activity might be causally related to the alterations during epileptogenesis. Transient receptor potential vanilloid 1 (TRPV1) as one of the non-selective ion channels has been shown to be involved in synaptic transmission. However, the potential role of TRPV1 receptors in synaptic function in the epileptic brain needs to be elucidated. In the present study, we used quantitative real-time PCR (qRT-PCR), western blotting, and immunohistochemistry to assess hippocampal TRPV1 mRNA expression, protein content, and distribution. Moreover, the effects of pharmacologic activation and inhibition of TRPV1 receptors on the slope of evoked field excitatory postsynaptic potentials (fEPSPs) were analyzed in CA1 and CA3 pyramidal neurons, after 3months of pilocarpine-induced status epilepticus (SE). SE induced an upregulation of TRPV1 mRNA and protein content in the whole hippocampal extract, as well as its distribution in both CA1 and CA3 regions. Activation and inhibition of TRPV1 receptors (via capsaicin 1μM and capsazepine 10μM, respectively) did not influence basal synaptic transmission in CA1 and CA3 regions of control slices, however, capsaicin increased and capsazepine decreased synaptic transmission in both regions in tissues from epileptic animals. Taken together, these findings suggest that a higher expression of TRPV1 in the epileptic condition is accompanied by alterations in basal synaptic transmission. PMID:26621124

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

    PubMed Central

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

    2014-01-01

    Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (τ≈200 ms), highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca2+ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form of synaptic modulation

  13. Extracellular ATP hydrolysis inhibits synaptic transmission by increasing ph buffering in the synaptic cleft.

    PubMed

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

    2014-05-01

    Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (τ≈200 ms), highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca²⁺ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form of synaptic

  14. Synaptic modulation of excitatory synaptic transmission by nicotinic acetylcholine receptors in spinal ventral horn neurons.

    PubMed

    Mine, N; Taniguchi, W; Nishio, N; Izumi, N; Miyazaki, N; Yamada, H; Nakatsuka, T; Yoshida, M

    2015-04-01

    Nicotinic acetylcholine receptors (nAChRs) are distributed widely in the central nervous system and play important roles in higher brain functions, including learning, memory, and recognition. However, functions of the cholinergic system in spinal motoneurons remain poorly understood. In this study, we investigated the actions of presynaptic and postsynaptic nAChRs in spinal ventral horn neurons by performing whole-cell patch-clamp recordings on lumbar slices from male rats. The application of nicotine or acetylcholine generated slow inward currents and increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Slow inward currents by acetylcholine or nicotine were not inhibited by tetrodotoxin (TTX) or glutamate receptor antagonists. In the presence of TTX, the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) were also increased by acetylcholine or nicotine. A selective α4β2 nicotinic receptor antagonist, dihydro-β-erythroidine hydrobromide (DhβE), significantly decreased nicotine-induced inward currents without affecting the enhancement of sEPSCs and mEPSCs. In addition, a selective α7 nicotinic receptor antagonist, methyllycaconitine, did not affect either nicotine-induced inward currents or the enhancement of sEPSCs and mEPSCs. These results suggest that α4β2 AChRs are localized at postsynaptic sites in the spinal ventral horn, non-α4β2 and non-α7 nAChRs are located presynaptically, and nAChRs enhance excitatory synaptic transmission in the spinal ventral horn. PMID:25613686

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

    PubMed

    Huang, YuYing; Chen, JunFang; Chen, Ying; Zhuang, YingHan; Sun, Mu; Behnisch, Thomas

    2015-01-01

    The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson's disease-like symptoms following administration to mice, monkeys, and humans. A common view is that MPTP is metabolized to 1-methyl-4-phenylpyridinium ion (MPP(+)) to induce its neurodegenerative effects on dopaminergic neurons in the substantia nigra (SN). Moreover, the hippocampus contains dopaminergic fibers, which are projecting from the ventral tegmental area, SN and pars compacta and contain the whole machinery required for dopamine synthesis making them sensitive to MPTP and MPP(+). Here, we present data showing that acute bath-application of MPP(+) elicited a dose-dependent facilitation followed by a depression of synaptic transmission of hippocampal Schaffer collaterals-CA1 synapses in mice. The effects of MPP(+) were not mediated by D1/D5- and D2-like receptor activation. Inhibition of the dopamine transporters did not prevent but increased the depression of excitatory post-synaptic field potentials. In the search for a possible mechanism, we observed that MPP(+) reduced the appearance of polyspikes in population spikes recorded in str. pyramidale and increased the frequency of miniature inhibitory post-synaptic currents. The acute effect of MPP(+) on synaptic transmission was attenuated by co-application of a GABAA receptor antagonist. Taking these data together, we suggest that MPP(+) affects hippocampal synaptic transmission by enhancing some aspects of the hippocampal GABAergic system. PMID:26300734

  16. TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

    PubMed Central

    Liu, Tong; Berta, Temugin; Xu, Zhen-Zhong; Park, Chul-Kyu; Zhang, Ling; Lü, Ning; Liu, Qin; Liu, Yang; Gao, Yong-Jing; Liu, Yen-Chin; Ma, Qiufu; Dong, Xinzhong; Ji, Ru-Rong

    2012-01-01

    Itch, also known as pruritus, is a common, intractable symptom of several skin diseases, such as atopic dermatitis and xerosis. TLRs mediate innate immunity and regulate neuropathic pain, but their roles in pruritus are elusive. Here, we report that scratching behaviors induced by histamine-dependent and -independent pruritogens are markedly reduced in mice lacking the Tlr3 gene. TLR3 is expressed mainly by small-sized primary sensory neurons in dorsal root ganglions (DRGs) that coexpress the itch signaling pathway components transient receptor potential subtype V1 and gastrin-releasing peptide. Notably, we found that treatment with a TLR3 agonist induces inward currents and action potentials in DRG neurons and elicited scratching in WT mice but not Tlr3–/– mice. Furthermore, excitatory synaptic transmission in spinal cord slices and long-term potentiation in the intact spinal cord were impaired in Tlr3–/– mice but not Tlr7–/– mice. Consequently, central sensitization–driven pain hypersensitivity, but not acute pain, was impaired in Tlr3–/– mice. In addition, TLR3 knockdown in DRGs also attenuated pruritus in WT mice. Finally, chronic itch in a dry skin condition was substantially reduced in Tlr3–/– mice. Our findings demonstrate a critical role of TLR3 in regulating sensory neuronal excitability, spinal cord synaptic transmission, and central sensitization. TLR3 may serve as a new target for developing anti-itch treatment. PMID:22565312

  17. Graphene Oxide Nanosheets Disrupt Lipid Composition, Ca(2+) Homeostasis, and Synaptic Transmission in Primary Cortical Neurons.

    PubMed

    Bramini, Mattia; Sacchetti, Silvio; Armirotti, Andrea; Rocchi, Anna; Vázquez, Ester; León Castellanos, Verónica; Bandiera, Tiziano; Cesca, Fabrizia; Benfenati, Fabio

    2016-07-26

    Graphene has the potential to make a very significant impact on society, with important applications in the biomedical field. The possibility to engineer graphene-based medical devices at the neuronal interface is of particular interest, making it imperative to determine the biocompatibility of graphene materials with neuronal cells. Here we conducted a comprehensive analysis of the effects of chronic and acute exposure of rat primary cortical neurons to few-layer pristine graphene (GR) and monolayer graphene oxide (GO) flakes. By combining a range of cell biology, microscopy, electrophysiology, and "omics" approaches we characterized the graphene-neuron interaction from the first steps of membrane contact and internalization to the long-term effects on cell viability, synaptic transmission, and cell metabolism. GR/GO flakes are found in contact with the neuronal membrane, free in the cytoplasm, and internalized through the endolysosomal pathway, with no significant impact on neuron viability. However, GO exposure selectively caused the inhibition of excitatory transmission, paralleled by a reduction in the number of excitatory synaptic contacts, and a concomitant enhancement of the inhibitory activity. This was accompanied by induction of autophagy, altered Ca(2+) dynamics, and a downregulation of some of the main players in the regulation of Ca(2+) homeostasis in both excitatory and inhibitory neurons. Our results show that, although graphene exposure does not impact neuron viability, it does nevertheless have important effects on neuronal transmission and network functionality, thus warranting caution when planning to employ this material for neurobiological applications. PMID:27359048

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-07-01

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

  20. Precise Synaptic Efficacy Alignment Suggests Potentiation Dominated Learning.

    PubMed

    Hartmann, Christoph; Miner, Daniel C; Triesch, Jochen

    2015-01-01

    Recent evidence suggests that parallel synapses from the same axonal branch onto the same dendritic branch have almost identical strength. It has been proposed that this alignment is only possible through learning rules that integrate activity over long time spans. However, learning mechanisms such as spike-timing-dependent plasticity (STDP) are commonly assumed to be temporally local. Here, we propose that the combination of temporally local STDP and a multiplicative synaptic normalization mechanism is sufficient to explain the alignment of parallel synapses. To address this issue, we introduce three increasingly complex models: First, we model the idealized interaction of STDP and synaptic normalization in a single neuron as a simple stochastic process and derive analytically that the alignment effect can be described by a so-called Kesten process. From this we can derive that synaptic efficacy alignment requires potentiation-dominated learning regimes. We verify these conditions in a single-neuron model with independent spiking activities but more realistic synapses. As expected, we only observe synaptic efficacy alignment for long-term potentiation-biased STDP. Finally, we explore how well the findings transfer to recurrent neural networks where the learning mechanisms interact with the correlated activity of the network. We find that due to the self-reinforcing correlations in recurrent circuits under STDP, alignment occurs for both long-term potentiation- and depression-biased STDP, because the learning will be potentiation dominated in both cases due to the potentiating events induced by correlated activity. This is in line with recent results demonstrating a dominance of potentiation over depression during waking and normalization during sleep. This leads us to predict that individual spine pairs will be more similar after sleep compared to after sleep deprivation. In conclusion, we show that synaptic normalization in conjunction with coordinated

  1. Precise Synaptic Efficacy Alignment Suggests Potentiation Dominated Learning

    PubMed Central

    Hartmann, Christoph; Miner, Daniel C.; Triesch, Jochen

    2016-01-01

    Recent evidence suggests that parallel synapses from the same axonal branch onto the same dendritic branch have almost identical strength. It has been proposed that this alignment is only possible through learning rules that integrate activity over long time spans. However, learning mechanisms such as spike-timing-dependent plasticity (STDP) are commonly assumed to be temporally local. Here, we propose that the combination of temporally local STDP and a multiplicative synaptic normalization mechanism is sufficient to explain the alignment of parallel synapses. To address this issue, we introduce three increasingly complex models: First, we model the idealized interaction of STDP and synaptic normalization in a single neuron as a simple stochastic process and derive analytically that the alignment effect can be described by a so-called Kesten process. From this we can derive that synaptic efficacy alignment requires potentiation-dominated learning regimes. We verify these conditions in a single-neuron model with independent spiking activities but more realistic synapses. As expected, we only observe synaptic efficacy alignment for long-term potentiation-biased STDP. Finally, we explore how well the findings transfer to recurrent neural networks where the learning mechanisms interact with the correlated activity of the network. We find that due to the self-reinforcing correlations in recurrent circuits under STDP, alignment occurs for both long-term potentiation- and depression-biased STDP, because the learning will be potentiation dominated in both cases due to the potentiating events induced by correlated activity. This is in line with recent results demonstrating a dominance of potentiation over depression during waking and normalization during sleep. This leads us to predict that individual spine pairs will be more similar after sleep compared to after sleep deprivation. In conclusion, we show that synaptic normalization in conjunction with coordinated

  2. The impact of synaptic conductance on action potential waveform: evoking realistic action potentials with a simulated synaptic conductance.

    PubMed

    Johnston, Jamie; Postlethwaite, Michael; Forsythe, Ian D

    2009-10-15

    Most current clamp studies trigger action potentials (APs) by step current injection through the recording electrode and assume that the resulting APs are essentially identical to those triggered by orthodromic synaptic inputs. However this assumption is not always valid, particularly when the synaptic conductance is of large magnitude and of close proximity to the axon initial segment. We addressed this question of similarity using the Calyx of Held/MNTB synapse; we compared APs evoked by long duration step current injections, short step current injections and orthodromic synaptic stimuli. Neither injected current protocol evoked APs that matched the evoked orthodromic AP waveform, showing differences in AP height, half-width and after-hyperpolarization. We postulated that this 'error' could arise from changes in the instantaneous conductance during the combined synaptic and AP waveforms, since the driving forces for the respective ionic currents are integrating and continually evolving over this time-course. We demonstrate that a simple Ohm's law manipulation of the EPSC waveform, which accounts for the evolving driving force on the synaptic conductance during the AP, produces waveforms that closely mimic those generated by physiological synaptic stimulation. This stimulation paradigm allows supra-threshold physiological stimulation (single stimuli or trains) without the variability caused by quantal fluctuation in transmitter release, and can be implemented without a specialised dynamic clamp system. Combined with pharmacological tools this method provides a reliable means to assess the physiological roles of postsynaptic ion channels without confounding affects from the presynaptic input. PMID:19560491

  3. Synaptic transmission and the susceptibility of HIV infection to anti-viral drugs

    NASA Astrophysics Data System (ADS)

    Komarova, Natalia L.; Levy, David N.; Wodarz, Dominik

    2013-07-01

    Cell-to-cell viral transmission via virological synapses has been argued to reduce susceptibility of the virus population to anti-viral drugs through multiple infection of cells, contributing to low-level viral persistence during therapy. Using a mathematical framework, we examine the role of synaptic transmission in treatment susceptibility. A key factor is the relative probability of individual virions to infect a cell during free-virus and synaptic transmission, a currently unknown quantity. If this infection probability is higher for free-virus transmission, then treatment susceptibility is lowest if one virus is transferred per synapse, and multiple infection of cells increases susceptibility. In the opposite case, treatment susceptibility is minimized for an intermediate number of virions transferred per synapse. Hence, multiple infection via synapses does not simply lower treatment susceptibility. Without further experimental investigations, one cannot conclude that synaptic transmission provides an additional mechanism for the virus to persist at low levels during anti-viral therapy.

  4. Differential Roles of Postsynaptic Density-93 Isoforms in Regulating Synaptic Transmission

    PubMed Central

    Krüger, Juliane M.; Favaro, Plinio D.; Liu, Mingna; Kitlińska, Agata; Huang, Xiaojie; Raabe, Monika; Akad, Derya S.; Liu, Yanling; Urlaub, Henning; Dong, Yan; Xu, Weifeng

    2013-01-01

    In the postsynaptic density of glutamatergic synapses, the discs large (DLG)-membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins coordinates a multiplicity of signaling pathways to maintain and regulate synaptic transmission. Postsynaptic density-93 (PSD-93) is the most variable paralog in this family; it exists in six different N-terminal isoforms. Probably because of the structural and functional variability of these isoforms, the synaptic role of PSD-93 remains controversial. To accurately characterize the synaptic role of PSD-93, we quantified the expression of all six isoforms in the mouse hippocampus and examined them individually in hippocampal synapses. Using molecular manipulations, including overexpression, gene knockdown, PSD-93 knock-out mice combined with biochemical assays, and slice electrophysiology both in rat and mice, we demonstrate that PSD-93 is required at different developmental synaptic states to maintain the strength of excitatory synaptic transmission. This strength is differentially regulated by the six isoforms of PSD-93, including regulations of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-active and inactive synapses, and activity-dependent modulations. Collectively, these results demonstrate that alternative combinations of N-terminal PSD-93 isoforms and DLG-MAGUK paralogs can fine-tune signaling scaffolds to adjust synaptic needs to regulate synaptic transmission. PMID:24068818

  5. High-Throughput All-Optical Analysis of Synaptic Transmission and Synaptic Vesicle Recycling in Caenorhabditis elegans

    PubMed Central

    Wabnig, Sebastian; Liewald, Jana Fiona; Yu, Szi-chieh; Gottschalk, Alexander

    2015-01-01

    Synaptic vesicles (SVs) undergo a cycle of biogenesis and membrane fusion to release transmitter, followed by recycling. How exocytosis and endocytosis are coupled is intensively investigated. We describe an all-optical method for identification of neurotransmission genes that can directly distinguish SV recycling factors in C. elegans, by motoneuron photostimulation and muscular RCaMP Ca2+ imaging. We verified our approach on mutants affecting synaptic transmission. Mutation of genes affecting SV recycling (unc-26 synaptojanin, unc-41 stonin, unc-57 endophilin, itsn-1 intersectin, snt-1 synaptotagmin) showed a distinct ‘signature’ of muscle Ca2+ dynamics, induced by cholinergic motoneuron photostimulation, i.e. faster rise, and earlier decrease of the signal, reflecting increased synaptic fatigue during ongoing photostimulation. To facilitate high throughput, we measured (3–5 times) ~1000 nematodes for each gene. We explored if this method enables RNAi screening for SV recycling genes. Previous screens for synaptic function genes, based on behavioral or pharmacological assays, allowed no distinction of the stage of the SV cycle in which a protein might act. We generated a strain enabling RNAi specifically only in cholinergic neurons, thus resulting in healthier animals and avoiding lethal phenotypes resulting from knockdown elsewhere. RNAi of control genes resulted in Ca2+ measurements that were consistent with results obtained in the respective genomic mutants, albeit to a weaker extent in most cases, and could further be confirmed by opto-electrophysiological measurements for mutants of some of the genes, including synaptojanin. We screened 95 genes that were previously implicated in cholinergic transmission, and several controls. We identified genes that clustered together with known SV recycling genes, exhibiting a similar signature of their Ca2+ dynamics. Five of these genes (C27B7.7, erp-1, inx-8, inx-10, spp-10) were further assessed in respective

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

    PubMed

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

    2016-02-01

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

  7. Munc18-1 mutations that strongly impair SNARE-complex binding support normal synaptic transmission

    PubMed Central

    Meijer, Marieke; Burkhardt, Pawel; de Wit, Heidi; Toonen, Ruud F; Fasshauer, Dirk; Verhage, Matthijs

    2012-01-01

    Synaptic transmission depends critically on the Sec1p/Munc18 protein Munc18-1, but it is unclear whether Munc18-1 primarily operates as a integral part of the fusion machinery or has a more upstream role in fusion complex assembly. Here, we show that point mutations in Munc18-1 that interfere with binding to the free Syntaxin1a N-terminus and strongly impair binding to assembled SNARE complexes all support normal docking, priming and fusion of synaptic vesicles, and normal synaptic plasticity in munc18-1 null mutant neurons. These data support a prevailing role of Munc18-1 before/during SNARE-complex assembly, while its continued association to assembled SNARE complexes is dispensable for synaptic transmission. PMID:22446389

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-08-23

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

  10. Organization of synaptic transmission in the mammalian solitary complex, studied in vitro.

    PubMed Central

    Champagnat, J; Denavit-Saubié, M; Grant, K; Shen, K F

    1986-01-01

    1. Synaptic transmission and neuronal morphology were studied in the nucleus tractus solitarius and in the dorsal vagal motor nucleus (solitary complex), in coronal brain-stem slices of rat or cat, superfused in vitro. 2. Electrical stimulation of afferent fibres of the solitary tract evoked two different types of post-synaptic response recorded intracellularly in different solitary complex neurones. Labelling with horseradish peroxidase showed that these two sorts of orthodromically evoked responses were correlated with different post-synaptic neuronal morphologies. 3. The majority of recorded neurones (n = 93) showed a prolonged reduction in excitability following the initial solitary-tract-evoked excitatory post-synaptic potential (e.p.s.p.). A smaller number of neurones (n = 53) showed a prolonged increase in excitability following solitary tract stimulation. In no case did the solitary tract stimulation induce a burst of action potentials at high frequency. 4. The time-to-peak and the half-width of the initial solitary-tract-evoked e.p.s.p. were shorter in neurones with prolonged increased excitability than in those with prolonged reduced excitability. In neurones with prolonged reduced excitability, this e.p.s.p. was followed by a hyperpolarization lasting 60-100 ms. The latency of this inhibitory post-synaptic potential (i.p.s.p.) was 3-5 ms longer than that of the initial e.p.s.p. and its reversal potential was 10 mV more negative than the reversal potential of the response measured following application of gamma-aminobutyric acid or glycine. In neurones with prolonged increased excitability, at a membrane potential of -40 to -50 mV, the initial solitary tract e.p.s.p. was followed by a prolonged depolarization lasting 100-400 ms. 5. Background synaptic activity was high in neurones with prolonged increased excitability, consisting of unitary e.p.s.p.s with an amplitude of more than 0.8 mV. This activity was increased for a period of 300-800 ms following

  11. Finite Post Synaptic Potentials Cause a Fast Neuronal Response

    PubMed Central

    Helias, Moritz; Deger, Moritz; Rotter, Stefan; Diesmann, Markus

    2011-01-01

    A generic property of the communication between neurons is the exchange of pulses at discrete time points, the action potentials. However, the prevalent theory of spiking neuronal networks of integrate-and-fire model neurons relies on two assumptions: the superposition of many afferent synaptic impulses is approximated by Gaussian white noise, equivalent to a vanishing magnitude of the synaptic impulses, and the transfer of time varying signals by neurons is assessable by linearization. Going beyond both approximations, we find that in the presence of synaptic impulses the response to transient inputs differs qualitatively from previous predictions. It is instantaneous rather than exhibiting low-pass characteristics, depends non-linearly on the amplitude of the impulse, is asymmetric for excitation and inhibition and is promoted by a characteristic level of synaptic background noise. These findings resolve contradictions between the earlier theory and experimental observations. Here we review the recent theoretical progress that enabled these insights. We explain why the membrane potential near threshold is sensitive to properties of the afferent noise and show how this shapes the neural response. A further extension of the theory to time evolution in discrete steps quantifies simulation artifacts and yields improved methods to cross check results. PMID:21427776

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

    PubMed

    Sun, Jianli; Kapur, Jaideep

    2012-08-15

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

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

    PubMed

    Maroteaux, Matthieu; Liu, Siqiong June

    2016-01-01

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

  14. Alteration of AMPA Receptor-Mediated Synaptic Transmission by Alexa Fluor 488 and 594 in Cerebellar Stellate Cells123

    PubMed Central

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

    Neuronal communication imposes a heavy metabolic burden in maintaining ionic gradients essential for action potential firing and synaptic signaling. Although cellular metabolism is known to regulate excitatory neurotransmission, it is still unclear whether the brain’s energy supply affects inhibitory signaling. Here we show that mitochondrial-derived reactive oxygen species (mROS) regulate the strength of postsynaptic GABAA receptors at inhibitory synapses of cerebellar stellate cells. Inhibition is strengthened through a mechanism that selectively recruits α3-containing GABAA receptors into synapses with no discernible effect on resident α1-containing receptors. Since mROS promotes the emergence of postsynaptic events with unique kinetic properties, we conclude that newly-recruited α3-containing GABAA receptors are activated by neurotransmitter released onto discrete postsynaptic sites. Although traditionally associated with oxidative stress in neurodegenerative disease, our data identifies mROS as a putative homeostatic signaling molecule coupling cellular metabolism to the strength of inhibitory transmission. PMID:24430741

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

    PubMed Central

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

    2016-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2014-01-01

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

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

    PubMed

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

    2016-01-01

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

  19. Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade

    PubMed Central

    Gainey, Melanie A.; Tatavarty, Vedakumar; Nahmani, Marc; Lin, Heather; Turrigiano, Gina G.

    2015-01-01

    Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to changes in synapse number and strength. Scaling up in response to action-potential blockade is accomplished through increased synaptic accumulation of GluA2-containing AMPA receptors (AMPAR), but the receptor trafficking steps that drive this process remain largely obscure. Here, we show that the AMPAR-binding protein glutamate receptor-interacting protein-1 (GRIP1) is essential for regulated synaptic AMPAR accumulation during scaling up. Synaptic abundance of GRIP1 was enhanced by activity deprivation, directly increasing synaptic GRIP1 abundance through overexpression increased the amplitude of AMPA miniature excitatory postsynaptic currents (mEPSCs), and shRNA-mediated GRIP1 knockdown prevented scaling up of AMPA mEPSCs. Furthermore, knockdown and replace experiments targeting either GRIP1 or GluA2 revealed that scaling up requires the interaction between GRIP1 and GluA2. Finally, GRIP1 synaptic accumulation during scaling up did not require GluA2 binding. Taken together, our data support a model in which activity-dependent trafficking of GRIP1 to synaptic sites drives the forward trafficking and enhanced synaptic accumulation of GluA2-containing AMPAR during synaptic scaling up. PMID:26109571

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

    PubMed

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

    2016-05-01

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

  1. Use-dependent inhibition of synaptic transmission by the secretion of intravesicularly accumulated antipsychotic drugs.

    PubMed

    Tischbirek, Carsten H; Wenzel, Eva M; Zheng, Fang; Huth, Tobias; Amato, Davide; Trapp, Stefan; Denker, Annette; Welzel, Oliver; Lueke, Katharina; Svetlitchny, Alexei; Rauh, Manfred; Deusser, Janina; Schwab, Annemarie; Rizzoli, Silvio O; Henkel, Andreas W; Müller, Christian P; Alzheimer, Christian; Kornhuber, Johannes; Groemer, Teja W

    2012-06-01

    Antipsychotic drugs are effective for the treatment of schizophrenia. However, the functional consequences and subcellular sites of their accumulation in nervous tissue have remained elusive. Here, we investigated the role of the weak-base antipsychotics haloperidol, chlorpromazine, clozapine, and risperidone in synaptic vesicle recycling. Using multiple live-cell microscopic approaches and electron microscopy of rat hippocampal neurons as well as in vivo microdialysis experiments in chronically treated rats, we demonstrate the accumulation of the antipsychotic drugs in synaptic vesicles and their release upon neuronal activity, leading to a significant increase in extracellular drug concentrations. The secreted drugs exerted an autoinhibitory effect on vesicular exocytosis, which was promoted by the inhibition of voltage-gated sodium channels and depended on the stimulation intensity. Taken together, these results indicate that accumulated antipsychotic drugs recycle with synaptic vesicles and have a use-dependent, autoinhibitory effect on synaptic transmission. PMID:22681688

  2. Computational quest for understanding the role of astrocyte signaling in synaptic transmission and plasticity

    PubMed Central

    De Pittà, Maurizio; Volman, Vladislav; Berry, Hugues; Parpura, Vladimir; Volterra, Andrea; Ben-Jacob, Eshel

    2012-01-01

    The complexity of the signaling network that underlies astrocyte-synapse interactions may seem discouraging when tackled from a theoretical perspective. Computational modeling is challenged by the fact that many details remain hitherto unknown and conventional approaches to describe synaptic function are unsuitable to explain experimental observations when astrocytic signaling is taken into account. Supported by experimental evidence is the possibility that astrocytes perform genuine information processing by means of their calcium signaling and are players in the physiological setting of the basal tone of synaptic transmission. Here we consider the plausibility of this scenario from a theoretical perspective, focusing on the modulation of synaptic release probability by the astrocyte and its implications on synaptic plasticity. The analysis of the signaling pathways underlying such modulation refines our notion of tripartite synapse and has profound implications on our understanding of brain function. PMID:23267326

  3. Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour.

    PubMed

    Pascoli, Vincent; Turiault, Marc; Lüscher, Christian

    2012-01-01

    Drug-evoked synaptic plasticity is observed at many synapses and may underlie behavioural adaptations in addiction. Mechanistic investigations start with the identification of the molecular drug targets. Cocaine, for example, exerts its reinforcing and early neuroadaptive effects by inhibiting the dopamine transporter, thus causing a strong increase in mesolimbic dopamine. Among the many signalling pathways subsequently engaged, phosphorylation of the extracellular signal-regulated kinase (ERK) in the nucleus accumbens is of particular interest because it has been implicated in NMDA-receptor and type 1 dopamine (D1)-receptor-dependent synaptic potentiation as well as in several behavioural adaptations. A causal link between drug-evoked plasticity at identified synapses and behavioural adaptations, however, is missing, and the benefits of restoring baseline transmission have yet to be demonstrated. Here we find that cocaine potentiates excitatory transmission in D1-receptor-expressing medium-sized spiny neurons (D1R-MSNs) in mice via ERK signalling with a time course that parallels locomotor sensitization. Depotentiation of cortical nucleus accumbens inputs by optogenetic stimulation in vivo efficiently restored normal transmission and abolished cocaine-induced locomotor sensitization. These findings establish synaptic potentiation selectively in D1R-MSNs as a mechanism underlying a core component of addiction, probably by creating an imbalance between distinct populations of MSNs in the nucleus accumbens. Our data also provide proof of principle that reversal of cocaine-evoked synaptic plasticity can treat behavioural alterations caused by addictive drugs and may inspire novel therapeutic approaches involving deep brain stimulation or transcranial magnetic stimulation. PMID:22158102

  4. PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex

    PubMed Central

    Béïque, Jean-Claude; Andrade, Rodrigo

    2003-01-01

    PSD-95 is one of the most abundant proteins found in the postsynaptic density of excitatory synapses. However, the precise functional role played by PSD-95 in regulating synaptic transmission and plasticity remains undefined. To address this issue, we have overexpressed PSD-95 in cortical pyramidal neurons in organotypic brain slices using particle-mediated gene transfer and assessed the consequences on synaptic transmission and plasticity. The AMPA receptor/NMDA receptor (AMPAR/NMDAR) ratio of evoked EPSCs recorded at +40 mV was greater in PSD-95-transfected pyramidal neurons than in controls. This difference could not be accounted for by a change in rectification of AMPAR-mediated synaptic currents since the current-voltage curves obtained in controls and in PSD-95-transfected neurons were indistinguishable. However, the amplitude of AMPAR-mediated evoked EPSCs was larger in PSD-95-transfected neurons compared to matched controls. Paired-pulse ratio analysis suggested that overexpression of PSD-95 did not alter presynaptic release probability. Transfection of PSD-95 was further accompanied by an increase in the frequency, but not amplitude, of AMPAR-mediated mEPSCs. Together, these results indicate that transfection of PSD-95 increased AMPAR-mediated synaptic transmission. Furthermore, they suggest that this phenomenon reflects an increased number of synapses expressing AMPARs rather than an increased number or function of these receptors at individual synapses. We tested the consequences of these changes on synaptic plasticity and found that PSD-95 transfection greatly enhanced the probability of observing long-term depression. These results thus identify a physiological role for PSD-95 and demonstrate that this protein can play a decisive role in controlling synaptic strength and activity-dependent synaptic plasticity. PMID:12563010

  5. Slow GABAA mediated synaptic transmission in rat visual cortex

    PubMed Central

    Sceniak, Michael P; MacIver, M Bruce

    2008-01-01

    Background Previous reports of inhibition in the neocortex suggest that inhibition is mediated predominantly through GABAA receptors exhibiting fast kinetics. Within the hippocampus, it has been shown that GABAA responses can take the form of either fast or slow response kinetics. Our findings indicate, for the first time, that the neocortex displays synaptic responses with slow GABAA receptor mediated inhibitory postsynaptic currents (IPSCs). These IPSCs are kinetically and pharmacologically similar to responses found in the hippocampus, although the anatomical specificity of evoked responses is unique from hippocampus. Spontaneous slow GABAA IPSCs were recorded from both pyramidal and inhibitory neurons in rat visual cortex. Results GABAA slow IPSCs were significantly different from fast responses with respect to rise times and decay time constants, but not amplitudes. Spontaneously occurring GABAA slow IPSCs were nearly 100 times less frequent than fast sIPSCs and both were completely abolished by the chloride channel blocker, picrotoxin. The GABAA subunit-specific antagonist, furosemide, depressed spontaneous and evoked GABAA fast IPSCs, but not slow GABAA-mediated IPSCs. Anatomical specificity was evident using minimal stimulation: IPSCs with slow kinetics were evoked predominantly through stimulation of layer 1/2 apical dendritic zones of layer 4 pyramidal neurons and across their basal dendrites, while GABAA fast IPSCs were evoked through stimulation throughout the dendritic arborization. Many evoked IPSCs were also composed of a combination of fast and slow IPSC components. Conclusion GABAA slow IPSCs displayed durations that were approximately 4 fold longer than typical GABAA fast IPSCs, but shorter than GABAB-mediated inhibition. The anatomical and pharmacological specificity of evoked slow IPSCs suggests a unique origin of synaptic input. Incorporating GABAA slow IPSCs into computational models of cortical function will help improve our understanding of

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

    PubMed Central

    Carlsen, Eva Meier; Perrier, Jean-François

    2014-01-01

    Spinal neuronal networks are essential for motor function. They are involved in the integration of sensory inputs and the generation of rhythmic motor outputs. They continuously adapt their activity to the internal state of the organism and to the environment. This plasticity can be provided by different neuromodulators. These substances are usually thought of being released by dedicated neurons. However, in other networks from the central nervous system synaptic transmission is also modulated by transmitters released from astrocytes. The star-shaped glial cell responds to neurotransmitters by releasing gliotransmitters, which in turn modulate synaptic transmission. Here we investigated if astrocytes present in the ventral horn of the spinal cord modulate synaptic transmission. We evoked synaptic inputs in ventral horn neurons recorded in a slice preparation from the spinal cord of neonatal mice. 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 an inhibition occurring at the presynaptic side of synapses. In the presence of blockers for extracellular ectonucleotidases, TFLLR did not induce presynaptic inhibition. Puffing adenosine reproduced the effect of TFLLR and blocking adenosine A1 receptors with 8-Cyclopentyl-1,3-dipropylxanthine prevented it. Altogether our results show that ventral horn astrocytes are responsible for a tonic and a phasic inhibition of excitatory synaptic transmission by releasing ATP, which gets

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

    PubMed Central

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

    2016-01-01

    Both adenosine A1 receptor and cGMP inhibit synaptic transmission at the hippocampus and recently it was found that A1 receptor increased cGMP levels in hippocampus, but the role of cGMP on A1 receptor-mediated inhibition of synaptic transmission remains to be established. In the present work we investigated if blocking the NOS/sGC/cGMP/PKG pathway using nitric oxide synthase (NOS), protein kinase G (PKG), and soluble guanylyl cyclase (sGC) inhibitors modify the A1 receptor effect on synaptic transmission. Neurotransmission was evaluated by measuring the slope of field excitatory postsynaptic potentials (fEPSPs) evoked by electrical stimulation at hippocampal slices. N6-cyclopentyladenosine (CPA, 15 nM), a selective A1 receptor agonist, reversibly decreased the fEPSPs by 54 ± 5%. Incubation of the slices with an inhibitor of NOS (L-NAME, 200 μM) decreased the CPA effect on fEPSPs by 57 ± 9% in female rats. In males, ODQ (10 μM), an sGC inhibitor, decreased the CPA inhibitory effect on fEPSPs by 23 ± 6%, but only when adenosine deaminase (ADA,1 U/ml) was present; similar results were found in females, where ODQ decreased CPA-induced inhibition of fEPSP slope by 23 ± 7%. In male rats, the presence of the PKG inhibitor (KT5823, 1 nM) decreased the CPA effect by 45.0 ± 9%; similar results were obtained in females, where KT5823 caused a 32 ± 9% decrease on the CPA effect. In conclusion, the results suggest that the inhibitory action of adenosine A1 receptors on synaptic transmission at hippocampus is, in part, mediated by the NOS/sGC/cGMP/PKG pathway. PMID:27148059

  8. MATERNAL HYPOTHYROXENEMIA LEADS TO PERSISTENT DEFICITS IN HIPPOCAMPAL SYNAPTIC TRANSMISSION AND LEARNING IN OFFSPRING.

    EPA Science Inventory

    MATERNAL HYPOTHYROXINEMIA LEADS TO PERSISTENT DEFICITS IN HIPPOCAMPAL SYNAPTIC TRANSMISSION AND LEARNING IN RAT OFFSPRING. M.E. Gilbert1 and Li Sui2, Neurotoxicology Division, 1US EPA and 2National Research Council, Research Triangle Pk, NC 27711.
    While severe hypothyroidis...

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

    PubMed

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

    2016-09-22

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

  10. Competition between recently potentiated synaptic inputs reveals a winner-take-all phase of synaptic tagging and capture

    PubMed Central

    Sajikumar, Sreedharan; Morris, Richard G. M.; Korte, Martin

    2014-01-01

    Canonical models suggest that mechanisms of long-term memory consist of a synapse-specific, protein synthesis-independent induction phase (changes in synaptic weights/temporary tagging of such synapses) and, within adjacent dendritic compartments, a protein synthesis-dependent distribution phase that may accompany or immediately precede induction and whose protein products enable consolidation through synaptic capture. We now report that this distribution phase is competitive in a “winner-take-all” fashion when synapses potentiated at induction compete with each other for plasticity-related proteins. This finding highlights the importance of synaptic competition in creating stable long-lasting memory in neural networks without disruption. PMID:25092326

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

    PubMed

    Garthwaite, John

    2016-01-01

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

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

    PubMed

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

    2015-11-01

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

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

    PubMed

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

    2012-02-01

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

  14. Increased Gene Dosage of Ube3a Results in Autism Traits and Decreased Glutamate Synaptic Transmission in Mice

    PubMed Central

    Smith, Stephen E. P.; Zhou, Yu-Dong; Zhang, Guangping; Jin, Zhe; Stoppel, David C.; Anderson, Matthew P.

    2012-01-01

    People with autism spectrum disorder are characterized by impaired social interaction, reduced communication, and increased repetitive behaviors. The disorder has a substantial genetic component, and recent studies have revealed frequent genome copy number variations (CNVs) in some individuals. A common CNV that occurs in 1 to 3% of those with autism—maternal 15q11-13 duplication (dup15) and triplication (isodicentric extranumerary chromosome, idic15)—affects several genes that have been suggested to underlie autism behavioral traits. To test this, we tripled the dosage of one of these genes, the ubiquitin protein ligase Ube3a, which is expressed solely from the maternal allele in mature neurons, and reconstituted the three core autism traits in mice: defective social interaction, impaired communication, and increased repetitive stereotypic behavior. The penetrance of these autism traits depended on Ube3a gene copy number. In animals with increased Ube3a gene dosage, glutamatergic, but not GABAergic, synaptic transmission was suppressed as a result of reduced presynaptic release probability, synaptic glutamate concentration, and postsynaptic action potential coupling. These results suggest that Ube3a gene dosage may contribute to the autism traits of individuals with maternal 15q11-13 duplication and support the idea that increased E3A ubiquitin ligase gene dosage results in reduced excitatory synaptic transmission. PMID:21974935

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

    PubMed

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

    2016-10-01

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

  16. Nitric oxide regulates synaptic transmission between spiny projection neurons

    PubMed Central

    Sagi, Yotam; Heiman, Myriam; Peterson, Jayms D.; Musatov, Sergei; Scarduzio, Mariangela; Logan, Stephen M.; Kaplitt, Michael G.; Surmeier, Dalton J.; Heintz, Nathaniel; Greengard, Paul

    2014-01-01

    Recurrent axon collaterals are a major means of communication between spiny projection neurons (SPNs) in the striatum and profoundly affect the function of the basal ganglia. However, little is known about the molecular and cellular mechanisms that underlie this communication. We show that intrastriatal nitric oxide (NO) signaling elevates the expression of the vesicular GABA transporter (VGAT) within recurrent collaterals of SPNs. Down-regulation of striatal NO signaling resulted in an attenuation of GABAergic signaling in SPN local collaterals, down-regulation of VGAT expression in local processes of SPNs, and impaired motor behavior. PKG1 and cAMP response element-binding protein are involved in the signal transduction that transcriptionally regulates VGAT by NO. These data suggest that transcriptional control of the vesicular GABA transporter by NO regulates GABA transmission and action selection. PMID:25413364

  17. Statistical models of synaptic transmission evaluated using the expectation-maximization algorithm.

    PubMed Central

    Stricker, C; Redman, S

    1994-01-01

    Amplitude fluctuations of evoked synaptic responses can be used to extract information on the probabilities of release at the active sites, and on the amplitudes of the synaptic responses generated by transmission at each active site. The parameters that describe this process must be obtained from an incomplete data set represented by the probability density of the evoked synaptic response. In this paper, the equations required to calculate these parameters using the Expectation-Maximization algorithm and the maximum likelihood criterion have been derived for a variety of statistical models of synaptic transmission. These models are ones where the probabilities associated with the different discrete amplitudes in the evoked responses are a) unconstrained, b) binomial, and c) compound binomial. The discrete amplitudes may be separated by equal (quantal) or unequal amounts, with or without quantal variance. Alternative models have been considered where the variance associated with the discrete amplitudes is sufficiently large such that no quantal amplitudes can be detected. These models involve the sum of a normal distribution (to represent failures) and a unimodal distribution (to represent the evoked responses). The implementation of the algorithm is described in each case, and its accuracy and convergence have been demonstrated. PMID:7948679

  18. Synaptic and circuit mechanisms promoting broadband transmission of olfactory stimulus dynamics.

    PubMed

    Nagel, Katherine I; Hong, Elizabeth J; Wilson, Rachel I

    2015-01-01

    Sensory stimuli fluctuate on many timescales. However, short-term plasticity causes synapses to act as temporal filters, limiting the range of frequencies that they can transmit. How synapses in vivo might transmit a range of frequencies in spite of short-term plasticity is poorly understood. The first synapse in the Drosophila olfactory system exhibits short-term depression, but can transmit broadband signals. Here we describe two mechanisms that broaden the frequency characteristics of this synapse. First, two distinct excitatory postsynaptic currents transmit signals on different timescales. Second, presynaptic inhibition dynamically updates synaptic properties to promote accurate transmission of signals across a wide range of frequencies. Inhibition is transient, but grows slowly, and simulations reveal that these two features of inhibition promote broadband synaptic transmission. Dynamic inhibition is often thought to restrict the temporal patterns that a neuron responds to, but our results illustrate a different idea: inhibition can expand the bandwidth of neural coding. PMID:25485755

  19. Synaptic and circuit mechanisms promoting broadband transmission of olfactory stimulus dynamics

    PubMed Central

    Nagel, Katherine I.; Hong, Elizabeth J.; Wilson, Rachel I.

    2014-01-01

    Sensory stimuli fluctuate on many timescales. However, short-term plasticity causes synapses to act as temporal filters, limiting the range of frequencies they can transmit. How synapses in vivo might transmit a range of frequencies in spite of short-term plasticity is poorly understood. The first synapse in the Drosophila olfactory system exhibits short-term depression, and yet can transmit broadband signals. Here we describe two mechanisms that broaden the frequency characteristics of this synapse. First, two distinct excitatory postsynaptic currents transmit signals on different timescales. Second, presynaptic inhibition dynamically updates synaptic properties to promote accurate transmission of signals across a wide range of frequencies. Inhibition is transient but grows slowly, and simulations show that these two features of inhibition promote broadband synaptic transmission. Dynamic inhibition is often thought to restrict the temporal patterns that a neuron responds to, but our results illustrate a different idea: inhibition can expand the bandwidth of neural coding. PMID:25485755

  20. Postsynaptic conversion of silent synapses during LTP affects synaptic gain and transmission dynamics.

    PubMed

    Poncer, J C; Malinow, R

    2001-10-01

    Synaptic transmission relies on both the gain and the dynamics of synapses. Activity-dependent changes in synaptic gain are well-documented at excitatory synapses and may represent a substrate for information storage in the brain. Here we examine the mechanisms of changes in transmission dynamics at excitatory synapses. We show that paired-pulse ratios (PPRs) of AMPAR and NMDAR EPSCs onto dentate gyrus granule cells are often different; this difference is reduced during LTP, reflecting PPR changes of AMPAR but not NMDAR EPSCs. Presynaptic manipulations, however, produce parallel changes in AMPAR and NMDAR EPSCs. LTP at these synapses reflects a reduction in the proportion of silent synapses lacking functional AMPARs. Changes in PPR during LTP therefore reflect the initial difference between PPRs of silent and functional synapses. Functional conversion of silent synapses permits postsynaptic sampling from additional release sites and thereby affects the dynamics and gain of signals conveyed between neurons. PMID:11544481

  1. Astrocytes contribute to the effects of etomidate on synaptic transmission in rat primary somatosensory cortex.

    PubMed

    Yang, Hao; Wang, Yuan; Zhang, Yu; Zhang, You; Xu, Mao-Sheng; Yuan, Jie; Yu, Tian

    2016-07-01

    Little is known about the mechanisms of unconsciousness induced by general anesthetics. Previous studies have shown that the primary somatosensory cortex (S1) is a sensitive region to a variety of intravenous general anesthetics. Etomidate is a widely used intravenous anesthetic that can influence synaptic transmission. Recently, there are some evidences suggesting that astrocytes, a type of glia cell, also contribute to information transmission in the brain, and modulate synaptic function by releasing neuroactive substances. However, it is unknown whether astrocytes influence the effects of etomidate on information transmission in S1 pyramidal neurons. In the present study, the role of astrocytes in etomidate-induced unconsciousness was investigated by using the whole-cell patch clamp technique. We observed etomidate at clinically relevant concentrations inhibited the spontaneous postsynaptic currents (sPSCs) of rat S1 pyramidal neurons in a concentration-dependent manner, and the EC50 value of etomidate for inhibiting sPSCs from the concentration-effect curve was 6.9μM. Furthermore, in the presence of fluorocitrate, a glia-selective metabolism inhibitor that blocks the aconitase enzyme, both the amplitude and frequency of sPSCs in rat S1 pyramidal neurons were reduced, and the inhibitory effects of etomidate on sPSCs amplitude was strengthened without affecting the effects of etomidate on frequency. From these data, we deduce that etomidate suppresses synaptic activity via presynaptic and postsynaptic components. Furthermore, astrocytes participate in synaptic transmission and influence the effects of etomidate on postsynaptic receptors. This study provides new insight into the role of astrocytes in etomidate-induced unconsciousness. PMID:27045115

  2. Effects of Modafinil on Behavioral Learning and Hippocampal Synaptic Transmission in Rats

    PubMed Central

    Chen, Chong; Wang, Hai-Xia; Li, Chu-Hua; Huang, Jun-Ni; Xiao, Peng

    2015-01-01

    Purpose: Modafinil is a wake-promoting agent that has been proposed to improve cognitive performance at the preclinical and clinical levels. Since there is insufficient evidence for modafinil to be regarded as a cognitive enhancer, the aim of this study was to investigate the effects of chronic modafinil administration on behavioral learning in healthy adult rats. Methods: Y-maze training was used to assess learning performance, and the whole-cell patch clamp technique was used to assess synaptic transmission in pyramidal neurons of the hippocampal CA1 region of rats. Results: Intraperitoneal administration of modafinil at 200 mg/kg or 300 mg/kg significantly improved learning performance. Furthermore, perfusion with 1mM modafinil enhanced the frequency and amplitude of spontaneous postsynaptic currents and spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons in hippocampal slices. However, the frequency and amplitude of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons were inhibited by treatment with 1mM modafinil. Conclusions: These results indicate that modafinil improves learning and memory in rats possibly by enhancing glutamatergic excitatory synaptic transmission and inhibiting GABAergic (gamma-aminobutyric acid-ergic) inhibitory synaptic transmission. PMID:26739176

  3. Systemic Hypoxia and the Depression of Synaptic Transmission in Rat Hippocampus after Carotid Artery Occlusion

    PubMed Central

    Fowler, J C; Gervitz, L M; Hamilton, M E; Walker, J A

    2003-01-01

    The relationship between step reductions in inspired oxygen and the amplitude of evoked field excitatory postsynaptic potentials (fEPSPs) recorded from hippocampal CA1 neurons was examined in anaesthetized rats with a unilateral common carotid artery occlusion. The amplitudes of fEPSPs recorded from the hippocampus ipsilateral to the occlusion were significantly more depressed with hypoxia than were the fEPSPs recorded from the contralateral hippocampus. The adenosine A1-selective antagonist, 8-cyclopentyl-1,3-dimethylxanthine (8-CPT), blunted the hypoxic depression of the fEPSP. Tissue partial pressure of oxygen (Ptiss,O2) was measured in the ipsilateral and contralateral hippocampus using glass Clark-style microelectrodes. Ptiss,O2 fell to similar levels as a function of inspired oxygen in the ipsilateral and contralateral hippocampus, and in the ipsilateral hippocampus after administration of 8-CPT. Hippocampal blood flow (HBF) was measured using laser Doppler flowmetry. A decline in HBF was associated with systemic hypoxia in both hippocampi. HBF, as a function of inspired oxygen, fell significantly more in the ipsilateral than in the contralateral hippocampus. We conclude that endogenous adenosine acting at the neuronal A1 receptor plays a major role in the depression of synaptic transmission during hypoxic ischaemia. The greater susceptibility of the fEPSP in the ipsilateral hippocampus to systemic hypoxia cannot be explained entirely by differences in Ptiss,O2 or HBF between the two hemispheres. PMID:12807994

  4. Raised Intracellular Calcium Contributes to Ischemia-Induced Depression of Evoked Synaptic Transmission

    PubMed Central

    Jalini, Shirin; Ye, Hui; Tonkikh, Alexander A.; Charlton, Milton P.; Carlen, Peter L.

    2016-01-01

    Oxygen-glucose deprivation (OGD) leads to depression of evoked synaptic transmission, for which the mechanisms remain unclear. We hypothesized that increased presynaptic [Ca2+]i during transient OGD contributes to the depression of evoked field excitatory postsynaptic potentials (fEPSPs). Additionally, we hypothesized that increased buffering of intracellular calcium would shorten electrophysiological recovery after transient ischemia. Mouse hippocampal slices were exposed to 2 to 8 min of OGD. fEPSPs evoked by Schaffer collateral stimulation were recorded in the stratum radiatum, and whole cell current or voltage clamp recordings were performed in CA1 neurons. Transient ischemia led to increased presynaptic [Ca2+]i, (shown by calcium imaging), increased spontaneous miniature EPSP/Cs, and depressed evoked fEPSPs, partially mediated by adenosine. Buffering of intracellular Ca2+ during OGD by membrane-permeant chelators (BAPTA-AM or EGTA-AM) partially prevented fEPSP depression and promoted faster electrophysiological recovery when the OGD challenge was stopped. The blocker of BK channels, charybdotoxin (ChTX), also prevented fEPSP depression, but did not accelerate post-ischemic recovery. These results suggest that OGD leads to elevated presynaptic [Ca2+]i, which reduces evoked transmitter release; this effect can be reversed by increased intracellular Ca2+ buffering which also speeds recovery. PMID:26934214

  5. Acute lipopolysaccharide exposure facilitates epileptiform activity via enhanced excitatory synaptic transmission and neuronal excitability in vitro

    PubMed Central

    Gao, Fei; Liu, Zhiqiang; Ren, Wei; Jiang, Wen

    2014-01-01

    Growing evidence indicates brain inflammation has been involved in the genesis of seizures. However, the direct effect of acute inflammation on neuronal circuits is not well known. Lipopolysaccharide (LPS) has been used extensively to stimulate brain inflammatory responses both in vivo and in vitro. Here, we observed the contribution of inflammation induced by 10 μg/mL LPS to the excitability of neuronal circuits in acute hippocampal slices. When slices were incubated with LPS for 30 minutes, significant increased concentration of tumor necrosis factor α and interleukin 1β were detected by enzyme-linked immunosorbent assay. In electrophysiological recordings, we found that frequency of epileptiform discharges and spikes per burst increased 30 minutes after LPS application. LPS enhanced evoked excitatory postsynaptic currents but did not modify evoked inhibitory postsynaptic currents. In addition, exposure to LPS enhanced the excitability of CA1 pyramidal neurons, as demonstrated by a decrease in rheobase and an increase in action potential frequency elicited by depolarizing current injection. Our observations suggest that acute inflammation induced by LPS facilitates epileptiform activity in vitro and that enhancement of excitatory synaptic transmission and neuronal excitability may contribute to this facilitation. These results may provide new clues for treating seizures associated with brain inflammatory disease. PMID:25170268

  6. Sulforhodamine 101 induces long-tem potentiation of intrinsic excitability and synaptic efficacy in hippocampal CA1 pyramidal neurons

    PubMed Central

    Kang, Jian; Kang, Ning; Yu, Yufei; Zhang, Jinsong; Petersen, Nicolas; Tian, Guo-Feng; Nedergaard, Maiken

    2010-01-01

    Sulforhodamine 101 (SR101) has been extensively used for investigation as a specific marker for astroglia in vivo and activity-dependent dye for monitoring regulated exocytosis. Here, we report that SR101 has bioactive effects on neuronal activity. Perfusion of slices with SR101 (1 μM) for 10 min induced long-term potentiation of intrinsic neuronal excitability (LTP-IE) and a long-lasting increase in evoked EPSCs (eEPSCs) in CA1 pyramidal neurons in hippocampal slices. The increase in intrinsic neuronal excitability was a result of negative shifts in the action potential (AP) threshold. The N-methyl D-aspartate receptor (NMDAR) antagonist, AP-5 (50 μM), blocked SR101-induced LTP-IE, but glutamate receptor blockers, AP-5 (50 μM), MCPG (200 μM), and MSOP (100 μM), only partially blocked SR101-induced potentiation of eEPSCs. SR101 induced an enhancement of evoked synaptic NMDAR currents, suggesting that SR101 enhances activation of synaptic NMDARs. SR101-induced LTP-IE and potentiation of synaptic transmission triggered spontaneous neuronal firing in slices and in vivo epileptic seizures. Our results suggest that SR101 is an epileptogenic agent that long-lastingly lowers the AP threshold to increase intrinsic neuronal excitability and enhances the synaptic efficacy to increase synaptic inputs. As such, SR101 can be used as an experimental tool to induce epileptic seizures. PMID:20600669

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

    EPA Science Inventory

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

  8. The Immunoglobulin super family protein RIG-3 prevents synaptic potentiation and regulates Wnt signaling

    PubMed Central

    Babu, Kavita; Hu, Zhitao; Chien, Shih-Chieh; Garriga, Gian; Kaplan, Joshua M.

    2011-01-01

    Cell surface Ig superfamily proteins (IgSF) have been implicated in several aspects of neuron development and function. Here, we describe a novel function for a C. elegans IgSF protein, RIG-3. Mutants lacking RIG-3 have an exaggerated paralytic response to a cholinesterase inhibitor, aldicarb. Although RIG-3 is expressed in motor neurons, heightened drug responsiveness was caused by an aldicarb-induced increase in muscle ACR-16 acetylcholine receptor (AChR) abundance, and a corresponding potentiation of post-synaptic responses at neuromuscular junctions. Mutants lacking RIG-3 also had defects in the anteroposterior polarity of the ALM mechanosensory neurons. RIG -3’s effects on synaptic transmission and ALM polarity were both mediated by changes in Wnt signaling, and in particular by inhibiting CAM-1, a Ror-type receptor tyrosine kinase that binds Wnt ligands. These results identify RIG-3 as a novel regulator of Wnt signaling, and suggest that RIG-3 has an anti-plasticity function that prevents activity-induced changes in post-synaptic receptor fields. PMID:21745641

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

    PubMed

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

    2016-07-01

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

  10. Effects of chronic stress in adolescence on learned fear, anxiety, and synaptic transmission in the rat prelimbic cortex.

    PubMed

    Negrón-Oyarzo, Ignacio; Pérez, Miguel Ángel; Terreros, Gonzalo; Muñoz, Pablo; Dagnino-Subiabre, Alexies

    2014-02-01

    The prelimbic cortex and amygdala regulate the extinction of conditioned fear and anxiety, respectively. In adult rats, chronic stress affects the dendritic morphology of these brain areas, slowing extinction of learned fear and enhancing anxiety. The aim of this study was to determine whether rats subjected to chronic stress in adolescence show changes in learned fear, anxiety, and synaptic transmission in the prelimbic cortex during adulthood. Male Sprague Dawley rats were subjected to seven days of restraint stress on postnatal day forty-two (PND 42, adolescence). Afterward, the fear-conditioning paradigm was used to study conditioned fear extinction. Anxiety-like behavior was measured one day (PND 50) and twenty-one days (PND 70, adulthood) after stress using the elevated-plus maze and dark-light box tests, respectively. With another set of rats, excitatory synaptic transmission was analyzed with slices of the prelimbic cortex. Rats that had been stressed during adolescence and adulthood had higher anxiety-like behavior levels than did controls, while stress-induced slowing of learned fear extinction in adolescence was reversed during adulthood. As well, the field excitatory postsynaptic potentials of stressed adolescent rats had significantly lower amplitudes than those of controls, although the amplitudes were higher in adulthood. Our results demonstrate that short-term stress in adolescence induces strong effects on excitatory synaptic transmission in the prelimbic cortex and extinction of learned fear, where the effect of stress on anxiety is more persistent than on the extinction of learned fear. These data contribute to the understanding of stress neurobiology. PMID:24216268

  11. Interaction of electrically evoked activity with intrinsic dynamics of cultured cortical networks with and without functional fast GABAergic synaptic transmission.

    PubMed

    Baltz, Thomas; Voigt, Thomas

    2015-01-01

    The modulation of neuronal activity by means of electrical stimulation is a successful therapeutic approach for patients suffering from a variety of central nervous system disorders. Prototypic networks formed by cultured cortical neurons represent an important model system to gain general insights in the input-output relationships of neuronal tissue. These networks undergo a multitude of developmental changes during their maturation, such as the excitatory-inhibitory shift of the neurotransmitter GABA. Very few studies have addressed how the output properties to a given stimulus change with ongoing development. Here, we investigate input-output relationships of cultured cortical networks by probing cultures with and without functional GABAAergic synaptic transmission with a set of stimulation paradigms at various stages of maturation. On the cellular level, low stimulation rates (<15 Hz) led to reliable neuronal responses; higher rates were increasingly ineffective. Similarly, on the network level, lowest stimulation rates (<0.1 Hz) lead to maximal output rates at all ages, indicating a network wide refractory period after each stimulus. In cultures aged 3 weeks and older, a gradual recovery of the network excitability within tens of milliseconds was in contrast to an abrupt recovery after about 5 s in cultures with absent GABAAergic synaptic transmission. In these GABA deficient cultures evoked responses were prolonged and had multiple discharges. Furthermore, the network excitability changed periodically, with a very slow spontaneous change of the overall network activity in the minute range, which was not observed in cultures with absent GABAAergic synaptic transmission. The electrically evoked activity of cultured cortical networks, therefore, is governed by at least two potentially interacting mechanisms: A refractory period in the order of a few seconds and a very slow GABA dependent oscillation of the network excitability. PMID:26236196

  12. Interaction of electrically evoked activity with intrinsic dynamics of cultured cortical networks with and without functional fast GABAergic synaptic transmission

    PubMed Central

    Baltz, Thomas; Voigt, Thomas

    2015-01-01

    The modulation of neuronal activity by means of electrical stimulation is a successful therapeutic approach for patients suffering from a variety of central nervous system disorders. Prototypic networks formed by cultured cortical neurons represent an important model system to gain general insights in the input–output relationships of neuronal tissue. These networks undergo a multitude of developmental changes during their maturation, such as the excitatory–inhibitory shift of the neurotransmitter GABA. Very few studies have addressed how the output properties to a given stimulus change with ongoing development. Here, we investigate input–output relationships of cultured cortical networks by probing cultures with and without functional GABAAergic synaptic transmission with a set of stimulation paradigms at various stages of maturation. On the cellular level, low stimulation rates (<15 Hz) led to reliable neuronal responses; higher rates were increasingly ineffective. Similarly, on the network level, lowest stimulation rates (<0.1 Hz) lead to maximal output rates at all ages, indicating a network wide refractory period after each stimulus. In cultures aged 3 weeks and older, a gradual recovery of the network excitability within tens of milliseconds was in contrast to an abrupt recovery after about 5 s in cultures with absent GABAAergic synaptic transmission. In these GABA deficient cultures evoked responses were prolonged and had multiple discharges. Furthermore, the network excitability changed periodically, with a very slow spontaneous change of the overall network activity in the minute range, which was not observed in cultures with absent GABAAergic synaptic transmission. The electrically evoked activity of cultured cortical networks, therefore, is governed by at least two potentially interacting mechanisms: A refractory period in the order of a few seconds and a very slow GABA dependent oscillation of the network excitability. PMID:26236196

  13. LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development.

    PubMed

    Boillot, Morgane; Lee, Chun-Yao; Allene, Camille; Leguern, Eric; Baulac, Stéphanie; Rouach, Nathalie

    2016-01-01

    The secreted leucine-rich glioma inactivated 1 (LGI1) protein is an important actor for human seizures of both genetic and autoimmune etiology: mutations in LGI1 cause inherited temporal lobe epilepsy, while LGI1 is involved in antibody-mediated encephalitis. Remarkably, Lgi1-deficient (Lgi1(-/-)) mice recapitulate the epileptic disorder and display early-onset spontaneous seizures. To understand how Lgi1-deficiency leads to seizures during postnatal development, we here investigated the early functional and structural defects occurring before seizure onset in Lgi1(-/-) mice. We found an increased excitatory synaptic transmission in hippocampal slices from Lgi1(-/-) mice. No structural alteration in the morphology of pyramidal cell dendrites and synapses was observed at this stage, indicating that Lgi1-deficiency is unlikely to trigger early developmental abnormalities. Consistent with the presynaptic subcellular localization of the protein, Lgi1-deficiency caused presynaptic defects, with no alteration in postsynaptic AMPA receptor activity in Lgi1-/- pyramidal cells before seizure onset. Presynaptic dysfunction led to increased synaptic glutamate levels, which were associated with hyperexcitable neuronal networks. Altogether, these data show that Lgi1 acts presynaptically as a negative modulator of excitatory synaptic transmission during early postnatal development. We therefore here reveal that increased presynaptic glutamate release is a key early event resulting from Lgi1-deficiency, which likely contributes to epileptogenesis. PMID:26878798

  14. LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development

    PubMed Central

    Boillot, Morgane; Lee, Chun-Yao; Allene, Camille; Leguern, Eric; Baulac, Stéphanie; Rouach, Nathalie

    2016-01-01

    The secreted leucine-rich glioma inactivated 1 (LGI1) protein is an important actor for human seizures of both genetic and autoimmune etiology: mutations in LGI1 cause inherited temporal lobe epilepsy, while LGI1 is involved in antibody-mediated encephalitis. Remarkably, Lgi1-deficient (Lgi1−/−) mice recapitulate the epileptic disorder and display early-onset spontaneous seizures. To understand how Lgi1-deficiency leads to seizures during postnatal development, we here investigated the early functional and structural defects occurring before seizure onset in Lgi1−/− mice. We found an increased excitatory synaptic transmission in hippocampal slices from Lgi1−/− mice. No structural alteration in the morphology of pyramidal cell dendrites and synapses was observed at this stage, indicating that Lgi1-deficiency is unlikely to trigger early developmental abnormalities. Consistent with the presynaptic subcellular localization of the protein, Lgi1-deficiency caused presynaptic defects, with no alteration in postsynaptic AMPA receptor activity in Lgi1−/− pyramidal cells before seizure onset. Presynaptic dysfunction led to increased synaptic glutamate levels, which were associated with hyperexcitable neuronal networks. Altogether, these data show that Lgi1 acts presynaptically as a negative modulator of excitatory synaptic transmission during early postnatal development. We therefore here reveal that increased presynaptic glutamate release is a key early event resulting from Lgi1-deficiency, which likely contributes to epileptogenesis. PMID:26878798

  15. Thrombin regulation of synaptic transmission and plasticity: implications for health and disease

    PubMed Central

    Ben Shimon, Marina; Lenz, Maximilian; Ikenberg, Benno; Becker, Denise; Shavit Stein, Efrat; Chapman, Joab; Tanne, David; Pick, Chaim G.; Blatt, Ilan; Neufeld, Miri; Vlachos, Andreas; Maggio, Nicola

    2015-01-01

    Thrombin, a serine protease involved in the blood coagulation cascade has been shown to affect neural function following blood-brain barrier breakdown. However, several lines of evidence exist that thrombin is also expressed in the brain under physiological conditions, suggesting an involvement of thrombin in the regulation of normal brain functions. Here, we review ours’ as well as others’ recent work on the role of thrombin in synaptic transmission and plasticity through direct or indirect activation of Protease-Activated Receptor-1 (PAR1). These studies propose a novel role of thrombin in synaptic plasticity, both in physiology as well as in neurological diseases associated with increased brain thrombin/PAR1 levels. PMID:25954157

  16. Taurine-Induced Long-Lasting Enhancement of Synaptic Transmission in Mice: Role of Transporters

    PubMed Central

    Sergeeva, O A; Chepkova, A N; Doreulee, N; Eriksson, K S; Poelchen, W; Mönnighoff, I; Heller-Stilb, B; Warskulat, U; Häussinger, D; Haas, H L

    2003-01-01

    Taurine, a major osmolyte in the brain evokes a long-lasting enhancement (LLETAU) of synaptic transmission in hippocampal and cortico-striatal slices. Hippocampal LLETAU was abolished by the GABA uptake blocker nipecotic acid (NPA) but not by the taurine-uptake inhibitor guanidinoethyl sulphonate (GES). Striatal LLETAU was sensitive to GES but not to NPA. Semiquantitative PCR analysis and immunohistochemistry revealed that taurine transporter expression is significantly higher in the striatum than in the hippocampus. Taurine transporter-deficient mice displayed very low taurine levels in both structures and a low ability to develop LLETAU in the striatum, but not in the hippocampus. The different mechanisms of taurine-induced synaptic plasticity may reflect the different vulnerabilities of these brain regions under pathological conditions that are accompanied by osmotic changes such as hepatic encephalopathy. PMID:12824447

  17. Synaptic long-term potentiation realized in Pavlov's dog model based on a NiOx-based memristor

    NASA Astrophysics Data System (ADS)

    Hu, S. G.; Liu, Y.; Liu, Z.; Chen, T. P.; Yu, Q.; Deng, L. J.; Yin, Y.; Hosaka, Sumio

    2014-12-01

    Synaptic Long-Term Potentiation (LTP), which is a long-lasting enhancement in signal transmission between neurons, is widely considered as the major cellular mechanism during learning and memorization. In this work, a NiOx-based memristor is found to be able to emulate the synaptic LTP. Electrical conductance of the memristor is increased by electrical pulse stimulation and then spontaneously decays towards its initial state, which resembles the synaptic LTP. The lasting time of the LTP in the memristor can be estimated with the relaxation equation, which well describes the conductance decay behavior. The LTP effect of the memristor has a dependence on the stimulation parameters, including pulse height, width, interval, and number of pulses. An artificial network consisting of three neurons and two synapses is constructed to demonstrate the associative learning and LTP behavior in extinction of association in Pavlov's dog experiment.

  18. Dendritic morphology, synaptic transmission, and activity of mature granule cells born following pilocarpine-induced status epilepticus in the rat

    PubMed Central

    Gao, Fei; Song, Xueying; Zhu, Dexiao; Wang, Xiaochen; Hao, Aijun; Nadler, J. Victor; Zhan, Ren-Zhi

    2015-01-01

    To understand the potential role of enhanced hippocampal neurogenesis after pilocarpine-induced status epilepticus (SE) in the development of epilepsy, we quantitatively analyzed the geometry of apical dendrites, synaptic transmission, and activation levels of normotopically distributed mature newborn granule cells in the rat. SE in male Sprague-Dawley rats (between 6 and 7 weeks old) lasting for more than 2 h was induced by an intraperitoneal injection of pilocarpine. The complexity, spine density, miniature post-synaptic currents, and activity-regulated cytoskeleton-associated protein (Arc) expression of granule cells born 5 days after SE were studied between 10 and 17 weeks after CAG-GFP retroviral vector-mediated labeling. Mature granule cells born after SE had dendritic complexity similar to that of granule cells born naturally, but with denser mushroom-like spines in dendritic segments located in the outer molecular layer. Miniature inhibitory post-synaptic currents (mIPSCs) were similar between the controls and rats subjected to SE; however, smaller miniature excitatory post-synaptic current (mEPSC) amplitude with a trend toward less frequent was found in mature granule cells born after SE. After maturation, granule cells born after SE did not show denser Arc expression in the resting condition or 2 h after being activated by pentylenetetrazol-induced transient seizure activity than vicinal GFP-unlabeled granule cells. Thus our results suggest that normotopic granule cells born after pilocarpine-induced SE are no more active when mature than age-matched, naturally born granule cells. PMID:26500490

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

    PubMed

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

    2016-04-01

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

  20. Membrane-tethered AKT kinase regulates basal synaptic transmission and early phase LTP expression by modulation of post-synaptic AMPA receptor level.

    PubMed

    Pen, Y; Borovok, N; Reichenstein, M; Sheinin, A; Michaelevski, I

    2016-09-01

    The serine/threonine kinase AKT/PKB plays a fundamental role in a wide variety of neuronal functions, including neuronal cell development, axonal growth, and synaptic plasticity. Multiple evidence link AKT signaling pathways to regulation of late phase long-term synaptic plasticity, synaptogenesis, and spinogenesis, as well as long-term memory formation. Nevertheless, the downstream effectors mediating the effects of AKT on early phase long-term potentiation (eLTP) are currently unknown. Here we report that using different regimes of pharmacological activation and inhibition of AKT activity in acute hippocampal slices, we found that AKT regulates the post-synaptic expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptors affecting solely the expression of eLTP, with no effect on its induction and maintenance. We further show that both maintenance of basal synaptic activity and expression of eLTP require plasma membrane tethering by activated AKT and that basal synaptic activity may be regulated via the direct effects of AKT1 on the expression level of post-synaptic AMPA receptors bypassing the canonical AKT signaling. Finally, we establish that eLTP expression requires the involvement of both the canonical AKT signaling pathways and the direct effect of AKT1 on AMPA receptor activity/expression in the post-synaptic membrane. © 2016 Wiley Periodicals, Inc. PMID:27068236

  1. Bidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression

    PubMed Central

    Brown, Joshua C.; Petersen, Amber; Zhong, Ling; Himelright, Miranda L.; Murphy, Jessica A.; Walikonis, Randall S.; Gerges, Nashaat Z.

    2016-01-01

    Dysfunction of the proteins regulating synaptic function can cause synaptic plasticity imbalance that underlies neurological disorders such as intellectual disability. A study found that four distinct mutations within BRAG1, an Arf-GEF synaptic protein, each led to X-chromosome-linked intellectual disability (XLID). Although the physiological functions of BRAG1 are poorly understood, each of these mutations reduces BRAG1's Arf-GEF activity. Here we show that BRAG1 is required for the activity-dependent removal of AMPA receptors in rat hippocampal pyramidal neurons. Moreover, we show that BRAG1 bidirectionally regulates synaptic transmission. On one hand, BRAG1 is required for the maintenance of synaptic transmission. On the other hand, BRAG1 expression enhances synaptic transmission, independently of BRAG1 Arf-GEF activity or neuronal activity, but dependently on its C-terminus interactions. This study demonstrates a dual role of BRAG1 in synaptic function and highlights the functional relevance of reduced BRAG1 Arf-GEF activity as seen in the XLID-associated human mutations. PMID:27009485

  2. Laser-evoked synaptic transmission in cultured hippocampal neurons expressing Channelrhodopsin-2 delivered by adeno-associated virus

    PubMed Central

    Wang, Jennifer; Hasan, Mazahir T.; Seung, H. Sebastian

    2009-01-01

    We present a method for studying synaptic transmission in mass cultures of dissociated hippocampal neurons based on patch clamp recording combined with laser stimulation of neurons expressing Channelrhodopsin-2 (ChR2). Our goal was to use the high spatial resolution of laser illumination to come as close as possible to the ideal of identifying monosynaptically coupled pairs of neurons, which is conventionally done using microisland rather than mass cultures. Using recombinant adeno-associated virus (rAAV) to deliver the ChR2 gene, we focused on the time period between 14 and 20 days in vitro, during which expression levels are high, and spontaneous bursting activity has not yet started. Stimulation by wide-field illumination is sufficient to make the majority of ChR2-expressing neurons spike. Stimulation with a laser spot at least 10 μm in diameter also produces action potentials, but in a reduced fraction of neurons. We studied synaptic transmission by voltage-clamping a neuron with low expression of ChR2 and scanning a 40 μm laser spot at surrounding locations. Responses were observed to stimulation at a subset of locations in the culture, indicating spatial localization of stimulation. Pharmacological means were used to identify responses that were synaptic. Many responses were of smaller amplitude than those typically found in microisland cultures. We were unable to find an entirely reliable criterion for distinguishing between monosynaptic and polysynaptic responses. However, we propose that postsynaptic currents with small amplitudes, simple shapes, and latencies not much greater than 8 msec are reasonable candidates for monosynaptic interactions. PMID:19560489

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

    PubMed

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

    2010-05-31

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

  4. A TRPV Channel in Drosophila Motor Neurons Regulates Presynaptic Resting Ca2+ Levels, Synapse Growth, and Synaptic Transmission

    PubMed Central

    Wong, Ching-On; Chen, Kuchuan; Lin, Yong Qi; Chao, Yufang; Duraine, Lita; Lu, Zhongmin; Yoon, Wan Hee; Sullivan, Jeremy M.; Broadhead, Geoffrey T.; Sumner, Charlotte J.; Lloyd, Thomas E.; Macleod, Gregory T.; Bellen, Hugo J.; Venkatachalam, Kartik

    2014-01-01

    SUMMARY Presynaptic resting Ca2+ influences synaptic vesicle (SV) release probability. Here, we report that a TRPV channel, Inactive (Iav), maintains presynaptic resting [Ca2+] by promoting Ca2+ release from the endoplasmic reticulum in Drosophila motor neurons, and is required for both synapse development and neurotransmission. We find that Iav activates the Ca2+/calmodulin-dependent protein phosphatase, calcineurin, which is essential for presynaptic microtubule stabilization at the neuromuscular junction. Thus, loss of Iav induces destabilization of presynaptic microtubules resulting in diminished synaptic growth. Interestingly, expression of human TRPV1 in Iav-deficient motor neurons rescues these defects. We also show that the absence of Iav causes lower SV release probability and diminished synaptic transmission, whereas Iav overexpression elevates these synaptic parameters. Together, our findings indicate that Iav acts as a key regulator of synaptic development and function by influencing presynaptic resting [Ca2+]. PMID:25451193

  5. Differential Dendritic Integration of Synaptic Potentials and Calcium in Cerebellar Interneurons.

    PubMed

    Tran-Van-Minh, Alexandra; Abrahamsson, Therése; Cathala, Laurence; DiGregorio, David A

    2016-08-17

    Dendritic voltage integration determines the transformation of synaptic inputs into output firing, while synaptic calcium integration drives plasticity mechanisms thought to underlie memory storage. Dendritic calcium integration has been shown to follow the same synaptic input-output relationship as dendritic voltage, but whether similar operations apply to neurons exhibiting sublinear voltage integration is unknown. We examined the properties and cellular mechanisms of these dendritic operations in cerebellar molecular layer interneurons using dendritic voltage and calcium imaging, in combination with synaptic stimulation or glutamate uncaging. We show that, while synaptic potentials summate sublinearly, concomitant dendritic calcium signals summate either linearly or supralinearly depending on the number of synapses activated. The supralinear dendritic calcium triggers a branch-specific, short-term suppression of neurotransmitter release that alters the pattern of synaptic activation. Thus, differential voltage and calcium integration permits dynamic regulation of neuronal input-output transformations without altering intrinsic nonlinear integration mechanisms. PMID:27537486

  6. Roles of N-Type and Q-Type Ca2+ Channels in Supporting Hippocampal Synaptic Transmission

    NASA Astrophysics Data System (ADS)

    Wheeler, David B.; Randall, Andrew; Tsien, Richard W.

    1994-04-01

    Several types of calcium channels found in the central nervous system are possible participants in triggering neurotransmitter release. Synaptic transmission between hippocampal CA3 and CA1 neurons was mediated by N-type calcium channels, together with calcium channels whose pharmacology differs from that of L- and P-type channels but resembles that of the Q-type channel encoded by the α1A subunit gene. Blockade of either population of channels strongly increased enhancement of synaptic transmission with repetitive stimuli. Even after complete blockade of N-type channels, transmission was strongly modulated by stimulation of neurotransmitter receptors or protein kinase C. These findings suggest a role for α1A subunits in synaptic transmission and support the idea that neurotransmitter release may depend on multiple types of calcium channels under physiological conditions.

  7. Carbamazepine and oxcarbazepine, but not eslicarbazepine, enhance excitatory synaptic transmission onto hippocampal CA1 pyramidal cells through an antagonist action at adenosine A1 receptors.

    PubMed

    Booker, Sam A; Pires, Nuno; Cobb, Stuart; Soares-da-Silva, Patrício; Vida, Imre

    2015-06-01

    This study assessed the anticonvulsant and seizure generation effects of carbamazepine (CBZ), oxcarbazepine (OXC) and eslicarbazepine (S-Lic) in wild-type mice. Electrophysiological recordings were made to discriminate potential cellular and synaptic mechanisms underlying anti- and pro-epileptic actions. The anticonvulsant and pro-convulsant effects were evaluated in the MES, the 6-Hz and the Irwin tests. Whole-cell patch-clamp recordings were used to investigate the effects on fast excitatory and inhibitory synaptic transmission in hippocampal area CA1. The safety window for CBZ, OXC and eslicarbazepine (ED50 value against the MES test and the dose that produces grade 5 convulsions in all mice), was 6.3, 6.0 and 12.5, respectively. At high concentrations the three drugs reduced synaptic transmission. CBZ and OXC enhanced excitatory postsynaptic currents (EPSCs) at low, therapeutically-relevant concentrations. These effects were associated with no change in inhibitory postsynaptic currents (IPSCs) resulting in altered balance between excitation and inhibition. S-Lic had no effect on EPSC or IPSC amplitudes over the same concentration range. The CBZ mediated enhancement of EPSCs was blocked by DPCPX, a selective antagonist, and occluded by CCPA, a selective agonist of the adenosine A1 receptor. Furthermore, reduction of endogenous adenosine by application of the enzyme adenosine deaminase also abolished the CBZ- and OXC-induced increase of EPSCs, indicating that the two drugs act as antagonists at native adenosine receptors. In conclusion, CBZ and OXC possess pro-epileptic actions at clinically-relevant concentrations through the enhancement of excitatory synaptic transmission. S-Lic by comparison has no such effect on synaptic transmission, explaining its lack of seizure exacerbation. PMID:25656478

  8. Synchronous and asynchronous modes of synaptic transmission utilize different calcium sources.

    PubMed

    Wen, Hua; Hubbard, Jeffrey M; Rakela, Benjamin; Linhoff, Michael W; Mandel, Gail; Brehm, Paul

    2013-01-01

    Asynchronous transmission plays a prominent role at certain synapses but lacks the mechanistic insights of its synchronous counterpart. The current view posits that triggering of asynchronous release during repetitive stimulation involves expansion of the same calcium domains underlying synchronous transmission. In this study, live imaging and paired patch clamp recording at the zebrafish neuromuscular synapse reveal contributions by spatially distinct calcium sources. Synchronous release is tied to calcium entry into synaptic boutons via P/Q type calcium channels, whereas asynchronous release is boosted by a propagating intracellular calcium source initiated at off-synaptic locations in the axon and axonal branch points. This secondary calcium source fully accounts for the persistence following termination of the stimulus and sensitivity to slow calcium buffers reported for asynchronous release. The neuromuscular junction and CNS neurons share these features, raising the possibility that secondary calcium sources are common among synapses with prominent asynchronous release. DOI: http://dx.doi.org/10.7554/eLife.01206.001. PMID:24368731

  9. Depression of Serotonin Synaptic Transmission by the Dopamine Precursor L-DOPA.

    PubMed

    Gantz, Stephanie C; Levitt, Erica S; Llamosas, Nerea; Neve, Kim A; Williams, John T

    2015-08-11

    Imbalance between the dopamine and serotonin (5-HT) neurotransmitter systems has been implicated in the comorbidity of Parkinson's disease (PD) and psychiatric disorders. L-DOPA, the leading treatment of PD, facilitates the production and release of dopamine. This study assessed the action of L-DOPA on monoamine synaptic transmission in mouse brain slices. Application of L-DOPA augmented the D2-receptor-mediated inhibitory postsynaptic current (IPSC) in dopamine neurons of the substantia nigra. This augmentation was largely due to dopamine release from 5-HT terminals. Selective optogenetic stimulation of 5-HT terminals evoked dopamine release, producing D2-receptor-mediated IPSCs following treatment with L-DOPA. In the dorsal raphe, L-DOPA produced a long-lasting depression of the 5-HT1A-receptor-mediated IPSC in 5-HT neurons. When D2 receptors were expressed in the dorsal raphe, application of L-DOPA resulted in a D2-receptor-mediated IPSC. Thus, treatment with L-DOPA caused ectopic dopamine release from 5-HT terminals and a loss of 5-HT-mediated synaptic transmission. PMID:26235617

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

    NASA Astrophysics Data System (ADS)

    Yu, Xian-Min; Salter, Michael W.

    1999-07-01

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

  11. Mutation of Drosophila Focal Adhesion Kinase Induces Bang-Sensitive Behavior and Disrupts Glial Function, Axonal Conduction and Synaptic Transmission

    PubMed Central

    Ueda, Atsushi; Grabbe, Caroline; Lee, Jihye; Lee, Jisue; Palmer, Ruth H.; Wu, Chun-Fang

    2009-01-01

    The role of the conserved Focal Adhesion Kinase (FAK) family of protein tyrosine kinases (PTKs) in the development and physiological functions of the CNS has long been an area of interest among neuroscientists. In this report, we observe that Drosophila mutants lacking Fak56 exhibit a decreased life span, accompanied by a bang-sensitive phenotype, which is characterised by sensitivity to mechanical and high-frequency electrical stimulation. Fak56 mutant animals display lower thresholds and higher rates of seizures in response to electroconvulsive stimuli, and direct measurements of action potential conduction in larval segmental nerves demonstrate a slowed propagation speed and failure during high-frequency nerve stimulation. In addition, neuromuscular junctions in Fak56 mutant animals display transmission blockade during high-frequency activity as a result of action potential failure. Endogenous Fak56 protein is abundant in glial cells ensheathing the axon bundles, and structural alterations of segmental nerve bundles can be observed in mutants. Manipulation of Fak56 function specifically in glial cells also disrupts action potential conduction and neurotransmission, suggesting a glial component in the Fak56 bang-sensitive phenotype. Furthermore, we show that increased intracellular calcium levels result in the dephosphorylation of endogenous Fak56 protein in Drosophila cell lines, in parallel with our observations of highly variable synaptic potentials at a higher Ca2+ level in Fak56 mutant larvae. Together these findings suggest that modulation of Fak56 function is important for action potential propagation and Ca2+-regulated neuromuscular transmission in vivo. PMID:18540882

  12. Pseudopterosin A: Protection of Synaptic Function and Potential as a Neuromodulatory Agent.

    PubMed

    Caplan, Stacee Lee; Zheng, Bo; Dawson-Scully, Ken; White, Catherine A; West, Lyndon M

    2016-03-01

    Natural products have provided an invaluable source of inspiration in the drug discovery pipeline. The oceans are a vast source of biological and chemical diversity. Recently, this untapped resource has been gaining attention in the search for novel structures and development of new classes of therapeutic agents. Pseudopterosins are group of marine diterpene glycosides that possess an array of potent biological activities in several therapeutic areas. Few studies have examined pseudopterosin effects during cellular stress and, to our knowledge, no studies have explored their ability to protect synaptic function. The present study probes pseudopterosin A (PsA) for its neuromodulatory properties during oxidative stress using the fruit fly, Drosophila melanogaster. We demonstrate that oxidative stress rapidly reduces neuronal activity, resulting in the loss of neurotransmission at a well-characterized invertebrate synapse. PsA mitigates this effect and promotes functional tolerance during oxidative stress by prolonging synaptic transmission in a mechanism that differs from scavenging activity. Furthermore, the distribution of PsA within mammalian biological tissues following single intravenous injection was investigated using a validated bioanalytical method. Comparable exposure of PsA in the mouse brain and plasma indicated good distribution of PsA in the brain, suggesting its potential as a novel neuromodulatory agent. PMID:26978375

  13. Pseudopterosin A: Protection of Synaptic Function and Potential as a Neuromodulatory Agent

    PubMed Central

    Caplan, Stacee Lee; Zheng, Bo; Dawson-Scully, Ken; White, Catherine A.; West, Lyndon M.

    2016-01-01

    Natural products have provided an invaluable source of inspiration in the drug discovery pipeline. The oceans are a vast source of biological and chemical diversity. Recently, this untapped resource has been gaining attention in the search for novel structures and development of new classes of therapeutic agents. Pseudopterosins are group of marine diterpene glycosides that possess an array of potent biological activities in several therapeutic areas. Few studies have examined pseudopterosin effects during cellular stress and, to our knowledge, no studies have explored their ability to protect synaptic function. The present study probes pseudopterosin A (PsA) for its neuromodulatory properties during oxidative stress using the fruit fly, Drosophila melanogaster. We demonstrate that oxidative stress rapidly reduces neuronal activity, resulting in the loss of neurotransmission at a well-characterized invertebrate synapse. PsA mitigates this effect and promotes functional tolerance during oxidative stress by prolonging synaptic transmission in a mechanism that differs from scavenging activity. Furthermore, the distribution of PsA within mammalian biological tissues following single intravenous injection was investigated using a validated bioanalytical method. Comparable exposure of PsA in the mouse brain and plasma indicated good distribution of PsA in the brain, suggesting its potential as a novel neuromodulatory agent. PMID:26978375

  14. GSG1L suppresses AMPA receptor-mediated synaptic transmission and uniquely modulates AMPA receptor kinetics in hippocampal neurons

    PubMed Central

    Gu, Xinglong; Mao, Xia; Lussier, Marc P.; Hutchison, Mary Anne; Zhou, Liang; Hamra, F. Kent; Roche, Katherine W.; Lu, Wei

    2016-01-01

    Regulation of AMPA receptor (AMPAR)-mediated synaptic transmission is a key mechanism for synaptic plasticity. In the brain, AMPARs assemble with a number of auxiliary subunits, including TARPs, CNIHs and CKAMP44, which are important for AMPAR forward trafficking to synapses. Here we report that the membrane protein GSG1L negatively regulates AMPAR-mediated synaptic transmission. Overexpression of GSG1L strongly suppresses, and GSG1L knockout (KO) enhances, AMPAR-mediated synaptic transmission. GSG1L-dependent regulation of AMPAR synaptic transmission relies on the first extracellular loop domain and its carboxyl-terminus. GSG1L also speeds up AMPAR deactivation and desensitization in hippocampal CA1 neurons, in contrast to the effects of TARPs and CNIHs. Furthermore, GSG1L association with AMPARs inhibits CNIH2-induced slowing of the receptors in heterologous cells. Finally, GSG1L KO rats have deficits in LTP and show behavioural abnormalities in object recognition tests. These data demonstrate that GSG1L represents a new class of auxiliary subunit with distinct functional properties for AMPARs. PMID:26932439

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

    PubMed

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

    2015-11-13

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

  16. Mutation of the Dyslexia-Associated Gene Dcdc2 Enhances Glutamatergic Synaptic Transmission Between Layer 4 Neurons in Mouse Neocortex.

    PubMed

    Che, Alicia; Truong, Dongnhu T; Fitch, R Holly; LoTurco, Joseph J

    2016-09-01

    Variants in DCDC2 have been associated with reading disability in humans, and targeted mutation of Dcdc2 in mice causes impairments in both learning and sensory processing. In this study, we sought to determine whether Dcdc2 mutation affects functional synaptic circuitry in neocortex. We found mutation in Dcdc2 resulted in elevated spontaneous and evoked glutamate release from neurons in somatosensory cortex. The probability of release was decreased to wild-type level by acute application of N-methyl-d-aspartate receptor (NMDAR) antagonists when postsynaptic NMDARs were blocked by intracellular MK-801, and could not be explained by elevated ambient glutamate, suggesting altered, nonpostsynaptic NMDAR activation in the mutants. In addition, we determined that the increased excitatory transmission was present at layer 4-layer 4 but not thalamocortical connections in Dcdc2 mutants, and larger evoked synaptic release appeared to enhance the NMDAR-mediated effect. These results demonstrate an NMDAR activation-gated, increased functional excitatory connectivity between layer 4 lateral connections in somatosensory neocortex of the mutants, providing support for potential changes in cortical connectivity and activation resulting from mutation of dyslexia candidate gene Dcdc2. PMID:26250775

  17. Loss of Predominant Shank3 Isoforms Results in Hippocampus-Dependent Impairments in Behavior and Synaptic Transmission

    PubMed Central

    Kouser, Mehreen; Speed, Haley E.; Dewey, Colleen M.; Reimers, Jeremy M.; Widman, Allie J.; Gupta, Natasha; Liu, Shunan; Jaramillo, Thomas C.; Bangash, Muhammad; Xiao, Bo; Worley, Paul F.

    2013-01-01

    The Shank3 gene encodes a scaffolding protein that anchors multiple elements of the postsynaptic density at the synapse. Previous attempts to delete the Shank3 gene have not resulted in a complete loss of the predominant naturally occurring Shank3 isoforms. We have now characterized a homozygous Shank3 mutation in mice that deletes exon 21, including the Homer binding domain. In the homozygous state, deletion of exon 21 results in loss of the major naturally occurring Shank3 protein bands detected by C-terminal and N-terminal antibodies, allowing us to more definitively examine the role of Shank3 in synaptic function and behavior. This loss of Shank3 leads to an increased localization of mGluR5 to both synaptosome and postsynaptic density-enriched fractions in the hippocampus. These mice exhibit a decrease in NMDA/AMPA excitatory postsynaptic current ratio in area CA1 of the hippocampus, reduced long-term potentiation in area CA1, and deficits in hippocampus-dependent spatial learning and memory. In addition, these mice also exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty, and minimal social abnormalities. These data suggest that Shank3 isoforms are required for normal synaptic transmission/plasticity in the hippocampus, as well as hippocampus-dependent spatial learning and memory. PMID:24259569

  18. Investigation of the juxtamembrane region of neuronal-Synaptobrevin in synaptic transmission at the Drosophila neuromuscular junction.

    PubMed

    DeMill, Colin M; Qiu, Xinping; Kisiel, Marta; Bolotta, Alanna; Stewart, Bryan A

    2014-09-15

    In this study, the juxtamembrane region of the Drosophila SNARE protein neuronal-Synaptobrevin (n-Syb) was tested for its role in synaptic transmission. A transgenic approach was used to express n-Syb mutant genes. The transgenes carried engineered point mutations that alter the amino acid sequence of the conserved tryptophan residues in the juxtamembrane sequence. Such transgenes were expressed in an n-syb hypomorphic background, which produces little endogenous protein. On their own, hypomorphic flies displayed severe motor inhibition, limited life span, reduced evoked junctional potentials (EJPs), decreased synchronicity in EJP time to peak, and potentiation of EJPs with 10-Hz stimulation. All of these deficits were restored to wild-type levels with the expression of wild-type transgenic n-syb, regulated by the endogenous promoter (n-syb(WT)). We created transgenic mutants with one additional tryptophan (n-syb(WW)) or one less tryptophan (n-syb(AA)) than the wild-type sequence. While n-syb(WW) resembled n-syb(WT) in all variables listed, n-syb(AA) exhibited decreased EJP amplitude, synchronicity, and quantal content. To determine whether the n-syb juxtamembrane region is important for transduction of force arising from SNARE complex assembly during membrane fusion, we introduced short 6-amino acid (n-syb(L6)) or long 24-amino acid (n-syb(L24)) flexible linkers into the n-syb transgene. We observed a reduced EJP amplitude in n-syb(L6) but not n-syb(L24), while both linker mutants showed a decreased quantal content and an effect on the readily releasable and recycling vesicle pools. In conclusion, mutation of the juxtamembrane region of n-syb deleteriously affected synaptic transmission at the Drosophila neuromuscular junction. PMID:24944220

  19. A computational model to investigate astrocytic glutamate uptake influence on synaptic transmission and neuronal spiking.

    PubMed

    Allam, Sushmita L; Ghaderi, Viviane S; Bouteiller, Jean-Marie C; Legendre, Arnaud; Ambert, Nicolas; Greget, Renaud; Bischoff, Serge; Baudry, Michel; Berger, Theodore W

    2012-01-01

    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. PMID:23060782

  20. Postsynaptic mGluR5 promotes evoked AMPAR-mediated synaptic transmission onto neocortical layer 2/3 pyramidal neurons during development

    PubMed Central

    Loerwald, Kristofer W.; Patel, Ankur B.; Huber, Kimberly M.

    2014-01-01

    Both short- and long-term roles for the group I metabotropic glutamate receptor number 5 (mGluR5) have been examined for the regulation of cortical glutamatergic synapses. However, how mGluR5 sculpts neocortical networks during development still remains unclear. Using a single cell deletion strategy, we examined how mGluR5 regulates glutamatergic synaptic pathways in neocortical layer 2/3 (L2/3) during development. Electrophysiological measurements were made in acutely prepared slices to obtain a functional understanding of the effects stemming from loss of mGluR5 in vivo. Loss of postsynaptic mGluR5 results in an increase in the frequency of action potential-independent synaptic events but, paradoxically, results in a decrease in evoked transmission in two separate synaptic pathways providing input to the same pyramidal neurons. Synaptic transmission through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, but not N-methyl-d-aspartate (NMDA) receptors, is specifically decreased. In the local L2/3 pathway, the decrease in evoked transmission appears to be largely due to a decrease in cell-to-cell connectivity and not in the strength of individual cell-to-cell connections. This decrease in evoked transmission correlates with a decrease in the total dendritic length in a region of the dendritic arbor that likely receives substantial input from these two pathways, thereby suggesting a morphological correlate to functional alterations. These changes are accompanied by an increase in intrinsic membrane excitability. Our data indicate that total mGluR5 function, incorporating both short- and long-term processes, promotes the strengthening of AMPA receptor-mediated transmission in multiple neocortical pathways. PMID:25392167

  1. Extracellular Ca2+ depletion contributes to fast activity-dependent modulation of synaptic transmission in the brain.

    PubMed

    Rusakov, D A; Fine, A

    2003-01-23

    Synaptic activation is associated with rapid changes in intracellular Ca(2+), while the extracellular Ca(2+) level is generally assumed to be constant. Here, using a novel optical method to measure changes in extracellular Ca(2+) at high spatial and temporal resolution, we find that brief trains of synaptic transmission in hippocampal area CA1 induce transient depletion of extracellular Ca(2+). We show that this depletion, which depends on postsynaptic NMDA receptor activation, decreases the Ca(2+) available to enter individual presynaptic boutons of CA3 pyramidal cells. This in turn reduces the probability of consecutive synaptic releases at CA3-CA1 synapses and therefore contributes to short-term paired-pulse depression of minimal responses. This activity-dependent depletion of extracellular Ca(2+) represents a novel form of fast retrograde synaptic signaling that can modulate glutamatergic information transfer in the brain. PMID:12546823

  2. Extracellular Ca2+ Depletion Contributes to Fast Activity-Dependent Modulation of Synaptic Transmission in the Brain

    PubMed Central

    Rusakov, D.A.; Fine, A.

    2012-01-01

    Summary Synaptic activation is associated with rapid changes in intracellular Ca2+, while the extracellular Ca2+ level is generally assumed to be constant. Here, using a novel optical method to measure changes in extracellular Ca2+ at high spatial and temporal resolution, we find that brief trains of synaptic transmission in hippocampal area CA1 induce transient depletion of extracellular Ca2+. We show that this depletion, which depends on postsynaptic NMDA receptor activation, decreases the Ca2+ available to enter individual presynaptic boutons of CA3 pyramidal cells. This in turn reduces the probability of consecutive synaptic releases at CA3–CA1 synapses and therefore contributes to short-term paired-pulse depression of minimal responses. This activity-dependent depletion of extracellular Ca2+ represents a novel form of fast retrograde synaptic signaling that can modulate glutamatergic information transfer in the brain. PMID:12546823

  3. Chronic activation of CB2 cannabinoid receptors in the hippocampus increases excitatory synaptic transmission

    PubMed Central

    Kim, Jimok; Li, Yong

    2015-01-01

    The roles of CB1 cannabinoid receptors in regulating neuronal activity have been extensively characterized. Although early studies show that CB1 receptors are present in the nervous system and CB2 cannabinoid receptors are in the immune system, recent evidence indicates that CB2 receptors are also expressed in the brain. Activation or blockade of CB2 receptors in vivo induces neuropsychiatric effects, but the cellular mechanisms of CB2 receptor function are unclear. The aim of this study is to determine how activation of CB2 receptors present in the hippocampus regulates synaptic function. Here, we show that when organotypic cultures of rodent hippocampal slices were treated with a CB2 receptor agonist (JWH133 or GP1a) for 7–10 days, quantal glutamate release became more frequent and spine density was increased via extracellular signal-regulated kinases. Chronic intraperitoneal injection of JWH133 into mice also increased excitatory synaptic transmission. These effects were blocked by a CB2 receptor antagonist (SR144528) or absent from hippocampal slices of CB2 receptor knock-out mice. This study reveals a novel cellular function of CB2 cannabinoid receptors in the hippocampus and provides insights into how cannabinoid receptor subtypes diversify the roles of cannabinoids in the brain. PMID:25504573

  4. Smaller Dendritic Spines, Weaker Synaptic Transmission, but Enhanced Spatial Learning in Mice Lacking Shank1

    PubMed Central

    Hung, Albert Y.; Futai, Kensuke; Sala, Carlo; Valtschanoff, Juli G.; Ryu, Jubin; Woodworth, Mollie A.; Kidd, Fleur L.; Sung, Clifford C.; Miyakawa, Tsuyoshi; Bear, Mark F.; Weinberg, Richard J.; Sheng, Morgan

    2009-01-01

    Experience-dependent changes in the structure of dendritic spines may contribute to learning and memory. Encoded by three genes, the Shank family of postsynaptic scaffold proteins are abundant and enriched in the postsynaptic density (PSD) of central excitatory synapses. When expressed in cultured hippocampal neurons, Shank promotes the maturation and enlargement of dendritic spines. Recently, Shank3 has been genetically implicated in human autism, suggesting an important role for Shank proteins in normal cognitive development. Here, we report the phenotype of Shank1 knock-out mice. Shank1 mutants showed altered PSD protein composition; reduced size of dendritic spines; smaller, thinner PSDs; and weaker basal synaptic transmission. Standard measures of synaptic plasticity were normal. Behaviorally, they had increased anxiety-related behavior and impaired contextual fear memory. Remarkably, Shank1-deficient mice displayed enhanced performance in a spatial learning task; however, their long-term memory retention in this task was impaired. These results affirm the importance of Shank1 for synapse structure and function in vivo, and they highlight a differential role for Shank1 in specific cognitive processes, a feature that may be relevant to human autism spectrum disorders. PMID:18272690

  5. LAMP5 Fine-Tunes GABAergic Synaptic Transmission in Defined Circuits of the Mouse Brain

    PubMed Central

    Tiveron, Marie-Catherine; Beurrier, Corinne; Céni, Claire; Andriambao, Naly; Combes, Alexis; Koehl, Muriel; Maurice, Nicolas; Gatti, Evelina; Abrous, Dhoher Nora; Kerkerian-Le Goff, Lydia; Pierre, Philippe; Cremer, Harold

    2016-01-01

    LAMP5 is member of the LAMP family of membrane proteins. In contrast to the canonical members of this protein family, LAMP1 and LAMP2, which show widespread expression in many tissues, LAMP 5 is brain specific in mice. In C. elegans, the LAMP5 ortholog UNC-46 has been suggested to act a trafficking chaperone, essential for the correct targeting of the nematode vesicular GABA-transporter UNC-47. We show here that in the mouse brain LAMP5 is expressed in subpopulations of GABAergic forebrain neurons in the striato-nigral system and the olfactory bulb. The protein was present at synaptic terminals, overlapping with the mammalian vesicular GABA-transporter VGAT. In LAMP5-deficient mice localization of the transporter was unaffected arguing against a conserved role in VGAT trafficking. Electrophysiological analyses in mutants showed alterations in short term synaptic plasticity suggesting that LAMP5 is involved in controlling the dynamics of evoked GABAergic transmission. At the behavioral level, LAMP5 mutant mice showed decreased anxiety and deficits in olfactory discrimination. Altogether, this work implicates LAMP5 function in GABAergic neurotransmission in defined neuronal subpopulations. PMID:27272053

  6. Synaptic transmission from rods to rod-dominated bipolar cells in the tiger salamander retina.

    PubMed

    Yang, X L; Wu, S M

    1993-06-11

    Synaptic transmission between photoreceptors and bipolar cells was studied in dark-adapted tiger salamander retinas. Based on the relative light sensitivity, bipolar cells, either depolarizing (DBC) or hyperpolarizing (HBC), fell into two groups: one receives inputs primarily from rods (rod-dominated bipolar cells, DBCR and HBCR) and the other receives inputs primarily from cones (cone-dominated bipolar cells, DBCC and HBCC). The input-output relations of the rod-DBCR and rod-HBCR synapses were determined by plotting the voltage responses of the rod and DBCR (or HBCR) to dim 500-nm light steps, which polarizes only the rods but not the cones. The slope gains of both synapses were the highest near the dark rod voltage (-2.5 for the rod-DBCR synapse and 4.0 for the rod-HBCR synapse), and they (the absolute values) became progressively smaller at more hyperpolarized rod voltages. PMID:8186975

  7. Propagation of Epileptiform Activity Can Be Independent of Synaptic Transmission, Gap Junctions, or Diffusion and Is Consistent with Electrical Field Transmission

    PubMed Central

    Zhang, Mingming; Ladas, Thomas P.; Qiu, Chen; Shivacharan, Rajat S.; Gonzalez-Reyes, Luis E.

    2014-01-01

    The propagation of activity in neural tissue is generally associated with synaptic transmission, but epileptiform activity in the hippocampus can propagate with or without synaptic transmission at a speed of ∼0.1 m/s. This suggests an underlying common nonsynaptic mechanism for propagation. To study this mechanism, we developed a novel unfolded hippocampus preparation, from CD1 mice of either sex, which preserves the transverse and longitudinal connections and recorded activity with a penetrating microelectrode array. Experiments using synaptic transmission and gap junction blockers indicated that longitudinal propagation is independent of chemical or electrical synaptic transmission. Propagation speeds of 0.1 m/s are not compatible with ionic diffusion or pure axonal conduction. The only other means of communication between neurons is through electric fields. Computer simulations revealed that activity can indeed propagate from cell to cell solely through field effects. These results point to an unexpected propagation mechanism for neural activity in the hippocampus involving endogenous field effect transmission. PMID:24453330

  8. New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster.

    PubMed

    Mejia, Monica; Heghinian, Mari D; Marí, Frank; Godenschwege, Tanja A

    2013-01-01

    Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The α7 subtype of nAChRs is involved in neurological pathologies such as Parkinson's disease, Alzheimer's disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster α7 (Dα7) has the closest sequence homology to the vertebrate α7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Dα7 subunits are essential for the function of the Giant Fiber circuit, which mediates the escape response of the fly. To further characterize the receptor function, we generated different missense mutations in the Dα7 nAChR's ligand binding domain. We characterized the effects of targeted expression of two UAS-constructs carrying a single mutation, D197A and Y195T, as well as a UAS-construct carrying a triple D77T, L117Q, I196P mutation in a Dα7 null mutant and in a wild type background. Expression of the triple mutation was able to restore the function of the circuit in Dα7 null mutants and had no disruptive effects when expressed in wild type. In contrast, both single mutations severely disrupted the synaptic transmission of Dα7-dependent but not glutamatergic or gap junction dependent synapses in wild type background, and did not or only partially rescued the synaptic defects of the null mutant. These observations are consistent with the formation of hybrid receptors, consisting of D197A or Y195T subunits and wild type Dα7 subunits, in which the binding of acetylcholine or acetylcholine-induced conformational changes of the Dα7 receptor are altered and causes inhibition of cholinergic responses. Thus targeted expression of D197A or Y195T can be used to selectively disrupt synaptic transmission of Dα7-dependent synapses in neuronal circuits. Hence, these constructs can be used as tools to study learning and memory or addiction associated behaviors by allowing the manipulation of neuronal processing in the circuits without

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

    PubMed

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

    2015-08-20

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

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

    PubMed

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

    2016-05-01

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

  11. Millisecond Coupling of Local Field Potentials to Synaptic Currents in the Awake Visual Cortex

    PubMed Central

    Haider, Bilal; Schulz, David P.A.; Häusser, Michael; Carandini, Matteo

    2016-01-01

    Summary The cortical local field potential (LFP) is a common measure of population activity, but its relationship to synaptic activity in individual neurons is not fully established. This relationship has been typically studied during anesthesia and is obscured by shared slow fluctuations. Here, we used patch-clamp recordings in visual cortex of anesthetized and awake mice to measure intracellular activity; we then applied a simple method to reveal its coupling to the simultaneously recorded LFP. LFP predicted membrane potential as accurately as synaptic currents, indicating a major role for synaptic currents in the relationship between cortical LFP and intracellular activity. During anesthesia, cortical LFP predicted excitation far better than inhibition; during wakefulness, it predicted them equally well, and visual stimulation further enhanced predictions of inhibition. These findings reveal a central role for synaptic currents, and especially inhibition, in the relationship between the subthreshold activity of individual neurons and the cortical LFP during wakefulness. PMID:27021173

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

    PubMed Central

    Halstead, James M.; Lin, Yong Qi; Durraine, Lita; Hamilton, Russell S.; Ball, Graeme; Neely, Greg G.; Bellen, Hugo J.; Davis, Ilan

    2014-01-01

    ABSTRACT Synaptic plasticity involves the modulation of synaptic connections in response to neuronal activity via multiple pathways. One mechanism modulates synaptic transmission by retrograde signals from the post-synapse that influence the probability of vesicle release in the pre-synapse. Despite its importance, very few factors required for the expression of retrograde signals, and proper synaptic transmission, have been identified. Here, we identify the conserved RNA binding protein Syncrip as a new factor that modulates the efficiency of vesicle release from the motoneuron and is required for correct synapse structure. We show that syncrip is required genetically and its protein product is detected only in the muscle and not in the motoneuron itself. This unexpected non-autonomy is at least partly explained by the fact that Syncrip modulates retrograde BMP signals from the muscle back to the motoneuron. We show that Syncrip influences the levels of the Bone Morphogenic Protein ligand Glass Bottom Boat from the post-synapse and regulates the pre-synapse. Our results highlight the RNA-binding protein Syncrip as a novel regulator of synaptic output. Given its known role in regulating translation, we propose that Syncrip is important for maintaining a balance between the strength of presynaptic vesicle release and postsynaptic translation. PMID:25171887

  13. Presynaptic group I metabotropic glutamate receptors modulate synaptic transmission in the rat superior colliculus via 4-AP sensitive K+ channels

    PubMed Central

    White, Anne-Marie; Kylänpää, Risto A; Christie, Louisa A; McIntosh, Simon J; Irving, Andrew J; Platt, Bettina

    2003-01-01

    Group I metabotropic glutamate receptors (mGluRs) are thought to be important modulators of neuronal function in the superior colliculus (SC). Here, we investigated the pharmacology and signalling mechanisms underlying group I mGluR-mediated inhibition of neuronal excitability and synaptic transmission in the rat SC slice. The group I agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) potently depressed synaptically evoked excitatory postsynaptic potentials (EPSPs), currents (EPSCs), and action potentials in a dose-dependent manner (IC50: 6.3 μM). This was strongly reduced by the broad-spectrum antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM, ∼95% reduction), by the mGluR1 antagonist LY367385 (100 μM, ∼80% reduction) but not by the mGluR5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP, 1–100 μM). The putative mGluR5-specific agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG, 500 μM) also inhibited EPSPs. Interestingly, CHPG's actions were not blocked by MPEP, but LY367385 (100 μM) reduced the effect of CHPG by 50%. Inhibition induced by DHPG was independent of phospholipase C (PLC)/protein kinase C pathways, and did not require intact intracellular Ca2+ stores. It was not abolished but enhanced by the GABAA antagonist bicuculline (5 μM), suggesting that DHPG's action was not due to facilitated inhibition or changes in neuronal network activity. The K+ channel antagonist 4-aminopyridine (4-AP, 50–100 μM) converted the inhibitory effect of DHPG into facilitation. Paired-pulse depression was strongly reduced by DHPG, an effect that was also prevented by 4-AP. Our data indicate that group I agonists regulate transmitter release, presumably via an autoreceptor in the SC. This receptor may be involved in adaptation to repetitive stimulation via a non-PLC mediated pathway. PMID:14623765

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

    PubMed

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

    2016-05-13

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

  15. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

    PubMed Central

    Appenzeller, Silke; Balling, Rudi; Barisic, Nina; Baulac, Stéphanie; Caglayan, Hande; Craiu, Dana; De Jonghe, Peter; Depienne, Christel; Dimova, Petia; Djémié, Tania; Gormley, Padhraig; Guerrini, Renzo; Helbig, Ingo; Hjalgrim, Helle; Hoffman-Zacharska, Dorota; Jähn, Johanna; Klein, Karl Martin; Koeleman, Bobby; Komarek, Vladimir; Krause, Roland; Kuhlenbäumer, Gregor; Leguern, Eric; Lehesjoki, Anna-Elina; Lemke, Johannes R.; Lerche, Holger; Linnankivi, Tarja; Marini, Carla; May, Patrick; Møller, Rikke S.; Muhle, Hiltrud; Pal, Deb; Palotie, Aarno; Pendziwiat, Manuela; Robbiano, Angela; Roelens, Filip; Rosenow, Felix; Selmer, Kaja; Serratosa, Jose M.; Sisodiya, Sanjay; Stephani, Ulrich; Sterbova, Katalin; Striano, Pasquale; Suls, Arvid; Talvik, Tiina; von Spiczak, Sarah; Weber, Yvonne; Weckhuysen, Sarah; Zara, Federico; Abou-Khalil, Bassel; Alldredge, Brian K.; Andermann, Eva; Andermann, Frederick; Amron, Dina; Bautista, Jocelyn F.; Berkovic, Samuel F.; Bluvstein, Judith; Boro, Alex; Cascino, Gregory; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Dlugos, Dennis; Epstein, Michael P.; Fiol, Miguel; Fountain, Nathan B.; French, Jacqueline; Friedman, Daniel; Geller, Eric B.; Glauser, Tracy; Glynn, Simon; Haas, Kevin; Haut, Sheryl R.; Hayward, Jean; Helmers, Sandra L.; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E.; Knowlton, Robert C.; Kossoff, Eric H.; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel H.; McGuire, Shannon M.; Motika, Paul V.; Novotny, Edward J.; Ottman, Ruth; Paolicchi, Juliann M.; Parent, Jack; Park, Kristen; Poduri, Annapurna; Sadleir, Lynette; Scheffer, Ingrid E.; Shellhaas, Renée A.; Sherr, Elliott; Shih, Jerry J.; Singh, Rani; Sirven, Joseph; Smith, Michael C.; Sullivan, Joe; Thio, Liu Lin; Venkat, Anu; Vining, Eileen P.G.; Von Allmen, Gretchen K.; Weisenberg, Judith L.; Widdess-Walsh, Peter; Winawer, Melodie R.; Allen, Andrew S.; Berkovic, Samuel F.; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Eichler, Evan E.; Epstein, Michael P.; Glauser, Tracy; Goldstein, David B.; Han, Yujun; Heinzen, Erin L.; Johnson, Michael R.; Kuzniecky, Ruben; Lowenstein, Daniel H.; Marson, Anthony G.; Mefford, Heather C.; Nieh, Sahar Esmaeeli; O’Brien, Terence J.; Ottman, Ruth; Petrou, Stephen; Petrovski, Slavé; Poduri, Annapurna; Ruzzo, Elizabeth K.; Scheffer, Ingrid E.; Sherr, Elliott

    2014-01-01

    Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the “classical” epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10−4), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction. PMID:25262651

  16. Vibrodissociation of Neurons from Rodent Brain Slices to Study Synaptic Transmission and Image Presynaptic Terminals

    PubMed Central

    Jun, Sang Beom; Cuzon Carlson, Verginia; Ikeda, Stephen; Lovinger, David

    2011-01-01

    Mechanical dissociation of neurons from the central nervous system has the advantage that presynaptic boutons remain attached to the isolated neuron of interest. This allows for examination of synaptic transmission under conditions where the extracellular and postsynaptic intracellular environments can be well controlled. A vibration-based technique without the use of proteases, known as vibrodissociation, is the most popular technique for mechanical isolation. A micropipette, with the tip fire-polished to the shape of a small ball, is placed into a brain slice made from a P1-P21 rodent. The micropipette is vibrated parallel to the slice surface and lowered through the slice thickness resulting in the liberation of isolated neurons. The isolated neurons are ready for study within a few minutes of vibrodissociation. This technique has advantages over the use of primary neuronal cultures, brain slices and enzymatically isolated neurons including: rapid production of viable, relatively mature neurons suitable for electrophysiological and imaging studies; superior control of the extracellular environment free from the influence of neighboring cells; suitability for well-controlled pharmacological experiments using rapid drug application and total cell superfusion; and improved space-clamp in whole-cell recordings relative to neurons in slice or cell culture preparations. This preparation can be used to examine synaptic physiology, pharmacology, modulation and plasticity. Real-time imaging of both pre- and postsynaptic elements in the living cells and boutons is also possible using vibrodissociated neurons. Characterization of the molecular constituents of pre- and postsynaptic elements can also be achieved with immunological and imaging-based approaches. PMID:21654624

  17. Modelling bidirectional modulations in synaptic plasticity: A biochemical pathway model to understand the emergence of long term potentiation (LTP) and long term depression (LTD).

    PubMed

    He, Yao; Kulasiri, Don; Samarasinghe, Sandhya

    2016-08-21

    Synaptic plasticity induces bidirectional modulations of the postsynaptic response following a synaptic transmission. The long term forms of synaptic plasticity, named long term potentiation (LTP) and long term depression (LTD), are critical for the antithetic functions of the memory system, memory formation and removal, respectively. A common Ca(2+) signalling upstream triggers both LTP and LTD, and the critical proteins and factors coordinating the LTP/LTD inductions are not well understood. We develop an integrated model based on the sub-models of the indispensable synaptic proteins in the emergence of synaptic plasticity to validate and understand their potential roles in the expression of synaptic plasticity. The model explains Ca(2+)/calmodulin (CaM) complex dependent coordination of LTP/LTD expressions by the interactions among the indispensable proteins using the experimentally estimated kinetic parameters. Analysis of the integrated model provides us with insights into the effective timescales of the key proteins and we conclude that the CaM pool size is critical for the coordination between LTP/LTD expressions. PMID:27185535

  18. Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice.

    PubMed

    Vecchia, Dania; Tottene, Angelita; van den Maagdenberg, Arn M J M; Pietrobon, Daniela

    2014-09-01

    Familial hemiplegic migraine type 1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. In FHM1 knockin mice, excitatory neurotransmission at cortical pyramidal cell synapses is enhanced, but inhibitory neurotransmission at connected pairs of fast-spiking (FS) interneurons and pyramidal cells is unaltered, despite being initiated by CaV2.1 channels. The mechanism underlying the unaltered GABA release at cortical FS interneuron synapses remains unknown. Here, we show that the FHM1 R192Q mutation does not affect inhibitory transmission at autapses of cortical FS and other types of multipolar interneurons in microculture from R192Q knockin mice, and investigate the underlying mechanism. Lowering the extracellular [Ca(2+)] did not reveal gain-of-function of evoked transmission neither in control nor after prolongation of the action potential (AP) with tetraethylammonium, indicating unaltered AP-evoked presynaptic calcium influx at inhibitory autapses in FHM1 KI mice. Neither saturation of the presynaptic calcium sensor nor short duration of the AP can explain the unaltered inhibitory transmission in the mutant mice. Recordings of the P/Q-type calcium current in multipolar interneurons in microculture revealed that the current density and the gating properties of the CaV2.1 channels expressed in these interneurons are barely affected by the FHM1 mutation, in contrast with the enhanced current density and left-shifted activation gating of mutant CaV2.1 channels in cortical pyramidal cells. Our findings suggest that expression of specific CaV2.1 channels differentially sensitive to modulation by FHM1 mutations in inhibitory and excitatory cortical neurons underlies the gain-of-function of excitatory but unaltered inhibitory synaptic transmission and the likely consequent dysregulation of the cortical excitatory-inhibitory balance in FHM1. PMID:24907493

  19. The effect of sevoflurane on the cognitive function of rats and its association with the inhibition of synaptic transmission

    PubMed Central

    Zhang, Deng-Xin; Jiang, Shan; Yu, Li-Na; Zhang, Feng-Jiang; Zhuang, Qing; Yan, Min

    2015-01-01

    To observe the effects of different concentrations of sevoflurane on synaptotagmin 1 (Syt1) expression, synaptic long term depression (LTD), and paired pulse depression (PPD) in the rat hippocampus as well as to investigate the association between these effects and the cognitive function of rats. A total of 24 male Sprague-Dawley (SD) rats were selected and randomly divided into 3 groups: the control group (group A), which inhaled air; group B, which inhaled 0.65 minimum alveolar concentration (MAC) sevoflurane for 2 h; and group C, which inhaled 1.30 MAC sevoflurane for 2 h. The subsequent experiments were performed after one day. (1) Y maze tests were performed, and the expression of Syt1 in hippocampal tissues was detected using western blot. (2) The changes in LTD and PPD in rat hippocampal slices were examined using electrophysiological techniques. Compared to the control group, the cognitive function was decreased and Syt1 expression in the hippocampus was significantly decreased in rats in the 1.30 MAC sevoflurane inhalation group. After 60 min of low frequency stimulation, the amplitudes of population spike (PS) potentials in rat hippocampal slices were significantly decreased. After induction of PPD, the P2/P1 ratio was significantly increased. No indicators in the 0.65 MAC sevoflurane inhalation group showed any significant changes. Inhalation of high concentrations of sevoflurane significantly reduced Syt1 protein levels in the rat hippocampus, significantly inhibited the release of presynaptic neurotransmitters, and reduced the efficiency of synaptic transmission, thus causing memory impairment. PMID:26885010

  20. A Model of Bidirectional Synaptic Plasticity: From Signaling Network to Channel Conductance

    ERIC Educational Resources Information Center

    Castellani, Gastone C.; Quinlan, Elizabeth M.; Bersani, Ferdinando; Cooper, Leon N.; Shouval, Harel Z.

    2005-01-01

    In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of…

  1. The C(2)B Ca(2+)-binding motif of synaptotagmin is required for synaptic transmission in vivo.

    PubMed

    Mackler, J M; Drummond, J A; Loewen, C A; Robinson, I M; Reist, N E

    2002-07-18

    Synaptotagmin is a synaptic vesicle protein that is postulated to be the Ca(2+) sensor for fast, evoked neurotransmitter release. Deleting the gene for synaptotagmin (syt(null)) strongly suppresses synaptic transmission in every species examined, showing that synaptotagmin is central in the synaptic vesicle cycle. The cytoplasmic region of synaptotagmin contains two C(2) domains, C(2)A and C(2)B. Five, highly conserved, acidic residues in both the C(2)A and C(2)B domains of synaptotagmin coordinate the binding of Ca(2+) ions, and biochemical studies have characterized several in vitro Ca(2+)-dependent interactions between synaptotagmin and other nerve terminal molecules. But there has been no direct evidence that any of the Ca(2+)-binding sites within synaptotagmin are required in vivo. Here we show that mutating two of the Ca(2+)-binding aspartate residues in the C(2)B domain (D(416,418)N in Drosophila) decreased evoked transmitter release by >95%, and decreased the apparent Ca(2+) affinity of evoked transmitter release. These studies show that the Ca(2+)-binding motif of the C(2)B domain of synaptotagmin is essential for synaptic transmission. PMID:12110842

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

    PubMed

    Su, Yan-Yan; Luo, Bin; Jin, Yan; Wu, Shu-Hui; Lobarinas, Edward; Salvi, Richard J; Chen, Lin

    2012-01-01

    Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus. PMID:23071681

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

    PubMed Central

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

    2015-01-01

    Double C2-like domain-containing proteins alpha and beta (Doc2α and Doc2β) are tandem C2-domain proteins proposed to function as Ca2+ sensors for asynchronous neurotransmitter release. Here, we systematically analyze each of the negatively charged residues that mediate binding of Ca2+ to the β isoform. The Ca2+ ligands in the C2A domain were dispensable for Ca2+-dependent translocation to the plasma membrane, with one exception: neutralization of D220 resulted in constitutive translocation. In contrast, three of the five Ca2+ ligands in the C2B domain are required for translocation. Importantly, translocation was correlated with the ability of the mutants to enhance asynchronous release when overexpressed in neurons. Finally, replacement of specific Ca2+/lipid-binding loops of synaptotagmin 1, a Ca2+ sensor for synchronous release, with corresponding loops from Doc2β, resulted in chimeras that yielded slower kinetics in vitro and slower excitatory postsynaptic current decays in neurons. Together, these data reveal the key determinants of Doc2β that underlie its function during the slow phase of synaptic transmission. PMID:26195798

  4. The quantal component of synaptic transmission from sensory hair cells to the vestibular calyx.

    PubMed

    Highstein, Stephen M; Mann, Mary Anne; Holstein, Gay R; Rabbitt, Richard D

    2015-06-01

    Spontaneous and stimulus-evoked excitatory postsynaptic currents (EPSCs) were recorded in calyx nerve terminals from the turtle vestibular lagena to quantify key attributes of quantal transmission at this synapse. On average, EPSC events had a magnitude of ∼ 42 pA, a rise time constant of τ(0) ∼ 229 μs, decayed to baseline with a time constant of τ(R) ∼ 690 μs, and carried ∼ 46 fC of charge. Individual EPSCs varied in magnitude and decay time constant. Variability in the EPSC decay time constant was hair cell dependent and due in part to a slow protraction of the EPSC in some cases. Variability in EPSC size was well described by an integer summation of unitary quanta, with each quanta of glutamate gating a unitary postsynaptic current of ∼ 23 pA. The unitary charge was ∼ 26 fC for EPSCs with a simple exponential decay and increased to ∼ 48 fC for EPSCs exhibiting a slow protraction. The EPSC magnitude and the number of simultaneous unitary quanta within each event increased with presynaptic stimulus intensity. During tonic hair cell depolarization, both the EPSC magnitude and event rate exhibited adaptive run down over time. Present data from a reptilian calyx are remarkably similar to noncalyceal vestibular synaptic terminals in diverse species, indicating that the skewed EPSC size distribution and multiquantal release might be an ancestral property of inner ear ribbon synapses. PMID:25878150

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

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

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

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

    SciTech Connect

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

    2015-12-31

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

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

    PubMed

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

    2015-08-01

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

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

    PubMed

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

    2015-09-14

    Although intrathecal orexin-A has been known to be antinociceptive in various pain models, the role of orexin-A in antinociception is not well characterized. In the present study, we examined whether orexin-A modulates primary afferent fiber-mediated or spontaneous excitatory synaptic transmission using transverse spinal cord slices with attached dorsal root. Bath-application of orexin-A (100nM) reduced the amplitude of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation of Aδ- or C-primary afferent fibers. The magnitude of reduction was much larger for EPSCs evoked by polysynaptic C-fibers than polysynaptic Aδ-fibers, whereas it was similar in EPSCs evoked by monosynaptic Aδ- or C-fibers. SB674042, an orexin-1 receptor antagonist, but not EMPA, an orexin-2 receptor antagonist, significantly inhibited the orexin-A-induced reduction in EPSC amplitude from mono- or polysynaptic Aδ-fibers, as well as from mono- or polysynaptic C-fibers. Furthermore, orexin-A significantly increased the frequency of spontaneous EPSCs but not the amplitude. This increase was almost completely blocked by both SB674042 and EMPA. On the other hand, orexin-A produced membrane oscillations and inward currents in the SG neurons that were partially or completely inhibited by SB674042 or EMPA, respectively. Thus, this study suggests that the spinal actions of orexin-A underlie orexin-A-induced antinociceptive effects via different subtypes of orexin receptors. PMID:26254164

  9. The quantal component of synaptic transmission from sensory hair cells to the vestibular calyx

    PubMed Central

    Highstein, Stephen M.; Mann, Mary Anne; Holstein, Gay R.

    2015-01-01

    Spontaneous and stimulus-evoked excitatory postsynaptic currents (EPSCs) were recorded in calyx nerve terminals from the turtle vestibular lagena to quantify key attributes of quantal transmission at this synapse. On average, EPSC events had a magnitude of ∼42 pA, a rise time constant of τ0 ∼229 μs, decayed to baseline with a time constant of τR ∼690 μs, and carried ∼46 fC of charge. Individual EPSCs varied in magnitude and decay time constant. Variability in the EPSC decay time constant was hair cell dependent and due in part to a slow protraction of the EPSC in some cases. Variability in EPSC size was well described by an integer summation of unitary quanta, with each quanta of glutamate gating a unitary postsynaptic current of ∼23 pA. The unitary charge was ∼26 fC for EPSCs with a simple exponential decay and increased to ∼48 fC for EPSCs exhibiting a slow protraction. The EPSC magnitude and the number of simultaneous unitary quanta within each event increased with presynaptic stimulus intensity. During tonic hair cell depolarization, both the EPSC magnitude and event rate exhibited adaptive run down over time. Present data from a reptilian calyx are remarkably similar to noncalyceal vestibular synaptic terminals in diverse species, indicating that the skewed EPSC size distribution and multiquantal release might be an ancestral property of inner ear ribbon synapses. PMID:25878150

  10. Regulation of Synaptic Transmission at the Caenorhabditis elegans M4 Neuromuscular Junction by an Antagonistic Relationship Between Two Calcium Channels

    PubMed Central

    Steciuk, Mark; Cheong, Mi Cheong; Waite, Christopher; You, Young-Jai; Avery, Leon

    2014-01-01

    In wild-type Caenorhabditis elegans, the synapse from motor neuron M4 to pharyngeal terminal bulb (TB) muscles is silent, and the muscles are instead excited by gap junction connections from adjacent muscles. An eat-5 innexin mutant lacking this electrical connection has few TB contractions and is unable to grow well on certain foods. We showed previously that this defect can be overcome by activation of the M4 → TB synapse. To identify genes that negatively regulate synaptic transmission, we isolated new suppressors of eat-5. To our surprise, these suppressors included null mutations in NPQR-type calcium channel subunit genes unc-2 and unc-36. Our results are consistent with the hypothesis that Ca2+ entry through the NPQR-type channel inhibits synaptic transmission by activating the calcium-activated K+ channel SLO-1, thus antagonizing the EGL-19 L-type calcium channel. PMID:25378475

  11. Cross-synaptic synchrony and transmission of signal and noise across the mouse retina.

    PubMed

    Grimes, William N; Hoon, Mrinalini; Briggman, Kevin L; Wong, Rachel O; Rieke, Fred

    2014-01-01

    Cross-synaptic synchrony--correlations in transmitter release across output synapses of a single neuron--is a key determinant of how signal and noise traverse neural circuits. The anatomical connectivity between rod bipolar and A17 amacrine cells in the mammalian retina, specifically that neighboring A17s often receive input from many of the same rod bipolar cells, provides a rare technical opportunity to measure cross-synaptic synchrony under physiological conditions. This approach reveals that synchronization of rod bipolar cell synapses is near perfect in the dark and decreases with increasing light level. Strong synaptic synchronization in the dark minimizes intrinsic synaptic noise and allows rod bipolar cells to faithfully transmit upstream signal and noise to downstream neurons. Desynchronization in steady light lowers the sensitivity of the rod bipolar output to upstream voltage fluctuations. This work reveals how cross-synaptic synchrony shapes retinal responses to physiological light inputs and, more generally, signaling in complex neural networks. PMID:25180102

  12. Membrane Potentials, Synaptic Responses, Neuronal Circuitry, Neuromodulation and Muscle Histology Using the Crayfish: Student Laboratory Exercises

    PubMed Central

    2011-01-01

    The purpose of this report is to help develop an understanding of the effects caused by ion gradients across a biological membrane. Two aspects that influence a cell's membrane potential and which we address in these experiments are: (1) Ion concentration of K+ on the outside of the membrane, and (2) the permeability of the membrane to specific ions. The crayfish abdominal extensor muscles are in groupings with some being tonic (slow) and others phasic (fast) in their biochemical and physiological phenotypes, as well as in their structure; the motor neurons that innervate these muscles are correspondingly different in functional characteristics. We use these muscles as well as the superficial, tonic abdominal flexor muscle to demonstrate properties in synaptic transmission. In addition, we introduce a sensory-CNS-motor neuron-muscle circuit to demonstrate the effect of cuticular sensory stimulation as well as the influence of neuromodulators on certain aspects of the circuit. With the techniques obtained in this exercise, one can begin to answer many questions remaining in other experimental preparations as well as in physiological applications related to medicine and health. We have demonstrated the usefulness of model invertebrate preparations to address fundamental questions pertinent to all animals. PMID:21304459

  13. Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels.

    PubMed

    Nishio, N; Taniguchi, W; Sugimura, Y K; Takiguchi, N; Yamanaka, M; Kiyoyuki, Yasukuni; Yamada, H; Miyazaki, N; Yoshida, M; Nakatsuka, T

    2013-09-01

    Central neuropathic pain (CNP) in the spinal cord, such as chronic pain after spinal cord injury (SCI), is an incurable ailment. However, little is known about the spinal cord mechanisms underlying CNP. Recently, reactive oxygen species (ROS) have been recognized to play an important role in CNP of the spinal cord. However, it is unclear how ROS affect synaptic transmission in the dorsal horn of the spinal cord. To clarify how ROS impact on synaptic transmission, we investigated the effects of ROS on synaptic transmission in rat spinal cord substantia gelatinosa (SG) neurons using whole-cell patch-clamp recordings. Administration of tert-butyl hydroperoxide (t-BOOH), an ROS donor, into the spinal cord markedly increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in SG neurons. This t-BOOH-induced enhancement was not suppressed by the Na(+) channel blocker tetrodotoxin. However, in the presence of a non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, t-BOOH did not generate any sEPSCs. Furthermore, in the presence of a transient receptor potential ankyrin 1 (TRPA1) channel antagonist (HC-030031) or a transient receptor potential vanilloid 1 (TRPV1) channel antagonist (capsazepine or AMG9810), the t-BOOH-induced increase in the frequency of sEPSCs was inhibited. These results indicate that ROS enhance the spontaneous release of glutamate from presynaptic terminals onto SG neurons through TRPA1 and TRPV1 channel activation. Excessive activation of these ion channels by ROS may induce central sensitization in the spinal cord and result in chronic pain such as that following SCI. PMID:23707800

  14. ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization

    PubMed Central

    Tindi, Jaafar O.; Chávez, Andrés E.; Cvejic, Svetlana; Calvo-Ochoa, Erika; Castillo, Pablo E.

    2015-01-01

    NMDA receptors (NMDARs) are key mediators of glutamatergic transmission and synaptic plasticity, and their dysregulation has been linked to diverse neuropsychiatric and neurodegenerative disorders. While normal NMDAR function requires regulated expression and trafficking of its different subunits, the molecular mechanisms underlying these processes are not fully understood. Here we report that the amyloid precursor protein intracellular domain associated-1 protein (AIDA-1), which associates with NMDARs and is encoded by ANKS1B, a gene recently linked to schizophrenia, regulates synaptic NMDAR subunit composition. Forebrain-specific AIDA-1 conditional knock-out (cKO) mice exhibit reduced GluN2B-mediated and increased GluN2A-mediated synaptic transmission, and biochemical analyses show AIDA-1 cKO mice have low GluN2B and high GluN2A protein levels at isolated hippocampal synaptic junctions compared with controls. These results are corroborated by immunocytochemical and electrophysiological analyses in primary neuronal cultures following acute lentiviral shRNA-mediated knockdown of AIDA-1. Moreover, hippocampal NMDAR-dependent but not metabotropic glutamate receptor-dependent plasticity is impaired in AIDA-1 cKO mice, further supporting a role for AIDA-1 in synaptic NMDAR function. We also demonstrate that AIDA-1 preferentially associates with GluN2B and with the adaptor protein Ca2+/calmodulin-dependent serine protein kinase and kinesin KIF17, which regulate the transport of GluN2B-containing NMDARs from the endoplasmic reticulum (ER) to synapses. Consistent with this function, GluN2B accumulates in ER-enriched fractions in AIDA-1 cKO mice. These findings suggest that AIDA-1 regulates NMDAR subunit composition at synapses by facilitating transport of GluN2B from the ER to synapses, which is critical for NMDAR plasticity. Our work provides an explanation for how AIDA-1 dysfunction might contribute to neuropsychiatric conditions, such as schizophrenia. PMID:26085624

  15. Dynamic effects of TNF-α on synaptic transmission in mice over time following sciatic nerve chronic constriction injury

    PubMed Central

    Zhang, Hongmei; Zhang, Haijun

    2013-01-01

    Nerve injury-induced central sensitization can manifest as an increase in excitatory synaptic transmission and/or as a decrease in inhibitory synaptic transmission in spinal dorsal horn neurons. Cytokines such as tumor necrosis factor-α (TNF-α) are induced in the spinal cord under various injury conditions and contribute to neuropathic pain. In this study we examined the effect of TNF-α in modulating excitatory and inhibitory synaptic input to spinal substantia gelatinosa (SG) neurons over time in mice following chronic constriction injury (CCI) of the sciatic nerve. Whole cell patch-clamp studies from SG neurons showed that TNF-α enhanced overall excitability of the spinal cord early in time following nerve injury 3 days after CCI compared with that in sham control mice. In contrast, the effects of TNF were blunted 14 days after CCI in nerve-injured mice compared with sham surgery mice. Immunohistochemical staining showed that the expression of TNF-α receptor 1 (TNFR1) was increased at 3 days but decreased at 14 days following CCI in the ipsilateral vs. the contralateral spinal cord dorsal horn. These results suggest that TNF-α acting at TNFR1 is important in the development of neuropathic pain by facilitating excitatory synaptic signaling in the acute phases after nerve injury but has a reduced effect on spinal neuron signaling in the later phases of nerve injury-induced pain. Failure of the facilatory effects of TNF-α on excitatory synaptic signaling in the dorsal horn to resolve following nerve injury may be an important component in the transition between acute and chronic pain conditions. PMID:23864372

  16. Brief environmental enrichment elicits metaplasticity of hippocampal synaptic potentiation in vivo

    PubMed Central

    Buschler, Arne; Manahan-Vaughan, Denise

    2012-01-01

    Long-term environmental enrichment (EE) elicits enduring effects on the adult brain, including altered synaptic plasticity. Synaptic plasticity may underlie memory formation and includes robust (>24 h) and weak (<2 h) forms of long-term potentiation (LTP) and long-term depression (LTD). Most studies of the effect of EE on synaptic efficacy have examined the consequences of very prolonged EE-exposure. It is unclear whether brief exposure to EE can alter synaptic plasticity. Clarifying this issue could help develop strategies to address cognitive deficits arising from neglect in children or adults. We assessed whether short-term EE elicits alterations in hippocampal synaptic plasticity and if social context may play a role. Adult mice were exposed to EE for 14 consecutive days. We found that robust late-LTP (>24 h) and short-term depression (<2 h) at Schaffer-collateral-CA1 synapses in freely behaving mice were unaltered, whereas early-LTP (E-LTP, <2 h) was significantly enhanced by EE. Effects were transient: E-LTP returned to control levels 1 week after cessation of EE. Six weeks later, animals were re-exposed to EE for 14 days. Under these conditions, E-LTP was facilitated into L-LTP (>24 h), suggesting that metaplasticity was induced during the first EE experience and that EE-mediated modifications are cumulative. Effects were absent in mice that underwent solitary enrichment or were group-housed without EE. These data suggest that EE in naïve animals strengthens E-LTP, and also promotes L-LTP in animals that underwent EE in the past. This indicates that brief exposure to EE, particularly under social conditions can elicit lasting positive effects on synaptic strength that may have beneficial consequences for cognition that depends on synaptic plasticity. PMID:23248592

  17. Long-term potentiation at excitatory synaptic inputs to the intercalated cell masses of the amygdala.

    PubMed

    Huang, Chiung-Chun; Chen, Chien-Chung; Liang, Ying-Ching; Hsu, Kuei-Sen

    2014-08-01

    The intercalated cell masses (ITCs) of the amygdala are clusters of GABAergic interneurons that surround the basolateral complex of the amygdala. ITCs have been increasingly implicated in the acquisition and extinction of conditioned fear responses, but the underlying cellular mechanisms remain unexplored. Here, we report that repetitive stimulation of lateral amygdala (LA) afferents with a modified theta burst stimulation (TBS) protocol and induces long-term potentiation (LTP) of excitatory synapses onto medial paracapsular ITC (Imp) neurons. This TBS-induced LTP is; (1) induced and expressed post-synaptically, (2) involves a rise in post-synaptic Ca2+ and the activation of NR2B-containing N-methyl-D-aspartate receptors (NMDARs), (3) dependent on calcium/calmodulin-dependent protein kinase II and cAMP-dependent protein kinase activation, and (4) associated with increased exocytotic delivery of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) to the post-synaptic membrane. Remarkably, auditory fear conditioning led to a persistent increase in AMPAR/NMDAR ratio of glutamatergic synaptic currents and occluded TBS-induced LTP at LA-Imp synapses. Furthermore, extinction training rescued the effect of fear conditioning on AMPAR/NMDAR ratio and LTP induction. These results show that a prominent form of LTP can be elicited at LA-Imp synapses and suggest that this synaptic plasticity may contribute to the expression of fear conditioning. PMID:24556032

  18. Light-evoked recovery from wortmannin-induced inhibition of catecholamine secretion and synaptic transmission.

    PubMed

    Warashina, A

    1999-07-15

    Wortmannin (WT) is known to inhibit catecholamine (CA) secretion in chromaffin cells. This effect was found to be sensitive to UV light in experiments designed to perform simultaneous monitoring of changes in [Ca2+]i and CA secretion in perfused rat adrenal medullas. When the change in [Ca2+]i was measured using calcium green-1 (490 nm excitation), a 35-min treatment with 10 microM WT caused a 69% inhibition of CA secretion evoked by excess (30 mM) extracellular K+ and a moderate inhibition of the [Ca2+]i response. In contrast, the same treatment of fura-2-loaded cells with WT caused only an 11% inhibition of the high-K+-evoked secretion and no significant attenuation of the [Ca2+]i response. However, during interruption of fluorometry with fura-2, the inhibitory effect of WT developed at a rate similar to that exhibited in calcium green-1-loaded cells. The WT-induced inhibition of high-K+- or bradykinin-evoked secretory responses, which was otherwise irreversible, was reversed by exposing WT-treated chromaffin cells to 380-nm light. When WT was reapplied to the cells of which the secretory ability had been restored by light irradiation, the secretory response was inhibited with a time course similar to that shown during the initial treatment with WT. The photosensitive effect of WT was also demonstrated using bullfrog sympathetic ganglia in which WT-induced inhibition of synaptic transmission was reversed by irradiation with 380-nm light. These results suggest that UV light removes the inhibitory effects of WT by disrupting the covalent bond formed between WT and a target molecule which remains to be determined, although myosin light chain kinase has been reported as the target molecule in both cases examined in this study. PMID:10395748

  19. Mechanisms underlying H(2)O(2)-mediated inhibition of synaptic transmission in rat hippocampal slices.

    PubMed

    Avshalumov, M V; Chen, B T; Rice, M E

    2000-11-01

    Hydrogen peroxide (H(2)O(2)) inhibits the population spike (PS) evoked by Schaffer collateral stimulation in hippocampal slices. Proposed mechanisms underlying this effect include generation of hydroxyl radicals (.OH) and inhibition of presynaptic Ca(2+) entry. We have examined these possible mechanisms in rat hippocampal slices. Inhibition of the evoked PS by H(2)O(2) was sharply concentration-dependent: 1.2 mM H(2)O(2) had no effect, whereas 1.5 and 2.0 mM H(2)O(2) reversibly depressed PS amplitude by roughly 80%. The iron chelator, deferoxamine (1 mM), and the endogenous.OH scavenger, ascorbate (400 microM), prevented PS inhibition, confirming.OH involvement. Isoascorbate (400 microM), which unlike ascorbate is not taken up by brain cells, also prevented PS inhibition, indicating an extracellular site of.OH generation or action. We then investigated whether H(2)O(2)-induced PS depression could be overcome by prolonged stimulation, which enhances Ca(2+) entry. During 5-s, 10-Hz trains under control conditions, PS amplitude increased to over 200% during the first three-four pulses, then stabilized. In the presence of H(2)O(2), PS amplitude was initially depressed, but began to recover after 2.5 s of stimulation, finally reaching 80% of the control maximum. In companion experiments, we assessed the effect of H(2)O(2) on presynaptic Ca(2+) entry by monitoring extracellular Ca(2+) concentration ([Ca(2+)](o)) during train stimulation in the presence of postsynaptic receptor blockers. Evoked [Ca(2+)](o) shifts were apparently unaltered by H(2)O(2), suggesting a lack of effect on Ca(2+) entry. Taken together, these findings suggest new ways in which reactive oxygen species (ROS) might act as signaling agents, specifically as modulators of synaptic transmission. PMID:11056187

  20. Environmental enrichment rescues the effects of early life inflammation on markers of synaptic transmission and plasticity.

    PubMed

    Kentner, Amanda C; Khoury, Antoine; Lima Queiroz, Erika; MacRae, Molly

    2016-10-01

    Environmental enrichment (EE) has been successful at rescuing the brain from a variety of early-life psychogenic stressors. However, its ability to reverse the behavioral and neural alterations induced by a prenatal maternal infection model of schizophrenia is less clear. Moreover, the specific interactions between the components (i.e. social enhancement, novelty, physical activity) of EE that lead to its success as a supportive intervention have not been adequately identified. In the current study, standard housed female Sprague-Dawley rats were administered either the inflammatory endotoxin lipopolysaccharide (LPS; 100μg/kg) or pyrogen-free saline (equivolume) on gestational day 15. On postnatal day 50, offspring were randomized into one of three conditions: EE (group housed in a large multi-level cage with novel toys, tubes and ramps), Colony Nesting (CN; socially-housed in a larger style cage), or Standard Care (SC; pair-housed in standard cages). Six weeks later we scored social engagement and performance in the object-in-place task. Afterwards hippocampus and prefrontal cortex (n=7-9) were collected and evaluated for excitatory amino acid transporter (EAAT) 1-3, brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor type 2 (TrkB) gene expression (normalized to GAPDH) using qPCR methods. Overall, we show that gestational inflammation downregulates genes critical to synaptic transmission and plasticity, which may underlie the pathogenesis of neurodevelopmental disorders such as schizophrenia and autism. Additionally, we observed disruptions in both social engagement and spatial discrimination. Importantly, behavioral and neurophysiological effects were rescued in an experience dependent manner. Given the evidence that schizophrenia and autism may be associated with infection during pregnancy, these data have compelling implications for the prevention and reversibility of the consequences that follow immune activation in early in

  1. Excitability and Synaptic Transmission in the Enteric Nervous System: Does Diet Play a Role?

    PubMed

    Bertrand, Paul P; Polglaze, Kate E; Chen, Hui; Sandow, Shaun L; Walduck, Anna; Jenkins, Trisha A; Bertrand, Rebecca L; Lomax, Alan E; Liu, Lu

    2016-01-01

    Changes in diet are a challenge to the gastrointestinal tract which needs to alter its processing mechanisms to continue to process nutrients and maintain health. In particular, the enteric nervous system (ENS) needs to adapt its motor and secretory programs to deal with changes in nutrient type and load in order to optimise nutrient absorption.The nerve circuits in the gut are complex, and the numbers and types of neurons make recordings of specific cell types difficult, time-consuming, and prone to sampling errors. Nonetheless, traditional research methods like intracellular electrophysiological approaches have provided the basis for our understanding of the ENS circuitry. In particular, animal models of intestinal inflammation have shown us that we can document changes to neuronal excitability and synaptic transmission.Recent studies examining diet-induced changes to ENS programming have opted to use fast imaging techniques to reveal changes in neuron function. Advances in imaging techniques using voltage- or calcium-sensitive dyes to record neuronal activity promise to overcome many limitations inherent to electrophysiological approaches. Imaging techniques allow access to a wide range of ENS phenotypes and to the changes they undergo during dietary challenges. These sorts of studies have shown that dietary variation or obesity can change how the ENS processes information-in effect reprogramming the ENS. In this review, the data gathered from intracellular recordings will be compared with measurements made using imaging techniques in an effort to determine if the lessons learnt from inflammatory changes are relevant to the understanding of diet-induced reprogramming. PMID:27379647

  2. Interactions of Human Autoantibodies with Hippocampal GABAergic Synaptic Transmission – Analyzing Antibody-Induced Effects ex vivo

    PubMed Central

    Haselmann, Holger; Röpke, Luise; Werner, Christian; Kunze, Albrecht; Geis, Christian

    2015-01-01

    Autoantibodies (aAB) to the presynaptic located enzyme glutamate decarboxylase 65 (GAD65) are a characteristic attribute for a variety of autoimmune diseases of the central nervous system including subtypes of limbic encephalitis, stiff person-syndrome, cerebellar ataxia, and Batten’s disease. Clinical signs of hyperexcitability and improvement of disease symptoms upon immunotherapy in some of these disorders suggest a possible pathogenic role of associated aAB. Recent experimental studies report inconsistent results regarding a direct pathogenic influence of anti-GAD65 aAB affecting inhibitory synaptic transmission in central GABAergic pathways. We here provide a method for direct evaluation of aAB-induced pathomechanisms in the intact hippocampal network. Purified patient IgG fractions containing aAB to GAD65 together with fixable lipophilic styryl dyes (FMdyes) are stereotactically injected into the hilus and the dentate gyrus in anesthetized mice. Twenty-four hours after intrahippocampal injection, acute hippocampal slices are prepared and transferred to a patch-clamp recording setup equipped with a fluorescence light source. Intraneural incorporated FMdyes show correct injection site for patch-clamp recording. Whole-cell patch-clamp recordings are performed from granule cells in the dentate gyrus and extracellular stimulation is applied in the border area of the dentate gyrus-hilus region to stimulate GABAergic afferents arising from parvalbumin positive basket cells. GABA-A receptor mediated inhibitory postsynaptic currents (IPSC) and miniature IPSC are recorded after blocking glutamatergic transmission. This approach allows investigation of potential aAB-induced effects on GABA-A receptor signaling ex vivo in an intact neuronal network. This offers several advantages compared to experimental procedures used in previous studies by in vitro AB preincubation of primary neurons or slice preparations. Furthermore, this method requires only small amounts of

  3. Timing is Essential for Rapid Effects of Corticosterone on Synaptic Potentiation in the Mouse Hippocampus

    ERIC Educational Resources Information Center

    Joels, Marian; Krugers, Harm; Wiegert, Olof

    2006-01-01

    Stress facilitates memory formation, but only when the stressor is closely linked to the learning context. These effects are, at least in part, mediated by corticosteroid hormones. Here we demonstrate that corticosterone rapidly facilitates synaptic potentiation in the mouse hippocampal CA1 area when high levels of the hormone and high-frequency…

  4. Adenosine receptor activation is responsible for prolonged depression of synaptic transmission after spreading depolarization in brain slices.

    PubMed

    Lindquist, B E; Shuttleworth, C W

    2012-10-25

    Spreading depolarization (SD) is a slowly propagating, coordinated depolarization of brain tissue, which is followed by a transient (5-10min) depression of synaptic activity. The mechanisms for synaptic depression after SD are incompletely understood. We examined the relative contributions of action potential failure and adenosine receptor activation to the suppression of evoked synaptic activity in murine brain slices. Focal micro-injection of potassium chloride (KCl) was used to induce SD and synaptic potentials were evoked by electrical stimulation of Schaffer collateral inputs to hippocampal area Cornu Ammonis area 1 (CA1). SD was accompanied by loss of both presynaptic action potentials (as assessed from fiber volleys) and field excitatory postsynaptic potentials (fEPSPs). Fiber volleys recovered rapidly upon neutralization of the extracellular direct current (DC) potential, whereas fEPSPs underwent a secondary suppression phase lasting several minutes. Paired-pulse ratio was elevated during the secondary suppression period, consistent with a presynaptic mechanism of synaptic depression. A transient increase in extracellular adenosine concentration was detected during the period of secondary suppression. Antagonists of adenosine A1 receptors (8-cyclopentyl-1,3-dipropylxanthine [DPCPX] or 8-cyclopentyl-1,3-dimethylxanthine [8-CPT]) greatly accelerated fEPSP recovery and abolished increases in paired-pulse ratio normally observed after SD. The duration of fEPSP suppression was correlated with both the duration of the DC shift and the area of tissue depolarized, consistent with the model that adenosine accumulates in proportion to the metabolic burden of SD. These results suggest that in brain slices, the duration of the DC shift approximately defined the period of action potential failure, but the secondary depression of evoked responses was in large part due to endogenous adenosine accumulation after SD. PMID:22864185

  5. Short-term potentiation of GABAergic synaptic inputs to vasopressin and oxytocin neurones

    PubMed Central

    Morton, Linda A; Popescu, Ion R; Haam, Juhee; Tasker, Jeffrey G

    2014-01-01

    The magnocellular vasopressin (VP) and oxytocin (OT) neurones undergo long-term synaptic plasticity to accommodate prolonged hormone demand. By contrast, rapidly induced, transient synaptic plasticity in response to brief stimuli could enable the activation of magnocellular neurones in response to acute challenges. Here, we report a robust short-term potentiation of asynchronous GABAergic synaptic inputs (STPGABA) to VP and OT neurones of the hypothalamic supraoptic nucleus elicited by repetitive extracellular electrical stimulation. The STPGABA required extracellular Ca2+, but did not require activation of glutamate, VP or OT receptors or nitric oxide synthesis. Presynaptic action potential generation was necessary for the induction, but not the maintenance, of STPGABA. The STPGABA led to a minutes-long GABAA receptor-dependent increase in spike frequency in VP neurones, but not in OT neurones, consistent with an excitatory function of GABA in only VP neurones and with the generation of prolonged bursts of action potentials in VP neurones. Therefore, this short-term plasticity of GABAergic synaptic inputs is likely to play very different roles in the regulation of OT and VP neurones and their distinct patterns of physiological activation. PMID:25063825

  6. Short-term plasticity and modulation of synaptic transmission at mammalian inhibitory cholinergic olivocochlear synapses

    PubMed Central

    Katz, Eleonora; Elgoyhen, Ana Belén

    2014-01-01

    The organ of Corti, the mammalian sensory epithelium of the inner ear, has two types of mechanoreceptor cells, inner hair cells (IHCs) and outer hair cells (OHCs). In this sensory epithelium, vibrations produced by sound waves are transformed into electrical signals. When depolarized by incoming sounds, IHCs release glutamate and activate auditory nerve fibers innervating them and OHCs, by virtue of their electromotile property, increase the amplification and fine tuning of sound signals. The medial olivocochlear (MOC) system, an efferent feedback system, inhibits OHC activity and thereby reduces the sensitivity and sharp tuning of cochlear afferent fibers. During neonatal development, IHCs fire Ca2+ action potentials which evoke glutamate release promoting activity in the immature auditory system in the absence of sensory stimuli. During this period, MOC fibers also innervate IHCs and are thought to modulate their firing rate. Both the MOC-OHC and the MOC-IHC synapses are cholinergic, fast and inhibitory and mediated by the α9α10 nicotinic cholinergic receptor (nAChR) coupled to the activation of calcium-activated potassium channels that hyperpolarize the hair cells. In this review we discuss the biophysical, functional and molecular data which demonstrate that at the synapses between MOC efferent fibers and cochlear hair cells, modulation of transmitter release as well as short term synaptic plasticity mechanisms, operating both at the presynaptic terminal and at the postsynaptic hair-cell, determine the efficacy of these synapses and shape the hair cell response pattern. PMID:25520631

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

    PubMed

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

    2013-10-01

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

  8. Central dysmyelination reduces the temporal fidelity of synaptic transmission and the reliability of postsynaptic firing during high-frequency stimulation.

    PubMed

    Kim, Sei Eun; Turkington, Karl; Kushmerick, Christopher; Kim, Jun Hee

    2013-10-01

    Auditory brain stem circuits rely on fast, precise, and reliable neurotransmission to process auditory information. To determine the fundamental role of myelination in auditory brain stem function, we examined the evoked auditory brain stem response (ABR) from the Long Evans shaker (LES) rat, which lacks myelin due to a genetic deletion of myelin basic protein. In control rats, the ABR evoked by a click consisted of five well-defined waves (denoted waves I-V). In LES rats, waves I, IV, and V were present, but waves II and III were undetectable, indicating disrupted function in the earliest stages of central nervous system auditory processing. In addition, the developmental shortening of the interval between waves I and IV that normally occurs in control rats was arrested and resulted in a significant increase in the central conduction time in LES rats. In brain stem slices, action potential transmission between the calyx of Held terminals and the medial nucleus of the trapezoid body (MNTB) neurons was delayed and less reliable in LES rats, although the resting potential, threshold, input resistance, and length of the axon initial segment of the postsynaptic MNTB neurons were normal. The amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) and the degree of synaptic depression during high-frequency stimulation were not different between LES rats and controls, but LES rats exhibited a marked slow component to the EPSC decay and a much higher rate of presynaptic failures. Together, these results indicate that loss of myelin disrupts brain stem auditory processing, increasing central conduction time and reducing the reliability of neurotransmission. PMID:23843435

  9. Excitatory and inhibitory synaptic transmission is differentially influenced by two ortho-substituted polychlorinated biphenyls in the hippocampal slice preparation

    SciTech Connect

    Kim, Kyung Ho; Inan, Salim Yalcin; Berman, Robert F.; Pessah, Isaac N.

    2009-06-01

    Exposure to polychlorinated biphenyls impairs cognition and behavior in children. Two environmental PCBs 2,2',3,3',4,4',5-heptachlorobiphenyl (PCB170) and 2,2',3,5',6-pentachlorobiphenyl (PCB95) were examined in vitro for influences on synaptic transmission in rat hippocampal slices. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region using a multi-electrode array. Perfusion with PCB170 (10 nM) had no effect on fEPSP slope relative to baseline period, whereas (100 nM) initially enhanced then depressed fEPSP slope. Perfusion of PCB95 (10 or 100 nM) persistently enhanced fEPSP slope > 200%, an effect that could be inhibited by dantrolene, a drug that attenuates ryanodine receptor signaling. Perfusion with picrotoxin (PTX) to block GABA neurotransmission resulted in a modest increase in fEPSP slope, whereas PTX + PCB170 (1-100 nM) persistently enhanced fEPSP slope in a dose dependent manner. fEPSP slope reached > 250% of baseline period in the presence of PTX + 100 nM PCB170, conditions that evoked marked epileptiform after-potential discharges. PCB95 and PCB170 were found to differentially influence the Ca{sup 2+}-dependence of [{sup 3}H]ryanodine-binding to hippocampal ryanodine receptors. Non-coplanar PCB congeners can differentially alter neurotransmission in a manner suggesting they can elicit imbalances between inhibitory and excitatory circuits within the hippocampus. Differential sensitization of ryanodine receptors by Ca{sup 2+} appears to mediate, at least in part, hippocampal excitotoxicity by non-coplanar PCBs.

  10. Diacylglycerol Kinases in the Coordination of Synaptic Plasticity

    PubMed Central

    Lee, Dongwon; Kim, Eunjoon; Tanaka-Yamamoto, Keiko

    2016-01-01

    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 evidences 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.

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

    PubMed

    Voronina, T A

    2003-01-01

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

  12. The synaptic glycoprotein neuroplastin is involved in long-term potentiation at hippocampal CA1 synapses

    PubMed Central

    Smalla, K. -H.; Matthies, H.; Langnäse, K.; Shabir, S.; Böckers, T. M.; Wyneken, U.; Staak, S.; Krug, M.; Beesley, P. W.; Gundelfinger, E. D.

    2000-01-01

    Neuroplastin-65 and -55 (previously known as gp65 and gp55) are glycoproteins of the Ig superfamily that are enriched in rat forebrain synaptic membrane preparations. Whereas the two-Ig domain isoform neuroplastin-55 is expressed in many tissues, the three-Ig domain isoform neuroplastin-65 is brain-specific and enriched in postsynaptic density (PSD) protein preparations. Here, we have assessed the function of neuroplastin in long-term synaptic plasticity. Immunocytochemical studies with neuroplastin-65-specific antibodies differentially stain distinct synaptic neuropil regions of the rat hippocampus with most prominent immunoreactivity in the CA1 region and the proximal molecular layer of the dentate gyrus. Kainate-induced seizures cause a significant enhancement of neuroplastin-65 association with PSDs. Similarly, long-term potentiation (LTP) of CA1 synapses in hippocampal slices enhanced the association of neuroplastin-65 with a detergent-insoluble PSD-enriched protein fraction. Several antibodies against the neuroplastins, including one specific for neuroplastin-65, inhibited the maintenance of LTP. A similar effect was observed when recombinant fusion protein containing the three extracellular Ig domains of neuroplastin-65 was applied to hippocampal slices before LTP induction. Microsphere binding experiments using neuroplastin-Fc chimeric proteins show that constructs containing Ig1–3 or Ig1 domains, but not Ig2–3 domains mediate homophilic adhesion. These data suggest that neuroplastin plays an essential role in implementing long-term changes in synaptic activity, possibly by means of a homophilic adhesion mechanism. PMID:10759566

  13. Activity-Dependent Calpain Activation Plays a Critical Role in Synaptic Facilitation and Post-Tetanic Potentiation

    ERIC Educational Resources Information Center

    Khoutorsky, Arkady; Spira, Micha E.

    2009-01-01

    Synaptic facilitation and post-tetanic potentiation (PTP) are believed to necessitate active regeneration of the release machinery and supply of synaptic vesicles to a ready-releasable site. The prevailing hypothesis assumes that synapsins play pivotal roles in these processes. Using a cholinergic synapse formed between cultured "Aplysia" neurons…

  14. Disruption of Akt signaling decreases dopamine sensitivity in modulation of inhibitory synaptic transmission in rat prefrontal cortex.

    PubMed

    Li, Yan-Chun; Yang, Sha-Sha; Gao, Wen-Jun

    2016-09-01

    Akt is a serine/threonine kinase, which is dramatically reduced in the prefrontal cortex (PFC) of patients with schizophrenia, and a deficiency in Akt1 results in PFC function abnormalities. Although the importance of Akt in dopamine (DA) transmission is well established, how impaired Akt signaling affects the DA modulation of synaptic transmission in the PFC has not been characterized. Here we show that Akt inhibitors significantly decreased receptor sensitivity to DA by shifting DA modulation of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in prefrontal cortical neurons. Akt inhibition caused a significant decrease in synaptic dopamine D2 receptor (D2R) levels with high-dose DA exposure. In addition, Akt inhibition failed to affect DA modulation of IPSCs after blockade of β-arrestin 2. β-arrestin 2-mediated interaction of clathrin with D2R was enhanced by co-application of a Akt inhibitor and DA. Taken together, the reduced response in DA modulation of inhibitory transmission mainly involved β-arrestin 2-dependent D2R desensitization. PMID:27163190

  15. Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway.

    PubMed

    Forrest, C M; Khalil, O S; Pisar, M; McNair, K; Kornisiuk, E; Snitcofsky, M; Gonzalez, N; Jerusalinsky, D; Darlington, L G; Stone, T W

    2013-12-19

    During early brain development, N-methyl-d-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog. PMID:24076085

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

    ERIC Educational Resources Information Center

    Gonzalez-Burgos, Ignacio

    2012-01-01

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

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

    PubMed

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

    2015-04-01

    The Shank genes (SHANK1, 2, 3) encode scaffold proteins highly enriched in postsynaptic densities where they regulate synaptic structure in spiny neurons. Mutations in human Shank genes are linked to autism spectrum disorder and schizophrenia. Shank1 mutant mice exhibit intriguing cognitive phenotypes reminiscent of individuals with autism spectrum disorder. However, the molecular mechanisms leading to the human pathophysiological phenotypes and mouse behaviors have not been elucidated. In this study it is shown that Shank1 protein is highly localized in parvalbumin-expressing (PV+) fast-spiking inhibitory interneurons in the hippocampus. Importantly, a lack of Shank1 in hippocampal CA1 PV+ neurons reduced excitatory synaptic inputs and inhibitory synaptic outputs to pyramidal neurons. Furthermore, it is demonstrated that hippocampal CA1 pyramidal neurons in Shank1 mutant mice exhibit a shift in the excitatory and inhibitory balance (E-I balance), a pathophysiological hallmark of autism spectrum disorder. The mutant mice also exhibit lower expression of gephyrin (a scaffold component of inhibitory synapses), supporting the dysregulation of E-I balance in the hippocampus. These results suggest that Shank1 scaffold in PV+ interneurons regulates excitatory synaptic strength and participates in the maintenance of E-I balance in excitatory neurons. PMID:25816842

  18. Modulation of neurosteroid potentiation by protein kinases at synaptic- and extrasynaptic-type GABAA receptors

    PubMed Central

    Adams, Joanna M.; Thomas, Philip; Smart, Trevor G.

    2015-01-01

    GABAA receptors are important for inhibition in the CNS where neurosteroids and protein kinases are potent endogenous modulators. Acting individually, these can either enhance or depress receptor function, dependent upon the type of neurosteroid or kinase and the receptor subunit combination. However, in vivo, these modulators probably act in concert to fine-tune GABAA receptor activity and thus inhibition, although how this is achieved remains unclear. Therefore, we investigated the relationship between these modulators at synaptic-type α1β3γ2L and extrasynaptic-type α4β3δ GABAA receptors using electrophysiology. For α1β3γ2L, potentiation of GABA responses by tetrahydro-deoxycorticosterone was reduced after inhibiting protein kinase C, and enhanced following its activation, suggesting this kinase regulates neurosteroid modulation. In comparison, neurosteroid potentiation was reduced at α1β3S408A,S409Aγ2L receptors, and unaltered by PKC inhibitors or activators, indicating that phosphorylation of β3 subunits is important for regulating neurosteroid activity. To determine whether extrasynaptic-type GABAA receptors were similarly modulated, α4β3δ and α4β3S408A,S409Aδ receptors were investigated. Neurosteroid potentiation was reduced at both receptors by the kinase inhibitor staurosporine. By contrast, neurosteroid-mediated potentiation at α4S443Aβ3S408A,S409Aδ receptors was unaffected by protein kinase inhibition, strongly suggesting that phosphorylation of α4 and β3 subunits is required for regulating neurosteroid activity at extrasynaptic receptors. Western blot analyses revealed that neurosteroids increased phosphorylation of β3S408,S409 implying that a reciprocal pathway exists for neurosteroids to modulate phosphorylation of GABAA receptors. Overall, these findings provide important insight into the regulation of GABAA receptors in vivo, and into the mechanisms by which GABAergic inhibitory transmission may be simultaneously tuned by

  19. Learning of Precise Spike Times with Homeostatic Membrane Potential Dependent Synaptic Plasticity

    PubMed Central

    Albers, Christian; Westkott, Maren; Pawelzik, Klaus

    2016-01-01

    Precise spatio-temporal patterns of neuronal action potentials underly e.g. sensory representations and control of muscle activities. However, it is not known how the synaptic efficacies in the neuronal networks of the brain adapt such that they can reliably generate spikes at specific points in time. Existing activity-dependent plasticity rules like Spike-Timing-Dependent Plasticity are agnostic to the goal of learning spike times. On the other hand, the existing formal and supervised learning algorithms perform a temporally precise comparison of projected activity with the target, but there is no known biologically plausible implementation of this comparison. Here, we propose a simple and local unsupervised synaptic plasticity mechanism that is derived from the requirement of a balanced membrane potential. Since the relevant signal for synaptic change is the postsynaptic voltage rather than spike times, we call the plasticity rule Membrane Potential Dependent Plasticity (MPDP). Combining our plasticity mechanism with spike after-hyperpolarization causes a sensitivity of synaptic change to pre- and postsynaptic spike times which can reproduce Hebbian spike timing dependent plasticity for inhibitory synapses as was found in experiments. In addition, the sensitivity of MPDP to the time course of the voltage when generating a spike allows MPDP to distinguish between weak (spurious) and strong (teacher) spikes, which therefore provides a neuronal basis for the comparison of actual and target activity. For spatio-temporal input spike patterns our conceptually simple plasticity rule achieves a surprisingly high storage capacity for spike associations. The sensitivity of the MPDP to the subthreshold membrane potential during training allows robust memory retrieval after learning even in the presence of activity corrupted by noise. We propose that MPDP represents a biophysically plausible mechanism to learn temporal target activity patterns. PMID:26900845

  20. Odor-Specific Habituation Arises from Interaction of Afferent Synaptic Adaptation and Intrinsic Synaptic Potentiation in Olfactory Cortex

    ERIC Educational Resources Information Center

    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…

  1. Effects of dimethylarsinic and dimethylarsinous acid on evoked synaptic potentials in hippocampal slices of young and adult rats

    SciTech Connect

    Krueger, Katharina Repges, Hendrik; Hippler, Joerg; Hartmann, Louise M.; Hirner, Alfred V.; Straub, Heidrun; Binding, Norbert; Musshoff, Ulrich

    2007-11-15

    In this study, the effects of pentavalent dimethylarsinic acid ((CH{sub 3}){sub 2}AsO(OH); DMA{sup V}) and trivalent dimethylarsinous acid ((CH{sub 3}){sub 2}As(OH); DMA{sup III}) on synaptic transmission generated by the excitatory Schaffer collateral-CA1 synapse were tested in hippocampal slices of young (14-21 day-old) and adult (2-4 month-old) rats. Both compounds were applied in concentrations of 1 to 100 {mu}mol/l. DMA{sup V} had no effect on the amplitudes of evoked fEPSPs or the induction of LTP recorded from the CA1 dendritic region either in adult or in young rats. However, application of DMA{sup III} significantly reduced the amplitudes of evoked fEPSPs in a concentration-dependent manner with a total depression following application of 100 {mu}mol/l DMA{sup III} in adult and 10 {mu}mol/l DMA{sup III} in young rats. Moreover, DMA{sup III} significantly affected the LTP-induction. Application of 10 {mu}mol/l DMA{sup III} resulted in a complete failure of the postsynaptic potentiation of the fEPSP amplitudes in slices taken both from adult and young rats. The depressant effect was not reversible after a 30-min washout of the DMA{sup III}. In slices of young rats, the depressant effects of DMA{sup III} were more pronounced than in those taken from adult ones. Compared to the (absent) effect of DMA{sup V} on synaptic transmission, the trivalent compound possesses a considerably higher neurotoxic potential.

  2. Molecular underpinnings of synaptic vesicle pool heterogeneity.

    PubMed

    Crawford, Devon C; Kavalali, Ege T

    2015-04-01

    Neuronal communication relies on chemical synaptic transmission for information transfer and processing. Chemical neurotransmission is initiated by synaptic vesicle fusion with the presynaptic active zone resulting in release of neurotransmitters. Classical models have assumed that all synaptic vesicles within a synapse have the same potential to fuse under different functional contexts. In this model, functional differences among synaptic vesicle populations are ascribed to their spatial distribution in the synapse with respect to the active zone. Emerging evidence suggests, however, that synaptic vesicles are not a homogenous population of organelles, and they possess intrinsic molecular differences and differential interaction partners. Recent studies have reported a diverse array of synaptic molecules that selectively regulate synaptic vesicles' ability to fuse synchronously and asynchronously in response to action potentials or spontaneously irrespective of action potentials. Here we discuss these molecular mediators of vesicle pool heterogeneity that are found on the synaptic vesicle membrane, on the presynaptic plasma membrane, or within the cytosol and consider some of the functional consequences of this diversity. This emerging molecular framework presents novel avenues to probe synaptic function and uncover how synaptic vesicle pools impact neuronal signaling. PMID:25620674

  3. Molecular Underpinnings of Synaptic Vesicle Pool Heterogeneity

    PubMed Central

    Crawford, Devon C.; Kavalali, Ege T.

    2015-01-01

    Neuronal communication relies on chemical synaptic transmission for information transfer and processing. Chemical neurotransmission is initiated by synaptic vesicle fusion with the presynaptic active zone resulting in release of neurotransmitters. Classical models have assumed that all synaptic vesicles within a synapse have the same potential to fuse under different functional contexts. In this model, functional differences among synaptic vesicle populations are ascribed to their spatial distribution in the synapse with respect to the active zone. Emerging evidence suggests, however, that synaptic vesicles are not a homogenous population of organelles, and they possess intrinsic molecular differences and differential interaction partners. Recent studies have reported a diverse array of synaptic molecules that selectively regulate synaptic vesicles' ability to fuse synchronously and asynchronously in response to action potentials or spontaneously irrespective of action potentials. Here we discuss these molecular mediators of vesicle pool heterogeneity that are found on the synaptic vesicle membrane, on the presynaptic plasma membrane, or within the cytosol and consider some of the functional consequences of this diversity. This emerging molecular framework presents novel avenues to probe synaptic function and uncover how synaptic vesicle pools impact neuronal signaling. PMID:25620674

  4. Membrane potential-dependent integration of synaptic inputs in entorhinal stellate neurons.

    PubMed

    Economo, Michael N; Martínez, Joan José; White, John A

    2014-12-01

    Stellate cells (SCs) of the medial entorhinal cortex exhibit robust spontaneous membrane-potential oscillations (MPOs) in the theta (4-12 Hz) frequency band as well as theta-frequency resonance in their membrane impedance spectra. Past experimental and modeling work suggests that these features may contribute to the phase-locking of SCs to the entorhinal theta rhythm and may be important for forming the hexagonally tiled grid cell place fields exhibited by these neurons in vivo. Among the major biophysical mechanisms contributing to MPOs is a population of persistent (non-inactivating or slowly inactivating) sodium channels. The resulting persistent sodium conductance (GNaP ) gives rise to an apparent increase in input resistance as the cell approaches threshold. In this study, we used dynamic clamp to test the hypothesis that this increased input resistance gives rise to voltage-dependent, and thus MPO phase-dependent, changes in the amplitude of excitatory and inhibitory post-synaptic potential (PSP) amplitudes. We find that PSP amplitude depends on membrane potential, exhibiting a 5-10% increase in amplitude per mV depolarization. The effect is larger than-and sums quasi-linearly with-the effect of the synaptic driving force, V - Esyn . Given that input-driven MPOs 10 mV in amplitude are commonly observed in MEC stellate cells in vivo, this voltage- and phase-dependent synaptic gain is large enough to modulate PSP amplitude by over 50% during theta-frequency MPOs. Phase-dependent synaptic gain may therefore impact the phase locking and phase precession of grid cells in vivo to ongoing network oscillations. © 2014 Wiley Periodicals, Inc. PMID:25044927

  5. Weak endogenous Ca2+ buffering supports sustained synaptic transmission by distinct mechanisms in rod and cone photoreceptors in salamander retina

    PubMed Central

    Van Hook, Matthew J; Thoreson, Wallace B

    2015-01-01

    Differences in synaptic transmission between rod and cone photoreceptors contribute to different response kinetics in rod- versus cone-dominated visual pathways. We examined Ca2+ dynamics in synaptic terminals of tiger salamander photoreceptors under conditions that mimicked endogenous buffering to determine the influence on kinetically and mechanistically distinct components of synaptic transmission. Measurements of ICl(Ca) confirmed that endogenous Ca2+ buffering is equivalent to ˜0.05 mmol/L EGTA in rod and cone terminals. Confocal imaging showed that with such buffering, depolarization stimulated large, spatially unconstrained [Ca2+] increases that spread throughout photoreceptor terminals. We calculated immediately releasable pool (IRP) size and release efficiency in rods by deconvolving excitatory postsynaptic currents and presynaptic Ca2+ currents. Peak efficiency of ˜0.2 vesicles/channel was similar to that of cones (˜0.3 vesicles/channel). Efficiency in both cell types was not significantly affected by using weak endogenous Ca2+ buffering. However, weak Ca2+ buffering speeded Ca2+/calmodulin (CaM)-dependent replenishment of vesicles to ribbons in both rods and cones, thereby enhancing sustained release. In rods, weak Ca2+ buffering also amplified sustained release by enhancing CICR and CICR-stimulated release of vesicles at nonribbon sites. By contrast, elevating [Ca2+] at nonribbon sites in cones with weak Ca2+ buffering and by inhibiting Ca2+ extrusion did not trigger additional release, consistent with the notion that exocytosis from cones occurs exclusively at ribbons. The presence of weak endogenous Ca2+ buffering in rods and cones facilitates slow, sustained exocytosis by enhancing Ca2+/CaM-dependent replenishment of ribbons in both rods and cones and by stimulating nonribbon release triggered by CICR in rods. PMID:26416977

  6. Nicotinic Transmission onto Layer 6 Cortical Neurons Relies on Synaptic Activation of Non-α7 Receptors.

    PubMed

    Hay, Y Audrey; Lambolez, Bertrand; Tricoire, Ludovic

    2016-06-01

    Nicotinic excitation in neocortex is mediated by low-affinity α7 receptors and by high-affinity α4β2 receptors. There is evidence that α7 receptors are synaptic, but it is unclear whether high-affinity receptors are activated by volume transmission or synaptic transmission. To address this issue, we characterized responses of excitatory layer 6 (L6) neurons to optogenetic release of acetylcholine (ACh) in cortical slices. L6 responses consisted in a slowly decaying α4β2 current and were devoid of α7 component. Evidence that these responses were mediated by synapses was 4-fold. 1) Channelrhodopsin-positive cholinergic varicosities made close appositions onto responsive neurons. 2) Inhibition of ACh degradation failed to alter onset kinetics and amplitude of currents. 3) Quasi-saturation of α4β2 receptors occurred upon ACh release. 4) Response kinetics were unchanged in low release probability conditions. Train stimulations increased amplitude and decay time of responses and these effects appeared to involve recruitment of extrasynaptic receptors. Finally, we found that the α5 subunit, known to be associated with α4β2 in L6, regulates short-term plasticity at L6 synapses. Our results are consistent with previous anatomical observations of widespread cholinergic synapses and suggest that a significant proportion of these small synapses operate via high-affinity nicotinic receptors. PMID:25934969

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

    PubMed

    Kaneda, Katsuyuki; Kasahara, Hironori; Matsui, Ryosuke; Katoh, Tomoko; Mizukami, Hiroaki; Ozawa, Keiya; Watanabe, Dai; Isa, Tadashi

    2011-01-01

    The superficial layer of the superior colliculus (sSC) receives visual inputs via two different pathways: from the retina and the primary visual cortex. However, the functional significance of each input for the operation of the sSC circuit remains to be identified. As a first step toward understanding the functional role of each of these inputs, we developed an optogenetic method to specifically suppress the synaptic transmission in the retino-tectal pathway. We introduced enhanced halorhodopsin (eNpHR), a yellow light-sensitive, membrane-targeting chloride pump, into mouse retinal ganglion cells (RGCs) by intravitreously injecting an adeno-associated virus serotype-2 vector carrying the CMV-eNpHR-EYFP construct. Several weeks after the injection, whole-cell recordings made from sSC neurons in slice preparations revealed that yellow laser illumination of the eNpHR-expressing retino-tectal axons, putatively synapsing onto the recorded cells, effectively inhibited EPSCs evoked by electrical stimulation of the optic nerve layer. We also showed that sSC spike activities elicited by visual stimulation were significantly reduced by laser illumination of the sSC in anesthetized mice. These results indicate that photo-activation of eNpHR expressed in RGC axons enables selective blockade of retino-tectal synaptic transmission. The method established here can most likely be applied to a variety of brain regions for studying the function of individual inputs to these regions. PMID:21483674

  8. Effects of monomethylarsonic and monomethylarsonous acid on evoked synaptic potentials in hippocampal slices of adult and young rats

    SciTech Connect

    Krueger, Katharina Straub, Heidrun; Hirner, Alfred V.; Hippler, Joerg; Binding, Norbert; Musshoff, Ulrich

    2009-04-01

    Arsenite and its metabolites, dimethylarsinic or dimethylarsinous acid, have previously been shown to disturb synaptic transmission in hippocampal slices of rats (Krueger, K., Gruner, J., Madeja, M., Hartmann, L.M., Hirner, A.V., Binding, N., Mu{beta}hoff, U., 2006a. Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals. Arch. Toxicol. 80, 492-501, Krueger, K., Straub, H., Binding, N., Mu{beta}hoff, U., 2006b. Effects of arsenite on long-term potentiation in hippocampal slices from adult and young rats. Toxicol. Lett. 165, 167-173, Krueger, K., Repges, H., Hippler, J., Hartmann, L.M., Hirner, A.V., Straub, H., Binding, N., Mu{beta}hoff, U., 2007. Effects of dimethylarsinic and dimethylarsinous acid on evoked synaptic potentials in hippocampal slices of young and adult rats. Toxicol. Appl. Pharmacol. 225, 40-46). The present experiments investigate, whether the important arsenic metabolites monomethylarsonic acid (MMA{sup V}) and monomethylarsonous acid (MMA{sup III}) also influence the synaptic functions of the hippocampus. In hippocampal slices of young (14-21 days-old) and adult (2-4 months-old) rats, evoked synaptic field potentials from the Schaffer collateral-CA1 synapse were measured under control conditions and during and after 30 and 60 min of application of the arsenic compounds. MMA{sup V} had no effect on the synapse functions neither in slices of adult nor in those from young rats. However, MMA{sup III} strongly influenced the synaptic transmission: it totally depressed the amplitudes of fEPSPs at concentrations of 50 {mu}mol/l (adult rats) and 25 {mu}mol/l (young rats) and LTP amplitudes at concentrations of 25 {mu}mol/l (adult rats) and 10 {mu}mol/l (young rats), respectively. In contrast, application of 1 {mu}mol/l MMA{sup III} led to an enhancement of the LTP amplitude in young rats, which is interpretable by an enhancing effect on NMDA receptors and a lack of the blocking effect on AMPA receptors at

  9. Quantifying the transmission potential of pandemic influenza

    NASA Astrophysics Data System (ADS)

    Chowell, Gerardo; Nishiura, Hiroshi

    2008-03-01

    This article reviews quantitative methods to estimate the basic reproduction number of pandemic influenza, a key threshold quantity to help determine the intensity of interventions required to control the disease. Although it is difficult to assess the transmission potential of a probable future pandemic, historical epidemiologic data is readily available from previous pandemics, and as a reference quantity for future pandemic planning, mathematical and statistical analyses of historical data are crucial. In particular, because many historical records tend to document only the temporal distribution of cases or deaths (i.e. epidemic curve), our review focuses on methods to maximize the utility of time-evolution data and to clarify the detailed mechanisms of the spread of influenza. First, we highlight structured epidemic models and their parameter estimation method which can quantify the detailed disease dynamics including those we cannot observe directly. Duration-structured epidemic systems are subsequently presented, offering firm understanding of the definition of the basic and effective reproduction numbers. When the initial growth phase of an epidemic is investigated, the distribution of the generation time is key statistical information to appropriately estimate the transmission potential using the intrinsic growth rate. Applications of stochastic processes are also highlighted to estimate the transmission potential using similar data. Critically important characteristics of influenza data are subsequently summarized, followed by our conclusions to suggest potential future methodological improvements.

  10. Modulation of synaptic transmission by adenosine in layer 2/3 of the rat visual cortex in vitro

    PubMed Central

    Bannon, Nicholas; Zhang, Pei; Ilin, Vladimir; Chistiakova, Marina; Volgushev, Maxim

    2014-01-01

    Adenosine is a wide-spread endogenous neuromodulator. In the central nervous system it activates A1 and A2A receptors (A1Rs and A2ARs) which have differential distributions, different affinities to adenosine, are coupled to different G-proteins, and have opposite effects on synaptic transmission. Although effects of adenosine are studied in detail in several brain areas, such as hippocampus and striatum, the heterogeneity of the effects of A1R and A 2A R activation and their differential distribution preclude generalization over brain areas and cell types. Here we study adenosine's effects on excitatory synaptic transmission to layer 2/3 pyramidal neurons in slices of the rat visual cortex. We measured effects of bath application of adenosine receptor ligands on evoked EPSPs, miniature EPSPs (mEPSPs), and membrane properties. Adenosine reduced the amplitude of evoked EPSPs and EPSCs, and reduced frequency of mEPSPs in a concentration dependent and reversible manner. Concurrent with EPSP/C amplitude reduction was an increase in the paired-pulse ratio. These effects were blocked by application of the selective A1R antagonist DPCPX, suggesting that activation of presynaptic A1Rs suppresses excitatory transmission by reducing release probability. Adenosine (20 μM) hyperpolarized the cell membrane from 65.3±1.5 to -67.7±1.8 mV, and reduced input resistance from 396.5±44.4 to 314.0±36.3 MOhm (~20%). These effects were also abolished by DPCPX, suggesting postsynaptic A1Rs. Application of the selective A2AR antagonist SCH-58261 on the background of high adenosine concentrations revealed an additional decrease in EPSP amplitude. Moreover, application of the A2AR agonist CGS-21680 led to an A1R-dependent increase in mEPSP frequency. Dependence of the A2AR effects on the A1R availability suggests interaction between these receptors, whereby A2ARs exert their facilitatory effect on synaptic transmission by inhibiting the A1R mediated suppression. Our results demonstrate

  11. An apparatus for recording synaptic potentials from neuronal cultures using voltage-sensitive fluorescent dyes.

    PubMed

    Chien, C B; Pine, J

    1991-07-01

    Voltage-sensitive dyes offer the promise of noninvasive multicell recording of electrical activity, and should therefore be useful for studying the synaptic interactions of small networks of cultured neurons. We have designed and built a system for recording from microcultures of 1-15 neurons from the rat superior cervical ganglion (SCG), using voltage-sensitive fluorescent dyes of the styryl class. The apparatus comprises a standard inverted epifluorescence microscope; a mercury arc lamp with an optical feedback regulator; a 256-pixel fiber-optic camera with individual photodiode detectors and very low-noise amplifiers; and a personal computer-based data acquisition system. Its dark noise and illumination fluctuations are low enough that at typical fluorescence levels for these cells, it is limited by shot noise (the inherent physical limit of detection). Recording from SCG neurons, the signal-to-noise ratio is high enough to see large subthreshold synaptic potentials without signal averaging. This apparatus should be useful for studying long-term synaptic plasticity in cultures of vertebrate neurons, and several of its features should apply to optical recording from other preparations. PMID:1784131

  12. 5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders

    PubMed Central

    Ciranna, Lucia; Catania, Maria Vincenza

    2014-01-01

    Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD. PMID:25221471

  13. Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4 Myasthenia

    PubMed Central

    Selcen, Duygu; Ohkawara, Bisei; Shen, Xin-Ming; McEvoy, Kathleen; Ohno, Kinji; Engel, Andrew G.

    2015-01-01

    IMPORTANCE Congenital myasthenic syndromes (CMS) are heterogeneous disorders. Defining the phenotypic features, genetic basis, and pathomechanisms of a CMS is relevant to prognosis, genetic counseling, and therapy. OBJECTIVE To characterize clinical, structural, electrophysiologic, and genetic features of a CMS and search for optimal therapy. DESIGN, SETTINGS, AND PARTICIPANTS Two sisters, 34 and 20 years of age suffering from a CMS affecting the limb-girdle muscles were investigated at an academic medical center by clinical observation, in vitro analysis of neuromuscular transmission, cytochemical and electron microscopy studies of the neuromuscular junction, exome sequencing, expression studies in HEK293 and COS-7 cells, and for response to therapy. MAIN OUTCOMES AND MEASURES We identified the disease gene and mutation, confirmed pathogenicity of the mutation by expression studies, and instituted optimal pharmacotherapy. RESULTS Intercostal muscle endplates (EPs) were abnormally small with attenuated reactivities for the acetylcholine receptor and acetylcholine esterase. Most EPs had poorly differentiated or degenerate junctional folds and some appeared denuded of nerve terminals. The amplitude of the EP potential (EPP), the miniature EPP, and the quantal content of the EPP were all markedly reduced. Exome sequencing identified a novel homozygous p.Glu1233Ala mutation in LRP4, a coreceptor for agrin to activate MuSK, required for EP development and maintenance. Expression studies indicate the mutation compromises ability of LRP4 to bind to, phosphorylate, and activate MuSK. Albuterol improved the patients’ symptoms. CONCLUSIONS AND RELEVANCE We identify a second CMS kinship harboring mutations in LRP4, identify the mechanisms that impair neuromuscular transmission, and mitigate the disease by appropriate therapy. PMID:26052878

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

    PubMed

    Salgado, Humberto; Treviño, Mario; Atzori, Marco

    2016-06-15

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

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

    PubMed

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

    2016-06-01

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

  16. Orexin A induces bidirectional modulation of synaptic plasticity: Inhibiting long-term potentiation and preventing depotentiation.

    PubMed

    Lu, Guan-Ling; Lee, Chia-Hsu; Chiou, Lih-Chu

    2016-08-01

    The orexin system consists of two peptides, orexin A and B and two receptors, OX1R and OX2R. It is implicated in learning and memory regulation while controversy remains on its role in modulating hippocampal synaptic plasticity in vivo and in vitro. Here, we investigated effects of orexin A on two forms of synaptic plasticity, long-term potentiation (LTP) and depotentiation of field excitatory postsynaptic potentials (fEPSPs), at the Schaffer Collateral-CA1 synapse of mouse hippocampal slices. Orexin A (≧30 nM) attenuated LTP induced by theta burst stimulation (TBS) in a manner antagonized by an OX1R (SB-334867), but not OX2R (EMPA), antagonist. Conversely, at 1 pM, co-application of orexin A prevented the induction of depotentiation induced by low frequency stimulation (LFS), i.e. restoring LTP. This re-potentiation effect of sub-nanomolar orexin A occurred at LFS of 1 Hz, but not 2 Hz, and with LTP induced by either TBS or tetanic stimulation. It was significantly antagonized by SB-334867, EMPA and TCS-1102, selective OX1R, OX2R and dual OXR antagonists, respectively, and prevented by D609, SQ22536 and H89, inhibitors of phospholipase C (PLC), adenylyl cyclase (AC) and protein kinase A (PKA), respectively. LFS-induced depotentiation was antagonized by blockers of NMDA, A1-adenosine and type 1/5 metabotropic glutamate (mGlu1/5) receptors, respectively. However, orexin A (1 pM) did not affect chemical-induced depotentiation by agonists of these receptors. These results suggest that orexin A bidirectionally modulates hippocampal CA1 synaptic plasticity, inhibiting LTP via OX1Rs at moderate concentrations while inducing re-potentiation via OX1Rs and OX2Rs, possibly through PLC and AC-PKA signaling at sub-nanomolar concentrations. PMID:26965217

  17. Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits.

    PubMed

    Speed, Haley E; Kouser, Mehreen; Xuan, Zhong; Reimers, Jeremy M; Ochoa, Christine F; Gupta, Natasha; Liu, Shunan; Powell, Craig M

    2015-07-01

    SHANK3 (also known as PROSAP2) is a postsynaptic scaffolding protein at excitatory synapses in which mutations and deletions have been implicated in patients with idiopathic autism, Phelan-McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. In this study, we have created a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3(G)). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse. Shank3(G/G) mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, altered response to novelty, and sensory processing deficits. At the cellular level, Shank3(G/G) mice also exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. This work identifies clear alterations in synaptic function and behavior in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. Furthermore, these findings lay the foundation for future studies aimed to validate and study region-selective and temporally selective genetic reversal studies in the Shank3(G/G) mouse that was engineered with such future experiments in mind. PMID:26134648

  18. Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits

    PubMed Central

    Speed, Haley E.; Kouser, Mehreen; Xuan, Zhong; Reimers, Jeremy M.; Ochoa, Christine F.; Gupta, Natasha; Liu, Shunan

    2015-01-01

    SHANK3 (also known as PROSAP2) is a postsynaptic scaffolding protein at excitatory synapses in which mutations and deletions have been implicated in patients with idiopathic autism, Phelan–McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. In this study, we have created a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3G). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse. Shank3G/G mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, altered response to novelty, and sensory processing deficits. At the cellular level, Shank3G/G mice also exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. This work identifies clear alterations in synaptic function and behavior in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. Furthermore, these findings lay the foundation for future studies aimed to validate and study region-selective and temporally selective genetic reversal studies in the Shank3G/G mouse that was engineered with such future experiments in mind. PMID:26134648

  19. Population synaptic potentials evoked in lumbar motoneurons following stimulation of the nucleus reticularis gigantocellularis during carbachol-induced atonia.

    PubMed

    Yamuy, J; Jiménez, I; Morales, F; Rudomin, P; Chase, M

    1994-03-14

    The effect of electrical stimulation of the medullary nucleus reticularis gigantocellularis (NRGc) on lumbar spinal cord motoneurons was studied in the decerebrate cat using sucrose-gap recordings from ventral roots. The NRGc was stimulated ipsi- and contralaterally before and during atonia elicited by the microinjection of carbachol into the pontine reticular formation. Prior to carbachol administration, the NRGc-induced response recorded from the sucrose-gap consisted of two consecutive excitatory population synaptic potentials followed by a long-lasting, small amplitude inhibitory population synaptic potential. Following carbachol injection, the same NRGc stimulus evoked a distinct, large amplitude inhibitory population synaptic potential, whereas the excitatory population synaptic potentials decreased in amplitude. In addition, after carbachol administration, the amplitude of the monosynaptic excitatory population synaptic potential, which was evoked by stimulation of group Ia afferents in hindlimb nerves, was reduced by 18 to 43%. When evoked at the peak of the NRGc-induced inhibitory response, this potential was further decreased in amplitude. Systemic strychnine administration (0.07-0.1 mg/kg, i.v.) blocked the NRGc-induced inhibitory population synaptic potential and promoted an increase in the amplitude of the excitatory population synaptic potentials induced by stimulation of the NRGc and group Ia afferents. These data indicate that during the state of carbachol-induced atonia, the NRGc effects on ipsi- and contralateral spinal cord motoneurons are predominantly inhibitory and that glycine is likely to be involved in this inhibitory process. These results support the hypothesis that the nucleus reticularis gigantocellularis is part of the system responsible for state-dependent somatomotor inhibition that occurs during active sleep. PMID:8205484

  20. Glutamate-induced long-term potentiation of the frequency of miniature synaptic currents in cultured hippocampal neurons

    NASA Astrophysics Data System (ADS)

    Malgaroli, Antonio; Tsien, Richard W.

    1992-05-01

    Glutamate application at synapses between hippocampal neurons in culture produces long-term potentiation of the frequency of spontaneous miniature synaptic currents, together with long-term potentiation of evoked synaptic currents. The mini frequency potentiation is initiated postsynaptically and requires activity of NMDA receptors. Although the frequency of unitary quanta! responses increases strongly, their amplitude remains little changed with potentiation. Tests of postsynaptic responsiveness rule out recruitment of latent glutamate receptor clusters. Thus, postsynaptic induction can lead to enhancement of presynaptic transmitter release. The sustained potentiation of mini frequency is expressed even in the absence of Ca2+ entry into presynaptic terminals.

  1. Enhanced GABAergic synaptic transmission at VLPAG neurons and potent modulation by oxycodone in a bone cancer pain model

    PubMed Central

    Takasu, Keiko; Ogawa, Koichi; Nakamura, Atsushi; Kanbara, Tomoe; Ono, Hiroko; Tomii, Takako; Morioka, Yasuhide; Hasegawa, Minoru; Shibasaki, Masahiro; Mori, Tomohisa; Suzuki, Tsutomu; Sakaguchi, Gaku

    2015-01-01

    Background and Purpose We demonstrated previously that oxycodone has potent antinociceptive effects at supraspinal sites. In this study, we investigated changes in neuronal function and antinociceptive mechanisms of oxycodone at ventrolateral periaqueductal gray (VLPAG) neurons, which are a major site of opioid action, in a femur bone cancer (FBC) model with bone cancer-related pain. Experimental Approach We characterized the supraspinal antinociceptive profiles of oxycodone and morphine on mechanical hypersensitivity in the FBC model. Based on the disinhibition mechanism underlying supraspinal opioid antinociception, the effects of oxycodone and morphine on GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in VLPAG neurons were evaluated in slices from the FBC model. Key Results The supraspinal antinociceptive effects of oxycodone, but not morphine, were abolished by blocking G protein-gated inwardly rectifying potassium1 (Kir3.1) channels. In slices from the FBC model, GABAergic synaptic transmission at VLPAG neurons was enhanced, as indicated by a leftward shift of the input–output relationship curve of evoked IPSCs, the increased paired-pulse facilitation and the enhancement of miniature IPSC frequency. Following treatment with oxycodone and morphine, IPSCs were reduced in the FBC model, and the inhibition of presynaptic GABA release by oxycodone, but not morphine was enhanced and dependent on Kir3.1 channels. Conclusion and Implications Our results demonstrate that Kir3.1 channels are important for supraspinal antinociception and presynaptic GABA release inhibition by oxycodone in the FBC model. Enhanced GABAergic synaptic transmission at VLPAG neurons in the FBC model is an important site of supraspinal antinociception by oxycodone via Kir3.1 channel activation. PMID:25521524

  2. Retrograde Endocannabinoid Signaling Reduces GABAergic Synaptic Transmission to Gonadotropin-Releasing Hormone Neurons

    PubMed Central

    Farkas, Imre; Kalló, Imre; Deli, Levente; Vida, Barbara; Hrabovszky, Erik; Fekete, Csaba; Moenter, Suzanne M.; Watanabe, Masahiko; Liposits, Zsolt

    2010-01-01

    Cannabinoids suppress fertility via reducing hypothalamic GnRH output. γ-Aminobutyric acid (GABA)A receptor (GABAA-R)-mediated transmission is a major input to GnRH cells that can be excitatory. We hypothesized that cannabinoids act via inhibiting GABAergic input. We performed loose-patch electrophysiological studies of acute slices from adult male GnRH-green fluorescent protein transgenic mice. Bath application of type 1 cannabinoid receptor (CB1) agonist WIN55,212 decreased GnRH neuron firing rate. This action was detectable in presence of the glutamate receptor antagonist kynurenic acid but disappeared when bicuculline was also present, indicating GABAA-R involvement. In immunocytochemical experiments, CB1-immunoreactive axons formed contacts with GnRH neurons and a subset established symmetric synapses characteristic of GABAergic neurotransmission. Functional studies were continued with whole-cell patch-clamp electrophysiology in presence of tetrodotoxin. WIN55,212 decreased the frequency of GABAA-R-mediated miniature postsynaptic currents (mPSCs) (reflecting spontaneous vesicle fusion), which was prevented with the CB1 antagonist AM251, indicating collectively that activation of presynaptic CB1 inhibits GABA release. AM251 alone increased mPSC frequency, providing evidence that endocannabinoids tonically inhibit GABAA-R drive onto GnRH neurons. Increased mPSC frequency was absent when diacylglycerol lipase was blocked intracellularly with tetrahydrolipstatin, showing that tonic inhibition is caused by 2-arachidonoylglycerol production of GnRH neurons. CdCl2 in extracellular solution can maintain both action potentials and spontaneous vesicle fusion. Under these conditions, when endocannabinoid-mediated blockade of spontaneous vesicle fusion was blocked with AM251, GnRH neuron firing increased, revealing an endogenous endocannabinoid brake on GnRH neuron firing. Retrograde endocannabinoid signaling may represent an important mechanism under physiological and

  3. Postnatal down-regulation of the GABAA receptor γ2 subunit in neocortical NG2 cells accompanies synaptic-to-extrasynaptic switch in the GABAergic transmission mode.

    PubMed

    Balia, Maddalena; Vélez-Fort, Mateo; Passlick, Stefan; Schäfer, Christoph; Audinat, Etienne; Steinhäuser, Christian; Seifert, Gerald; Angulo, María Cecilia

    2015-04-01

    NG2 cells, a main pool of glial progenitors, express γ-aminobutyric acid A (GABA(A)) receptors (GABA(A)Rs), the functional and molecular properties of which are largely unknown. We recently reported that transmission between GABAergic interneurons and NG2 cells drastically changes during development of the somatosensory cortex, switching from synaptic to extrasynaptic communication. Since synaptic and extrasynaptic GABA(A)Rs of neurons differ in their subunit composition, we hypothesize that GABA(A)Rs of NG2 cells undergo molecular changes during cortical development accompanying the switch of transmission modes. Single-cell RT-PCR and the effects of zolpidem and α5IA on evoked GABAergic currents reveal the predominance of functional α1- and α5-containing GABA(A)Rs at interneuron-NG2 cell synapses in the second postnatal week, while the α5 expression declines later in development when responses are exclusively extrasynaptic. Importantly, pharmacological and molecular analyses demonstrate that γ2, a subunit contributing to the clustering of GABA(A)Rs at postsynaptic sites in neurons, is down-regulated in NG2 cells in a cell type-specific manner in concomitance with the decline of synaptic activity and the switch of transmission mode. In keeping with the synaptic nature of γ2 in neurons, the down-regulation of this subunit is an important molecular hallmark of the change of transmission modes between interneurons and NG2 cells during development. PMID:24217990

  4. Topoisomerase 1 inhibition reversibly impairs synaptic function

    PubMed Central

    Mabb, Angela M.; Kullmann, Paul H. M.; Twomey, Margaret A.; Miriyala, Jayalakshmi; Philpot, Benjamin D.; Zylka, Mark J.

    2014-01-01

    Topotecan is a topoisomerase 1 (TOP1) inhibitor that is used to treat various forms of cancer. We recently found that topotecan reduces the expression of multiple long genes, including many neuronal genes linked to synapses and autism. However, whether topotecan alters synaptic protein levels and synapse function is currently unknown. Here we report that in primary cortical neurons, topotecan depleted synaptic proteins that are encoded by extremely long genes, including Neurexin-1, Neuroligin-1, Cntnap2, and GABAAβ3. Topotecan also suppressed spontaneous network activity without affecting resting membrane potential, action potential threshold, or neuron health. Topotecan strongly suppressed inhibitory neurotransmission via pre- and postsynaptic mechanisms and reduced excitatory neurotransmission. The effects on synaptic protein levels and inhibitory neurotransmission were fully reversible upon drug washout. Collectively, our findings suggest that TOP1 controls the levels of multiple synaptic proteins and is required for normal excitatory and inhibitory synaptic transmission. PMID:25404338

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

    PubMed

    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. PMID:21350486

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

    SciTech Connect

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

    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.

  7. Adenylyl cyclase subtype 1 is essential for late-phase long term potentiation and spatial propagation of synaptic responses in the anterior cingulate cortex of adult mice.

    PubMed

    Chen, Tao; O'Den, Gerile; Song, Qian; Koga, Kohei; Zhang, Ming-Ming; Zhuo, Min

    2014-01-01

    Long-term potentiation (LTP) is a key cellular mechanism for pathological pain in the central nervous system. LTP contains at least two different phases: early-phase LTP (E-LTP) and late-phase LTP (L-LTP). Among several major cortical areas, the anterior cingulate cortex (ACC) is a critical brain region for pain perception and its related emotional changes. Periphery tissue or nerve injuries cause LTP of excitatory synaptic transmission in the ACC. Our previous studies have demonstrated that genetic deletion of calcium-stimulated adenylyl cyclase 1 (AC1) or pharmacological application of a selective AC1 inhibitor NB001 blocked E-LTP in the ACC. However, the effect of AC1 on L-LTP, which requires new protein synthesis and is important for the process of chronic pain, has not been investigated. Here we tested the effects of NB001 on the ACC L-LTP and found that bath application of NB001 (0.1 μM) totally blocked the induction of L-LTP and recruitment of cortical circuitry without affecting basal excitatory transmission. In contrast, gabapentin, a widely used analgesic drug for neuropathic pain, did not block the induction of L-LTP and circuitry recruitment even at a high concentration (100 μM). Gabapentin non-selectively decreased basal synaptic transmission. Our results provide strong evidence that the selective AC1 inhibitor NB001 can be used to inhibit pain-related cortical L-LTP without affecting basal synaptic transmission. It also provides basic mechanisms for possible side effects of gabapentin in the central nervous system and its ineffectiveness in some patients with neuropathic pain. PMID:25304256

  8. Synaptic Vesicle Endocytosis

    PubMed Central

    Saheki, Yasunori; De Camilli, Pietro

    2012-01-01

    Neurons can sustain high rates of synaptic transmission without exhausting their supply of synaptic vesicles. This property relies on a highly efficient local endocytic recycling of synaptic vesicle membranes, which can be reused for hundreds, possibly thousands, of exo-endocytic cycles. Morphological, physiological, molecular, and genetic studies over the last four decades have provided insight into the membrane traffic reactions that govern this recycling and its regulation. These studies have shown that synaptic vesicle endocytosis capitalizes on fundamental and general endocytic mechanisms but also involves neuron-specific adaptations of such mechanisms. Thus, investigations of these processes have advanced not only the field of synaptic transmission but also, more generally, the field of endocytosis. This article summarizes current information on synaptic vesicle endocytosis with an emphasis on the underlying molecular mechanisms and with a special focus on clathrin-mediated endocytosis, the predominant pathway of synaptic vesicle protein internalization. PMID:22763746

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-08-01

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

  12. Cholinergic Synaptic Transmissions Were Altered after Single Sevoflurane Exposure in Drosophila Pupa

    PubMed Central

    Chen, Rongfa; Zhang, Tao; Kuang, Liting; Chen, Zhen; Ran, Dongzhi; Niu, Yang; Gu, Huaiyu

    2015-01-01

    Purpose. Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. Methods. Wide types of Drosophila (canton-s flies) were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane) were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. Results. The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced (P < 0.05). Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure (P < 0.05). Conclusions. All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure. PMID:25705662

  13. Learning-induced synaptic potentiation in implanted neural precursor cell-derived neurons

    PubMed Central

    Park, Kyungjoon; Heo, Hwon; Han, Ma Eum; Choi, Kyuhyun; Yi, Jee Hyun; Kang, Shin Jung; Kwon, Yunhee Kim; Shin, Ki Soon

    2015-01-01

    Neuronal loss caused by neurodegenerative diseases, traumatic brain injury and stroke results in cognitive dysfunctioning. Implantation of neural stem/precursor cells (NPCs) can improve the brain function by replacing lost neurons. Proper synaptic integration following neuronal differentiation of implanted cells is believed to be a prerequisite for the functional recovery. In the present study, we characterized the functional properties of immortalized neural progenitor HiB5 cells implanted into the rat hippocampus with chemically induced lesion. The implanted HiB5 cells migrated toward CA1 pyramidal layer and differentiated into vGluT1-positive glutamatergic neurons with morphological and electrophysiological properties of endogenous CA1 pyramidal cells. Functional synaptic integration of HiB5 cell-derived neurons was also evidenced by immunohistochemical and electrophysiological data. Lesion-caused memory deficit was significantly recovered after the implantation when assessed by inhibitory avoidance (IA) learning. Remarkably, IA learning preferentially produced long-term potentiation (LTP) at the synapses onto HiB5 cell-derived neurons, which occluded paring protocol-induced LTP ex vivo. We conclude that the implanted HiB5 cell-derived neurons actively participate in learning process through LTP formation, thereby counteracting lesion-mediated memory impairment. PMID:26634434

  14. Post-anesthesia AMPA receptor potentiation prevents anesthesia-induced learning and synaptic deficits.

    PubMed

    Huang, Lianyan; Cichon, Joseph; Ninan, Ipe; Yang, Guang

    2016-06-22

    Accumulating evidence has shown that repeated exposure to general anesthesia during critical stages of brain development results in long-lasting behavioral deficits later in life. To date, there has been no effective treatment to mitigate the neurotoxic effects of anesthesia on brain development. By performing calcium imaging in the mouse motor cortex, we show that ketamine anesthesia causes a marked and prolonged reduction in neuronal activity during the period of post-anesthesia recovery. Administration of the AMPAkine drug CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine] to potentiate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor activity during emergence from anesthesia in mice enhances neuronal activity and prevents long-term motor learning deficits induced by repeated neonatal anesthesia. In addition, we show that CX546 administration also ameliorates various synaptic deficits induced by anesthesia, including reductions in synaptic expression of NMDA (N-methyl-d-aspartate) and AMPA receptor subunits, motor training-evoked neuronal activity, and dendritic spine remodeling associated with motor learning. Together, our results indicate that pharmacologically enhancing neuronal activity during the post-anesthesia recovery period could effectively reduce the adverse effects of early-life anesthesia. PMID:27334260

  15. Isoflurane-sensitive presynaptic R-type calcium channels contribute to inhibitory synaptic transmission in the rat thalamus

    PubMed Central

    Joksovic, Pavle M.; Weiergräber, Marco; Lee, WooYong; Struck, Henrik; Schneider, Toni; Todorovic, Slobodan M.

    2009-01-01

    Since inhibitory synaptic transmission is a major mechanism of general anesthesia, we examined the effects of isoflurane on properties of GABAergic inhibitory currents in the reticular thalamic nucleus (nRT) in brain slices. The evoked inhibitory postsynaptic currents (eIPSCs) and spontaneous miniature synaptic currents (mIPSCs) of visualized nRT cells in young and adult rats were recorded. Consistent with postsynaptic effects on GABAA receptors, isoflurane prolonged the decay-time constants of both eIPSCs and mIPCSs. Surprisingly, isoflurane completely inhibited the amplitude of eIPSCs at clinically relevant concentrations (IC50 of 240 ± 20 μM), increased the paired-pulse ratio, and decreased the frequency of mIPSCs, indicating that presynaptic mechanisms may also contribute to the effects of isoflurane on IPSCs. The overall effect of isoflurane on eIPSCs in nRT cells was a decrease of net charge-transfer across the postsynaptic membrane. The application of 100 μM nickel (Ni2+) and the more specific R-type Ca2+ channel blocker SNX-482 (0.5 μM) decreased eIPSC amplitudes, increased the paired-pulse ratio, and attenuated isoflurane-induced inhibition of eIPSCs. In addition, isoflurane potently blocked currents in recombinant human CaV2.3 (α1E) channels with an IC50 of 206 ± 22 μM. Importantly, in vivo electroencephalographic (EEG) recordings in adult CaV2.3 knockout mice demonstrated alterations in isoflurane-induced burst-suppression activity. Because the thalamus has a key function in processing sensory information, sleep, and cognition, modulation of its GABAergic tone by presynaptic R-type Ca2+ channels may contribute to the clinical effects of general anesthesia. PMID:19193890

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

    PubMed

    Wang, Tiantian; de Kok, Laura; Willemsen, Rob; Elgersma, Ype; Borst, J Gerard G

    2015-01-01

    Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1(+/-) and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1 (+/) (-) mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission. PMID:26190969

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

    PubMed Central

    Wang, Tiantian; de Kok, Laura; Willemsen, Rob; Elgersma, Ype; Borst, J. Gerard G.

    2015-01-01

    Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1+/- and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1+/- mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission. PMID:26190969

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

    PubMed Central

    2010-01-01

    Background There is anatomical and behavioural evidence that μ- and δ-opioid receptors modulate distinct nociceptive modalities within the superficial dorsal horn. The aim of the present study was to examine whether μ- and δ-opioid receptor activation differentially modulates TRP sensitive inputs to neurons within the superficial dorsal horn. To do this, whole cell patch clamp recordings were made from lamina I - II neurons in rat spinal cord slices in vitro to examine the effect of opioids on TRP agonist-enhanced glutamatergic spontaneous miniature excitatory postsynaptic currents (EPSCs). Results Under basal conditions the μ-opioid agonist DAMGO (3 μM) reduced the rate of miniature EPSCs in 68% of neurons, while the δ- and κ-opioid agonists deltorphin-II (300 nM) and U69593 (300 nM) did so in 13 - 17% of neurons tested. The TRP agonists menthol (400 μM) and icilin (100 μM) both produced a Ca2+-dependent increase in miniature EPSC rate which was unaffected by the voltage dependent calcium channel (VDCC) blocker Cd2+. The proportion of neurons in which deltorphin-II reduced the miniature EPSC rate was enhanced in the presence of icilin (83%), but not menthol (0%). By contrast, the proportion of DAMGO and U69593 responders was unaltered in the presence of menthol (57%, 0%), or icilin (57%, 17%). Conclusions These findings demonstrate that δ-opioid receptor activation selectively inhibits inputs activated by icilin, whereas μ-opioid receptor activation has a more widespread effect on synaptic inputs to neurons in the superficial dorsal horn. These findings suggest that δ-opioids may provide a novel analgesic approach for specific, TRPA1-like mediated pain modalities. PMID:20977770

  19. Biphasic modulation of synaptic transmission by hypertonicity at the embryonic Drosophila neuromuscular junction

    PubMed Central

    Suzuki, Kazuhiro; Okamoto, Tomonori; Kidokoro, Yoshiaki

    2002-01-01

    Puff-application of hypertonic saline (sucrose added to external saline) causes a transient increase in the frequency of spontaneous miniature synaptic currents (mSCs) at the neuromuscular junctions of Drosophila embryos. The frequency gradually returns to pre-application levels. External Ca2+ is not needed for this response, but it may modify it. At 50 mm added sucrose, for example, enhanced spontaneous release was observed only in the presence of external Ca2+, suggesting that Ca2+ augments the response. In a high-K+ solution, in which the basal mSC frequency was elevated, higher sucrose concentrations produced an increase in mSC frequency that was followed (during and after the hypertonic exposure) by depression, with the magnitude of both effects increasing with hypertonicity between 100 and 500 mm. Evoked release by nerve stimulation showed only depression in response to hypertonicity. We do not believe that the depression of spontaneous or evoked release can be explained by the depletion of releasable quanta, however, since the frequency of quantal release did not reach levels compatible with this explanation and the enhancement and depression could be obtained independent of one another. In a mutant lacking neuronal synaptobrevin, only the depression of mSC frequency was induced by hypertonicity. Conversely, only the enhancing effect was observed in wild-type embryos when the mSC frequency was elevated with forskolin in Ca2+-free saline. In cultured embryonic Drosophila neurons, Ca2+ signals that were induced by high K+ and detected by Fura-2, were reduced by hypertonicity, suggesting that the depressing response is due to a direct effect of hypertonicity on Ca2+ influx. PMID:12433954

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

    PubMed

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

    2016-01-01

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

  1. Translational control of nicotine-evoked synaptic potentiation in mice and neuronal responses in human smokers by eIF2α

    PubMed Central

    Placzek, Andon N; Molfese, David L; Khatiwada, Sanjeev; Viana Di Prisco, Gonzalo; Huang, Wei; Sidrauski, Carmela; Krnjević, Krešimir; Amos, Christopher L; Ray, Russell; Dani, John A; Walter, Peter; Salas, Ramiro; Costa-Mattioli, Mauro

    2016-01-01

    Adolescents are particularly vulnerable to nicotine, the principal addictive component driving tobacco smoking. In a companion study, we found that reduced activity of the translation initiation factor eIF2α underlies the hypersensitivity of adolescent mice to the effects of cocaine. Here we report that nicotine potentiates excitatory synaptic transmission in ventral tegmental area dopaminergic neurons more readily in adolescent mice compared to adults. Adult mice with genetic or pharmacological reduction in p-eIF2α-mediated translation are more susceptible to nicotine’s synaptic effects, like adolescents. When we investigated the influence of allelic variability of the Eif2s1 gene (encoding eIF2α) on reward-related neuronal responses in human smokers, we found that a single nucleotide polymorphism in the Eif2s1 gene modulates mesolimbic neuronal reward responses in human smokers. These findings suggest that p-eIF2α regulates synaptic actions of nicotine in both mice and humans, and that reduced p-eIF2α may enhance susceptibility to nicotine (and other drugs of abuse) during adolescence. DOI: http://dx.doi.org/10.7554/eLife.12056.001 PMID:26928076

  2. Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission

    PubMed Central

    Cao, Yu-Qing; Tsien, Richard W.

    2005-01-01

    Inhibitory synapses play key roles in the modulatory circuitry that regulates pain signaling and generation of migraine headache. A rare, dominant form of this common disease, familial hemiplegic migraine type 1 (FHM1), arises from missense mutations in the pore-forming α1A subunit of P/Q-type Ca2+ channels. These channels are normally vital for presynaptic Ca2+ entry and neurotransmitter release at many central synapses, raising questions about effects of FHM1 mutations on neuronal Ca2+ influx and inhibitory and excitatory neurotransmission. We have expressed the four original FHM1 mutant channels in hippocampal neurons from α1A knockout mice. Whole-cell recordings indicated that FHM1 mutant channels were less effective than wild-type channels in their ability to conduct P/Q-type current, but not generally different from wild type in voltage-dependent channel gating. Ca2+ influx triggered by action potential waveforms was also diminished. In keeping with decreased channel activity, FHM1 mutant channels were correspondingly impaired in supporting the P/Q-type component of inhibitory neurotransmission. When expressed in wild-type inhibitory neurons, FHM1 mutant channels reduced the contribution of P/Q-type channels to GABAergic synaptic currents, consistent with a competition of mutant and endogenous channels for P/Q-specific slots. In all cases, N-type channels took up the burden of supporting transmission and homeostatic mechanisms maintained overall synaptic strength. The shift to reliance on N-type channels greatly increased the susceptibility to G protein-coupled modulation of neurotransmission, studied with the GABAB agonist baclofen. Thus, mutant-expressing synapses might be weakened in a heightened state of neuromodulation like that provoked by triggers of migraine such as stress. PMID:15699344

  3. Spike-timing control by dendritic plateau potentials in the presence of synaptic barrages

    PubMed Central

    Shai, Adam S.; Koch, Christof; Anastassiou, Costas A.

    2014-01-01

    Apical and tuft dendrites of pyramidal neurons support regenerative electrical potentials, giving rise to long-lasting (approximately hundreds of milliseconds) and strong (~50 mV from rest) depolarizations. Such plateau events rely on clustered glutamatergic input, can be mediated by calcium or by NMDA currents, and often generate somatic depolarizations that last for the time course of the dendritic plateau event. We address the computational significance of such single-neuron processing via reduced but biophysically realistic modeling. We introduce a model based on two discrete integration zones, a somatic and a dendritic one, that communicate from the dendritic to the somatic compartment via a long plateau-conductance. We show principled differences in the way dendritic vs. somatic inhibition controls spike timing, and demonstrate how this could implement spike time control in the face of barrages of synaptic inputs. PMID:25177288

  4. Signaling mechanism underlying α2A -adrenergic suppression of excitatory synaptic transmission in the medial prefrontal cortex of rats.

    PubMed

    Yi, Feng; Liu, Shu-Su; Luo, Fei; Zhang, Xue-Han; Li, Bao-Ming

    2013-08-01

    Stimulation of α2A -adrenoceptors (ARs) in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. A previous study in our laboratory showed that α2A -AR stimulation suppresses excitatory synaptic transmission in layer V-VI pyramidal cells of the rat medial PFC (mPFC). However, the intracellular mechanism underlying the α2A -AR suppression remains unclear. In the present study, we recorded evoked excitatory postsynaptic current (eEPSC) in layer V-VI pyramidal cells of the mPFC, using whole-cell patch-clamp recording. We found that the α2A -AR agonist guanfacine significantly suppresses eEPSC in mPFC pyramidal cells. The α2A -AR inhibition is mediated by the Gi-cAMP-PKA-PP1-CaMKII-AMPAR signaling pathway, as such inhibition no longer exists when each step of this pathway is blocked with NF023, Rp-cAMP, PKI5-24 or H89, tautomycin, and KN-62 or KN-93, respectively. PMID:23701442

  5. Long-term potentiation modulates synaptic phosphorylation networks and reshapes the structure of the postsynaptic interactome.

    PubMed

    Li, Jing; Wilkinson, Brent; Clementel, Veronica A; Hou, Junjie; O'Dell, Thomas J; Coba, Marcelo P

    2016-01-01

    The postsynaptic site of neurons is composed of more than 1500 proteins arranged in protein-protein interaction complexes, the composition of which is modulated by protein phosphorylation through the actions of complex signaling networks. Components of these networks function as key regulators of synaptic plasticity, in particular hippocampal long-term potentiation (LTP). The postsynaptic density (PSD) is a complex multicomponent structure that includes receptors, enzymes, scaffold proteins, and structural proteins. We triggered LTP in the mouse hippocampus CA1 region and then performed large-scale analyses to identify phosphorylation-mediated events in the PSD and changes in the protein-protein interactome of the PSD that were associated with LTP induction. Our data indicated LTP-induced reorganization of the PSD. The dynamic reorganization of the PSD links glutamate receptor signaling to kinases (writers) and phosphatases (erasers), as well as the target proteins that are modulated by protein phosphorylation and the proteins that recognize the phosphorylation status of their binding partners (readers). Protein phosphorylation and protein interaction networks converged at highly connected nodes within the PSD network. Furthermore, the LTP-regulated phosphoproteins, which included the scaffold proteins Shank3, Syngap1, Dlgap1, and Dlg4, represented the "PSD risk" for schizophrenia and autism spectrum disorder, such that without these proteins in the analysis, the association with the PSD and these two psychiatric diseases was not present. These data are a rich resource for future studies of LTP and suggest that the PSD holds the keys to understanding the molecular events that contribute to complex neurological disorders that affect synaptic plasticity. PMID:27507650

  6. DEVELOPMENTAL EXPOSURE TO POLYBROMINATED DIPHENYL ETHERS DOES NOT ALTER SYNAPTIC TRANSMISSION AND LTP IN HIPPOCAMPUS.

    EPA Science Inventory

    Polybrominated diphenyl ether (PDE) flame retardants bioaccumulate in the environment, in wildlife, and in humans. Concern has been raised over potential thyrotoxic effects of this class of xenobiotics. Severe hypothyroidism during critical periods of brain development leads to...

  7. DEVELOPMENTAL HYPOTHYROIDISM ALTERS SYNAPTIC TRANSMISSION IN DENTATE GYRUS AND AREA CA1 OF HIPPOCAMPUS.

    EPA Science Inventory

    Hypothyroidism during critical periods of brain developmental leads to learning deficits and alterations in hippocampal structure. Neurophysiological properties of the hippocampus, however, have not been well characterized. The present study examined field potentials evoked in...

  8. A single amino acid difference between the intracellular domains of amyloid precursor protein and amyloid-like precursor protein 2 enables induction of synaptic depression and block of long-term potentiation.

    PubMed

    Trillaud-Doppia, Emilie; Paradis-Isler, Nicolas; Boehm, Jannic

    2016-07-01

    Alzheimer disease (AD) is initially characterized as a disease of the synapse that affects synaptic transmission and synaptic plasticity. While amyloid-beta and tau have been traditionally implicated in causing AD, recent studies suggest that other factors, such as the intracellular domain of the amyloid-precursor protein (APP-ICD), can also play a role in the development of AD. Here, we show that the expression of APP-ICD induces synaptic depression, while the intracellular domain of its homolog amyloid-like precursor protein 2 (APLP2-ICD) does not. We are able to show that this effect by APP-ICD is due to a single alanine vs. proline difference between APP-ICD and APLP2-ICD. The alanine in APP-ICD and the proline in APLP2-ICD lie directly behind a conserved caspase cleavage site. Inhibition of caspase cleavage of APP-ICD prevents the induction of synaptic depression. Finally, we show that the expression of APP-ICD increases and facilitates long-term depression and blocks induction of long-term potentiation. The block in long-term potentiation can be overcome by mutating the aforementioned alanine in APP-ICD to the proline of APLP2. Based on our results, we propose the emergence of a new APP critical domain for the regulation of synaptic plasticity and in consequence for the development of AD. PMID:26921470

  9. Developmental exposure to perchlorate alters synaptic transmission in hippocampus of the adult rat.

    EPA Science Inventory

    The Food Quality Protection Act and Safe Drinking Water Act mandate the EPA to identify potential health risks associated with chemicals that act on the endocrine system. Perchlorate, a contaminant found in food and water supplies throughout the USA, blocks iodine uptake into the...

  10. Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling.

    PubMed

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

    2012-10-24

    Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders (ASDs), including Neuroligins, Neurexins, and members of the ProSAP/Shank family, thereby suggesting that these genetic forms of autism may share common synaptic mechanisms. Initial studies of ASD-associated mutations in ProSAP2/Shank3 support a role for this protein in glutamate receptor function and spine morphology, but these synaptic phenotypes are not universally penetrant, indicating that other core facets of ProSAP2/Shank3 function must underlie synaptic deficits in patients with ASDs. In the present study, we have examined whether the ability of ProSAP2/Shank3 to interact with the cytoplasmic tail of Neuroligins functions to coordinate pre/postsynaptic signaling through the Neurexin-Neuroligin signaling complex in hippocampal neurons of Rattus norvegicus. Indeed, we find that synaptic levels of ProSAP2/Shank3 regulate AMPA and NMDA receptor-mediated synaptic transmission and induce widespread changes in the levels of presynaptic and postsynaptic proteins via Neurexin-Neuroligin transsynaptic signaling. ASD-associated mutations in ProSAP2/Shank3 disrupt not only postsynaptic AMPA and NMDA receptor signaling but also interfere with the ability of ProSAP2/Shank3 to signal across the synapse to alter presynaptic structure and function. These data indicate that ASD-associated mutations in a subset of synaptic proteins may target core cellular pathways that coordinate the functional matching and maturation of excitatory synapses in the CNS. PMID:23100419