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Sample records for affect synaptic transmission

  1. Astrocytes Potentiate Synaptic Transmission

    NASA Astrophysics Data System (ADS)

    Nadkarni, Suhita

    2005-03-01

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

  2. Pentylenetetrazol-Induced Epileptiform Activity Affects Basal Synaptic Transmission and Short-Term Plasticity in Monosynaptic Connections

    PubMed Central

    Giachello, Carlo Natale Giuseppe; Premoselli, Federica; Montarolo, Pier Giorgio; Ghirardi, Mirella

    2013-01-01

    Epileptic activity is generally induced in experimental models by local application of epileptogenic drugs, including pentylenetetrazol (PTZ), widely used on both vertebrate and invertebrate neurons. Despite the high prevalence of this neurological disorder and the extensive research on it, the cellular and molecular mechanisms underlying epileptogenesis still remain unclear. In this work, we examined PTZ-induced neuronal changes in Helix monosynaptic circuits formed in vitro, as a simpler experimental model to investigate the effects of epileptiform activity on both basal release and post-tetanic potentiation (PTP), a form of short-term plasticity. We observed a significant enhancement of basal synaptic strength, with kinetics resembling those of previously described use-dependent forms of plasticity, determined by changes in estimated quantal parameters, such as the readily releasable pool and the release probability. Moreover, these neurons exhibited a strong reduction in PTP expression and in its decay time constant, suggesting an impairment in the dynamic reorganization of synaptic vesicle pools following prolonged stimulation of synaptic transmission. In order to explain this imbalance, we determined whether epileptic activity is related to the phosphorylation level of synapsin, which is known to modulate synaptic plasticity. Using western blot and immunocytochemical staining we found a PTZ-dependent increase in synapsin phosphorylation at both PKA/CaMKI/IV and MAPK/Erk sites, both of which are important for modulating synaptic plasticity. Taken together, our findings suggest that prolonged epileptiform activity leads to an increase in the synapsin phosphorylation status, thereby contributing to an alteration of synaptic strength in both basal condition and tetanus-induced potentiation. PMID:23437283

  3. Graded Synaptic Transmission between Spiking Neurons

    NASA Astrophysics Data System (ADS)

    Graubard, Katherine; Raper, Jonathan A.; Hartline, Daniel K.

    1980-06-01

    Graded synaptic transmission occurs between spiking neurons of the lobster stomatogastric ganglion. In addition to eliciting spike-evoked inhibitory potentials in postsynaptic cells, these neurons also release functionally significant amounts of transmitter below the threshold for action potentials. The spikeless postsynaptic potentials grade in amplitude with presynaptic voltage and can be maintained for long periods. Graded synaptic transmission can be modulated by synaptic input to the presynaptic neuron.

  4. 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…

  5. 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.

  6. GPCR Mediated Regulation of Synaptic Transmission

    PubMed Central

    Betke, Katherine M.; Wells, Christopher A.; Hamm, Heidi E.

    2012-01-01

    Synaptic transmission is a finely regulated mechanism of neuronal communication. The release of neurotransmitter at the synapse is not only the reflection of membrane depolarization events, but rather, is the summation of interactions between ion channels, G protein coupled receptors, second messengers, and the exocytotic machinery itself which exposes the components within a synaptic vesicle to the synaptic cleft. The focus of this review is to explore the role of G protein signaling as it relates to neurotransmission, as well as to discuss the recently determined inhibitory mechanism of Gβγ dimers acting directly on the exocytotic machinery proteins to inhibit neurotransmitter release. PMID:22307060

  7. Astrocytes Optimize the Synaptic Transmission of Information

    PubMed Central

    Nadkarni, Suhita; Jung, Peter; Levine, Herbert

    2008-01-01

    Chemical synapses transmit information via the release of neurotransmitter-filled vesicles from the presynaptic terminal. Using computational modeling, we predict that the limited availability of neurotransmitter resources in combination with the spontaneous release of vesicles limits the maximum degree of enhancement of synaptic transmission. This gives rise to an optimal tuning that depends on the number of active zones. There is strong experimental evidence that astrocytes that enwrap synapses can modulate the probabilities of vesicle release through bidirectional signaling and hence regulate synaptic transmission. For low-fidelity hippocampal synapses, which typically have only one or two active zones, the predicted optimal values lie close to those determined by experimentally measured astrocytic feedback, suggesting that astrocytes optimize synaptic transmission of information. PMID:18516277

  8. LRIT3 Differentially Affects Connectivity and Synaptic Transmission of Cones to ON- and OFF-Bipolar Cells

    PubMed Central

    Neuillé, Marion; Cao, Yan; Caplette, Romain; Guerrero-Given, Debbie; Thomas, Connon; Kamasawa, Naomi; Sahel, José-Alain; Hamel, Christian P.; Audo, Isabelle; Picaud, Serge; Martemyanov, Kirill A.; Zeitz, Christina

    2017-01-01

    Purpose Mutations in LRIT3 lead to complete congenital stationary night blindness (cCSNB). Using a cCSNB mouse model lacking Lrit3 (nob6), we recently have shown that LRIT3 has a role in the correct localization of TRPM1 (transient receptor potential melastatin 1) to the dendritic tips of ON-bipolar cells (BCs), contacting both rod and cone photoreceptors. Furthermore, postsynaptic clustering of other mGluR6 cascade components is selectively eliminated at the dendritic tips of cone ON-BCs. The purpose of this study was to further define the role of LRIT3 in structural and functional organization of cone synapses. Methods Exhaustive electroretinogram analysis was performed in a patient with LRIT3 mutations. Multielectrode array recordings were performed at the level of retinal ganglion cells in nob6 mice. Targeting of GluR1 and GluR5 at the dendritic tips of OFF-BCs in nob6 retinas was assessed by immunostaining and confocal microscopy. The ultrastructure of photoreceptor synapses was evaluated by electron microscopy in nob6 mice. Results The patient with LRIT3 mutations had a selective ON-BC dysfunction with relatively preserved OFF-BC responses. In nob6 mice, complete lack of ON-pathway function with robust, yet altered signaling processing in OFF-pathways was detected. Consistent with these observations, molecules essential for the OFF-BC signaling were normally targeted to the synapse. Finally, synaptic contacts made by ON-BC but not OFF-BC neurons with the cone pedicles were disorganized without ultrastructural alterations in cone terminals, horizontal cell processes, or synaptic ribbons. Conclusions These results suggest that LRIT3 is likely involved in coordination of the transsynaptic communication between cones and ON-BCs during synapse formation and function. PMID:28334377

  9. 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.

  10. 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.

  11. Modeling synaptic transmission of the tripartite synapse

    NASA Astrophysics Data System (ADS)

    Nadkarni, Suhita; Jung, Peter

    2007-03-01

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

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

    PubMed

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

    2013-05-08

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

  13. Capsaicin augments synaptic transmission in the rat medial preoptic nucleus.

    PubMed

    Karlsson, Urban; Sundgren-Andersson, Anna K; Johansson, Staffan; Krupp, Johannes J

    2005-05-10

    The medial preoptic nucleus (MPN) is the major nucleus of the preoptic area (POA), a hypothalamic area involved in the regulation of body-temperature. Injection of capsaicin into this area causes hypothermia in vivo. Capsaicin also causes glutamate release from hypothalamic slices. However, no data are available on the effect of capsaicin on synaptic transmission within the MPN. Here, we have studied the effect of exogenously applied capsaicin on spontaneous synaptic activity in hypothalamic slices of the rat. Whole-cell patch-clamp recordings were made from visually identified neurons located in the MPN. In a subset of the studied neurons, capsaicin enhanced the frequency of spontaneous glutamatergic EPSCs. Remarkably, capsaicin also increased the frequency of GABAergic IPSCs, an effect that was sensitive to removal of extracellular calcium, but insensitive to tetrodotoxin. This suggests an action of capsaicin at presynaptic GABAergic terminals. In contrast to capsaicin, the TRPV4 agonist 4alpha-PDD did not affect GABAergic IPSCs. Our results show that capsaicin directly affects synaptic transmission in the MPN, likely through actions at presynaptic terminals as well as on projecting neurons. Our data add to the growing evidence that capsaicin receptors are not only expressed in primary afferent neurons, but also contribute to synaptic processing in some CNS regions.

  14. Regulation of NMDA-receptor synaptic transmission by Wnt signaling

    PubMed Central

    Cerpa, Waldo; Gambrill, Abigail; Inestrosa, Nibaldo C.; Barria, Andres

    2011-01-01

    Wnt ligands are secreted glycoproteins controlling gene expression and cytoskeleton reorganization involved in embryonic development of the nervous system. However, their role in later stages of brain development, particularly in the regulation of established synaptic connections is not known. We found that Wnt-5a acutely and specifically up-regulates synaptic NMDAR currents in rat hippocampal slices facilitating induction of LTP, a cellular model of learning and memory. This effect requires an increase in postsynaptic Ca2+ and activation of non-canonical downstream effectors of the Wnt signaling pathway. In contrast, Wnt-7a, an activator of the canonical Wnt signaling pathway, has no effect on NMDAR mediated synaptic transmission. Moreover, endogenous Wnt ligands are necessary to maintain basal NMDAR synaptic transmission adjusting the threshold for synaptic potentiation. This novel role for Wnt ligands provides a mechanism for Wnt signaling to acutely modulate synaptic plasticity and brain function in later stages of development and in the mature organism. PMID:21715611

  15. 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

  16. Neurexin regulates nighttime sleep by modulating synaptic transmission

    PubMed Central

    Tong, Huawei; Li, Qian; Zhang, Zi Chao; Li, Yi; Han, Junhai

    2016-01-01

    Neurexins are cell adhesion molecules involved in synaptic formation and synaptic transmission. Mutations in neurexin genes are linked to autism spectrum disorders (ASDs), which are frequently associated with sleep problems. However, the role of neurexin-mediated synaptic transmission in sleep regulation is unclear. Here, we show that lack of the Drosophila α-neurexin homolog significantly reduces the quantity and quality of nighttime sleep and impairs sleep homeostasis. We report that neurexin expression in Drosophila mushroom body (MB) αβ neurons is essential for nighttime sleep. We demonstrate that reduced nighttime sleep in neurexin mutants is due to impaired αβ neuronal output, and show that neurexin functionally couples calcium channels (Cac) to regulate synaptic transmission. Finally, we determine that αβ surface (αβs) neurons release both acetylcholine and short neuropeptide F (sNPF), whereas αβ core (αβc) neurons release sNPF to promote nighttime sleep. Our findings reveal that neurexin regulates nighttime sleep by mediating the synaptic transmission of αβ neurons. This study elucidates the role of synaptic transmission in sleep regulation, and might offer insights into the mechanism of sleep disturbances in patients with autism disorders. PMID:27905548

  17. 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

  18. Very low concentrations of ethanol suppress excitatory synaptic transmission in rat visual cortex.

    PubMed

    Luong, Lucas; Bannon, Nicholas M; Redenti, Andrew; Chistiakova, Marina; Volgushev, Maxim

    2017-03-06

    Ethanol is one of the most commonly used substances in the world. Behavioral effects of alcohol are well described, however, cellular mechanisms of its action are poorly understood. There is an apparent contradiction between measurable behavioral changes produced by low concentrations of ethanol, and lack of evidence of synaptic changes at these concentrations. Furthermore, effects of ethanol on synaptic transmission in the neocortex are poorly understood. Here, we set to determine effects of ethanol on excitatory synaptic transmission in the neocortex. We show that 1-50 mm ethanol suppresses excitatory synaptic transmission to layer 2/3 pyramidal neurons in rat visual cortex in a concentration-dependent manner. To the best of our knowledge, this is the first demonstration of the effects of very low concentrations of ethanol (from 1 mm) on synaptic transmission in the neocortex. We further show that a selective antagonist of A1 adenosine receptors, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), blocks effects of 1-10 mm ethanol on synaptic transmission. However, the reduction in excitatory postsynaptic potential amplitude by 50 mm ethanol was not affected by DPCPX. We propose that ethanol depresses excitatory synaptic transmission in the neocortex by at least two mechanisms, engaged at different concentrations: low concentrations of ethanol reduce synaptic transmission via A1 R-dependent mechanism and involve presynaptic changes, while higher concentrations activate additional, adenosine-independent mechanisms with predominantly postsynaptic action. Involvement of adenosine signaling in mediating effects of low concentrations of ethanol may have important implications for understanding alcohol's effects on brain function, and provide a mechanistic explanation to the interaction between alcohol and caffeine.

  19. Kinetic model of excitatory synaptic transmission to cerebellar Purkinje cells.

    PubMed

    Marienhagen, J; Keller, B U; Zippelius, A

    1997-09-21

    We present a minimal kinetic model for excitatory synaptic transmission to cerebellar Purkinje cells. The main components are a kinetic model for a single glutamate receptor, which is calibrated with the help of patch clamp data, and a mean field approximation for the dynamics of a population of channels, which generate an EPSC. The resulting minimal model of the parallel fiber-Purkinje cell synapse is used to estimate the dynamics of glutamate in the synaptic cleft and to clarify the role of receptor desensitization in synaptic transmission. We also apply the model to different aspects of synaptic modulation, like long-term depression and potentiation by pharmacological application of ampakines. In the framework of the minimal model these effects can be understood as the result of modified receptor kinetics.

  20. Calcium channels, neuromuscular synaptic transmission and neurological diseases.

    PubMed

    Urbano, Francisco J; Pagani, Mario R; Uchitel, Osvaldo D

    2008-09-15

    Voltage-dependent calcium channels are essential in neuronal signaling and synaptic transmission, and their functional alterations underlie numerous human disorders whether monogenic (e.g., ataxia, migraine, etc.) or autoimmune. We review recent work on Ca(V)2.1 or P/Q channelopathies, mostly using neuromuscular junction preparations, and focus specially on the functional hierarchy among the calcium channels recruited to mediate neurotransmitter release when Ca(V)2.1 channels are mutated or depleted. In either case, synaptic transmission is greatly compromised; evidently, none of the reported functional replacements with other calcium channels compensates fully.

  1. 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

  2. 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…

  3. Slob, a Slowpoke channel–binding protein, modulates synaptic transmission

    PubMed Central

    Zhang, Jiaming

    2011-01-01

    Modulation of ion channels by regulatory proteins within the same macromolecular complex is a well-accepted concept, but the physiological consequences of such modulation are not fully understood. Slowpoke (Slo), a potassium channel critical for action potential repolarization and transmitter release, is regulated by Slo channel–binding protein (Slob), a Drosophila melanogaster Slo (dSlo) binding partner. Slob modulates the voltage dependence of dSlo channel activation in vitro and exerts similar effects on the dSlo channel in Drosophila central nervous system neurons in vivo. In addition, Slob modulates action potential duration in these neurons. Here, we investigate further the functional consequences of the modulation of the dSlo channel by Slob in vivo, by examining larval neuromuscular synaptic transmission in flies in which Slob levels have been altered. In Slob-null flies generated through P-element mutagenesis, as well as in Slob knockdown flies generated by RNA interference (RNAi), we find an enhancement of synaptic transmission but no change in the properties of the postsynaptic muscle cell. Using targeted transgenic rescue and targeted expression of Slob-RNAi, we find that Slob expression in neurons (but not in the postsynaptic muscle cell) is critical for its effects on synaptic transmission. Furthermore, inhibition of dSlo channel activity abolishes these effects of Slob. These results suggest that presynaptic Slob, by regulating dSlo channel function, participates in the modulation of synaptic transmission. PMID:21282401

  4. Mild hypoxia affects synaptic connectivity in cultured neuronal networks.

    PubMed

    Hofmeijer, Jeannette; Mulder, Alex T B; Farinha, Ana C; van Putten, Michel J A M; le Feber, Joost

    2014-04-04

    Eighty percent of patients with chronic mild cerebral ischemia/hypoxia resulting from chronic heart failure or pulmonary disease have cognitive impairment. Overt structural neuronal damage is lacking and the precise cause of neuronal damage is unclear. As almost half of the cerebral energy consumption is used for synaptic transmission, and synaptic failure is the first abrupt consequence of acute complete anoxia, synaptic dysfunction is a candidate mechanism for the cognitive deterioration in chronic mild ischemia/hypoxia. Because measurement of synaptic functioning in patients is problematic, we use cultured networks of cortical neurons from new born rats, grown over a multi-electrode array, as a model system. These were exposed to partial hypoxia (partial oxygen pressure of 150Torr lowered to 40-50Torr) during 3 (n=14) or 6 (n=8) hours. Synaptic functioning was assessed before, during, and after hypoxia by assessment of spontaneous network activity, functional connectivity, and synaptically driven network responses to electrical stimulation. Action potential heights and shapes and non-synaptic stimulus responses were used as measures of individual neuronal integrity. During hypoxia of 3 and 6h, there was a statistically significant decrease of spontaneous network activity, functional connectivity, and synaptically driven network responses, whereas direct responses and action potentials remained unchanged. These changes were largely reversible. Our results indicate that in cultured neuronal networks, partial hypoxia during 3 or 6h causes isolated disturbances of synaptic connectivity.

  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. Rescue of tau-induced synaptic transmission pathology by paclitaxel

    PubMed Central

    Erez, Hadas; Shemesh, Or A.; Spira, Micha E.

    2014-01-01

    Behavioral and electrophysiological studies of Alzheimer’s disease (AD) and other tauopathies have revealed that the onset of cognitive decline correlates better with synaptic dysfunctions than with hallmark pathologies such as extracellular amyloid-β plaques, intracellular hyperphosphorylated tau or neuronal loss. Recent experiments have also demonstrated that anti-cancer microtubule (MT)-stabilizing drugs can rescue tau-induced behavioral decline and hallmark neuron pathologies. Nevertheless, the mechanisms underlying tau-induced synaptic dysfunction as well as those involved in the rescue of cognitive decline by MTs-stabilizing drugs remain unclear. Here we began to study these mechanisms using the glutaminergic sensory-motoneuron synapse derived from Aplysia ganglia, electrophysiological methods, the expression of mutant-human tau (mt-htau) either pre or postsynaptically and the antimitotic drug paclitaxel. Expression of mt-htau in the presynaptic neurons led to reduced excitatory postsynaptic potential (EPSP) amplitude generated by rested synapses within 3 days of mt-htau expression, and to deeper levels of homosynaptic depression. mt-htau-induced synaptic weakening correlated with reduced releasable presynaptic vesicle pools as revealed by the induction of asynchronous neurotransmitter release by hypertonic sucrose solution. Paclitaxel totally rescued tau-induced synaptic weakening by maintaining the availability of the presynaptic vesicle stores. Postsynaptic expression of mt-htau did not impair the above described synaptic-transmission parameters for up to 5 days. Along with earlier confocal microscope observations from our laboratory, these findings suggest that tau-induced synaptic dysfunction is the outcome of impaired axoplasmic transport and the ensuing reduction in the releasable presynaptic vesicle stores rather than the direct effects of mt-htau or paclitaxel on the synaptic release mechanisms. PMID:24574970

  7. GABAAR-dependent synaptic transmission sculpts dendritic arbor structure in Xenopus tadpoles in vivo

    PubMed Central

    Shen, Wanhua; Da Silva, Jorge Santos; He, Haiyan; Cline, Hollis T.

    2009-01-01

    The emergence of dendritic arbor structure in vivo depends on synaptic inputs. We tested whether inhibitory GABAergic synaptic transmission regulates Xenopus optic tectal cell dendritic arbor development in vivo by expressing a peptide corresponding to an intracellular loop (ICL) of the γ2 subunit of GABAAR which is required to anchor GABAA receptors to the postsynaptic scaffold. GFP-tagged ICL (EGFP-ICL) was distributed in a punctate pattern at putative inhibitory synapses, identified by VGAT-immunoreactive puncta. ICL expression completely blocked GABAAR - mediated transmission in 36% of transfected neurons and significantly reduced GABAAR - mediated synaptic currents relative to AMPAR-mediated synaptic currents in the remaining transfected neurons without altering release probability or neuronal excitability. Further analysis of ICL-expressing neurons with residual GABAAR- mediated inputs showed that the capacity of benzodiazepine to enhance GABAergic synaptic responses was reduced in ICL-expressing neurons, indicating that they were likely depleted of γ2 subunit-containing GABAAR. Neurons expressing a mutant form of ICL were comparable to controls. In vivo time-lapse images showed that ICL-expressing neurons have more sparsely branched dendritic arbors which expand over larger neuropil areas than EGFP-expressing control neurons. Analysis of branch dynamics indicated that ICL expression affected arbor growth by reducing rates of branch addition. Furthermore, we found that decreasing GABAergic synaptic transmission with ICL expression blocked visual experience dependent dendritic arbor structural plasticity. Our findings establish an essential role for inhibitory GABAergic synaptic transmission in the regulation of dendritic structural plasticity in Xenopus in vivo. PMID:19369572

  8. An electrophysiological analysis of oxygen and pressure on synaptic transmission.

    PubMed

    Colton, C A; Colton, J S

    1982-11-18

    The effect of oxygen at high pressure (OHP), helium at 150 PSIG and 100% oxygen at ambient pressure on excitatory synaptic transmission was studied using the lobster walking leg neuromuscular preparation. Both 100% oxygen at 150 PSIG (7135 mm Hg oxygen) and helium at 150 PSIG (7000 mm Hg helium plus 135 mm Hg oxygen) produced a significant decrease in the amplitude of the junction potential (Vejp). The decrease in Vejp induced by OHP, however, was greater than with pressure alone. OHP also produced a significant decrease in short term facilitation. Exposure to 100% oxygen at ambient pressure produced a transient increase in Vejp and a large increase in frequency of miniature junction potentials. In each case the change in Vejp was due to changes in presynaptic release of transmitter since quantal content per fiber (M') was shown to decrease for OHP and helium at 150 PSIG and to transiently rise with 100% oxygen at ambient pressure. In addition, the response to exogenously applied glutamate (the putative neurotransmitter) was not affected by OHP, 150 PSIG helium or 100% oxygen at ambient pressure. This further indicates a presynaptic site of action.

  9. Separate serotonin and dopamine receptors modulate the duration of post-tetanic potentiation at an Aplysia synapse without affecting other aspects of synaptic transmission.

    PubMed

    Newlin, S A; Schlapfer, W T; Barondes, S H

    1980-01-06

    We have studied the effect of the biogenic amines, serotonin and dopamine, on post-tetanic potentiation (PTP) at an identified synapse in the abdominal ganglion of Aplysia californica. We found that: (1) 10(-7) M perfused serotonin doubles the rate constant of decay of PTP. The effect is specific in that neither the size of the non-potentiated (isolated) EPSP nor the amplitude of PTP is affected. As reported previously, higher doses of serotonin will also increase the amplitude of PTP and decrease the size of the isolated EPSP; (2) 5 X 10(-7) M dopamine in the perfusate increases the rate constant of decay of PTP by about 50%. The effect is also specific in that neither PTP amplitude nor the size of the isolated EPSP is affected; (3) SQ10,631, a serotonin antagonist, blocks the effect of perfused serotonin on PTP decay rate. It does not antagonize the dopamine effect. SQ10,631 also slows the endogenous decay of PTP in some preparations which exhibit an unusually fast PTP decay rate, suggesting a naturally occurring source of serotonin within the ganglion capable of affecting the rate constant of PTP decay; (4) (+)-butaclamol, a dopamine antagonist, blocks the effect of dopamine on the rate constant of PTP decay, whereas (-)-butaclamol has little effect. Butaclamol does not block the effect of serotonin on the rate constant of PTP decay; (5) phosphodiesterase inhibitors potentiate the effect of serotonin on the rate constant of PTP decay, and cyclic AMP analogues mimic the effect of the biogenic amines, suggesting that the aminergic modulation of the rate of decay of PTP is coupled with activation of adenylate cyclase and accumulation of cyclic AMP; and (6) the evidence presented is consistent with the hypothesis that serotonin and dopamine are capable of specifically modifying the rate of change in the efficacy of transmitter release which underlies PTP. It also suggests that the two biogenic amines operate separately and in parallel via presynaptic receptor

  10. 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

  11. 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

    2015-04-02

    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.

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

    PubMed Central

    Dallérac, Glenn; Chever, Oana; Rouach, Nathalie

    2013-01-01

    A major breakthrough in neuroscience has been the realization in the last decades that the dogmatic view of astroglial cells as being merely fostering and buffering elements of the nervous system is simplistic. A wealth of investigations now shows that astrocytes actually participate in the control of synaptic transmission in an active manner. This was first hinted by the intimate contacts glial processes make with neurons, particularly at the synaptic level, and evidenced using electrophysiological and calcium imaging techniques. Calcium imaging has provided critical evidence demonstrating that astrocytic regulation of synaptic efficacy is not a passive phenomenon. However, given that cellular activation is not only represented by calcium signaling, it is also crucial to assess concomitant mechanisms. We and others have used electrophysiological techniques to simultaneously record neuronal and astrocytic activity, thus enabling the study of multiple ionic currents and in depth investigation of neuro-glial dialogues. In the current review, we focus on the input such approach has provided in the understanding of astrocyte-neuron interactions underlying control of synaptic efficacy. PMID:24101894

  13. Alcohol effects on synaptic transmission in periaqueductal gray dopamine neurons

    PubMed Central

    Li, Chia; McCall, Nora M.; Lopez, Alberto J.; Kash, Thomas L.

    2014-01-01

    The role of dopamine (DA) signaling in regulating the rewarding properties of drugs, including alcohol, has been widely studied. The majority of these studies, however, have focused on the DA neurons located in the ventral tegmental area (VTA), and their projections to the nucleus accumbens. DA neurons within the ventral periaqueductal gray (vPAG) have been shown to regulate reward but little is known about the functional properties of these neurons, or how they are modified by drugs of abuse. This lack of knowledge is likely due to the highly heterogeneous cell composition of the vPAG, with both γ-amino-butyric acid (GABA) and glutamate neurons present in addition to DA neurons. In this study, we performed whole-cell recordings in a TH–eGFP transgenic mouse line to evaluate the properties of vPAG-DA neurons. Following this initial characterization, we examined how both acute and chronic alcohol exposure modify synaptic transmission onto vPAG-DA neurons. We found minimal effects of acute alcohol exposure on GABA transmission, but a robust enhancement of glutamatergic synaptic transmission in vPAG-DA. Consistent with this effect on excitatory transmission, we also found that alcohol caused an increase in firing rate. These data were in contrast to the effects of chronic intermittent alcohol exposure, which had no significant impact on either inhibitory or excitatory synaptic transmission on the vPAG-DA neurons. These data add to a growing body of literature that points to alcohol having both region-dependent and cell-type dependent effects on function. PMID:23597415

  14. Corticosterone targets distinct steps of synaptic transmission via concentration specific activation of mineralocorticoid and glucocorticoid receptors.

    PubMed

    Chatterjee, Sreejata; Sikdar, Sujit K

    2014-02-01

    Hippocampal neurons are affected by chronic stress and have a high density of cytoplasmic mineralocorticoid and glucocorticoid receptors (MR and GR). Detailed studies on the genomic effects of the stress hormone corticosterone at physiologically relevant concentrations on different steps in synaptic transmission are limited. In this study, we tried to delineate how activation of MR and GR by different concentrations of corticosterone affects synaptic transmission at various levels. The effect of 3-h corticosterone (25, 50, and 100 nM) treatment on depolarization-mediated calcium influx, vesicular release and properties of miniature excitatory post-synaptic currents (mEPSCs) were studied in cultured hippocampal neurons. Activation of MR with 25 nM corticosterone treatment resulted in enhanced depolarization-mediated calcium influx via a transcription-dependent process and increased frequency of mEPSCs with larger amplitude. On the other hand, activation of GR upon 100 nM corticosterone treatment resulted in increase in the rate of vesicular release via the genomic actions of GR. Furthermore, GR activation led to significant increase in the frequency of mEPSCs with larger amplitude and faster decay. Our studies indicate that differential activation of the dual receptor system of MR and GR by corticosterone targets the steps in synaptic transmission differently.

  15. Adult-born neurons modify excitatory synaptic transmission to existing neurons

    PubMed Central

    Adlaf, Elena W; Vaden, Ryan J; Niver, Anastasia J; Manuel, Allison F; Onyilo, Vincent C; Araujo, Matheus T; Dieni, Cristina V; Vo, Hai T; King, Gwendalyn D; Wadiche, Jacques I; Overstreet-Wadiche, Linda

    2017-01-01

    Adult-born neurons are continually produced in the dentate gyrus but it is unclear whether synaptic integration of new neurons affects the pre-existing circuit. Here we investigated how manipulating neurogenesis in adult mice alters excitatory synaptic transmission to mature dentate neurons. Enhancing neurogenesis by conditional deletion of the pro-apoptotic gene Bax in stem cells reduced excitatory postsynaptic currents (EPSCs) and spine density in mature neurons, whereas genetic ablation of neurogenesis increased EPSCs in mature neurons. Unexpectedly, we found that Bax deletion in developing and mature dentate neurons increased EPSCs and prevented neurogenesis-induced synaptic suppression. Together these results show that neurogenesis modifies synaptic transmission to mature neurons in a manner consistent with a redistribution of pre-existing synapses to newly integrating neurons and that a non-apoptotic function of the Bax signaling pathway contributes to ongoing synaptic refinement within the dentate circuit. DOI: http://dx.doi.org/10.7554/eLife.19886.001 PMID:28135190

  16. Brain-derived neurotrophic factor differentially regulates excitatory and inhibitory synaptic transmission in hippocampal cultures.

    PubMed

    Bolton, M M; Pittman, A J; Lo, D C

    2000-05-01

    Brain-derived neurotrophic factor (BDNF) has been postulated to be a key signaling molecule in regulating synaptic strength and overall circuit activity. In this context, we have found that BDNF dramatically increases the frequency of spontaneously initiated action potentials in hippocampal neurons in dissociated culture. Using analysis of unitary synaptic transmission and immunocytochemical methods, we determined that chronic treatment with BDNF potentiates both excitatory and inhibitory transmission, but that it does so via different mechanisms. BDNF strengthens excitation primarily by augmenting the amplitude of AMPA receptor-mediated miniature EPSCs (mEPSCs) but enhances inhibition by increasing the frequency of mIPSC and increasing the size of GABAergic synaptic terminals. In contrast to observations in other systems, BDNF-mediated increases in AMPA-receptor mediated mEPSC amplitudes did not require activity, because blocking action potentials with tetrodotoxin for the entire duration of BDNF treatment had no effect on the magnitude of this enhancement. These forms of synaptic regulations appear to be a selective action of BDNF because intrinsic excitability, synapse number, and neuronal survival are not affected in these cultures. Thus, although BDNF induces a net increase in overall circuit activity, this results from potentiation of both excitatory and inhibitory synaptic drive through distinct and selective physiological mechanisms.

  17. Regulation of information passing by synaptic transmission: a short review.

    PubMed

    Di Maio, Vito

    2008-08-15

    The largest part of information passed among neurons in the brain occurs by the means of chemical synapses connecting the axons of presynaptic neurons to the dendritic tree of the postsynaptic ones. In the present paper, the most relevant open problems related to the mechanisms of control of the information passing among neurons by synaptic transmission will be shortly reviewed. The "cross talking" between synapses, their mutual interactions and the control of the information flow between different areas of the dendritic tree will be also considered. The threshold mechanism based on the "reversal potential" will be considered for its role in the control of information transfer among neurons and also for its contribution to the information flow among different areas of the dendritic tree and to the computational ability of the single neuron. The concept of "competition for plasticity" will be proposed as a mechanism of competition based on the synaptic activation time.

  18. CNQX and AMPA inhibit electrical synaptic transmission: a potential interaction between electrical and glutamatergic synapses

    PubMed Central

    Li, Qin; Burrell, Brian D.

    2008-01-01

    Electrical synapses play an important role in signaling between neurons and the synaptic connections between many neurons possess both electrical and chemical components. Although modulation of electrical synapses is frequently observed, the cellular processes that mediate such changes have not been studied as thoroughly as plasticity in chemical synapses. In the leech (Hirudo sp), the competitive AMPA receptor antagonist CNQX inhibited transmission at the rectifying electrical synapse of a mixed glutamatergic/electrical synaptic connection. This CNQX-mediated inhibition of the electrical synapse was blocked by concanavalin A (Con A) and dynamin inhibitory peptide (DIP), both of which are known to inhibit endocytosis of neurotransmitter receptors. CNQX-mediated inhibition was also blocked by pep2-SVKI (SVKI), a synthetic peptide that prevents internalization of AMPA-type glutamate receptor. AMPA itself also inhibited electrical synaptic transmission and this AMPA-mediated inhibition was partially blocked by Con A, DIP and SVKI. Low frequency stimulation induced long-term depression (LTD) in both the electrical and chemical components of these synapses and this LTD was blocked by SVKI. GYKI 52466, a selective non-competitive antagonist of AMPA receptors, did not affect the electrical EPSP, although it did block the chemical component of these synapses. CNQX did not affect non-rectifying electrical synapses in two different pairs of neurons. These results suggest an interaction between AMPA-type glutamate receptors and the gap junction proteins that mediate electrical synaptic transmission. This putative interaction between glutamate receptors and gap junction proteins represents a novel mechanism for regulating the strength of synaptic transmission. PMID:18601913

  19. An Engineered Metal Sensor Tunes the Kinetics of Synaptic Transmission

    PubMed Central

    Evans, Chantell S.; Ruhl, David A.

    2015-01-01

    The Ca2+ sensor synaptotagmin-1 (syt-1) regulates neurotransmitter release by interacting with anionic phospholipids. Here we test the idea that the intrinsic kinetics of syt–membrane interactions determine, in part, the time course of synaptic transmission. To tune the kinetics of this interaction, we grafted structural elements from the slowest isoform, syt-7, onto the fastest isoform, syt-1, resulting in a chimera with intermediate kinetic properties. Moreover, the chimera coupled a physiologically irrelevant metal, Sr2+, to membrane fusion in vitro. When substituted for syt-1 in mouse hippocampal neurons, the chimera slowed the kinetics of synaptic transmission. Neurons expressing the chimera also evinced rapid and efficient Sr2+ triggered release, in contrast to the weak response of neurons expressing syt-1. These findings reveal presynaptic sensor–membrane interactions as a major factor regulating the speed of the release machinery. Finally, the chimera failed to clamp the elevated spontaneous fusion rate exhibited by syt-1 KO neurons, indicating that the metal binding loops of syt-1 regulate the two modes of release by distinct mechanisms. SIGNIFICANCE STATEMENT In calcium, synaptotagmin-1 triggers neurotransmitter release by interacting with membranes. Here, we demonstrate that intrinsic properties of this interaction control the time course of synaptic transmission. We engineered a “chimera” using synaptotagmin-1 and elements of a slower isoform, synaptotagmin-7. When expressed in neurons, the chimera slowed the rate of neurotransmitter release. Furthermore, unlike native synaptotagmin-1, the chimera was able to function robustly in the presence of strontium–a metal not present in cells. We exploited this ability to show that a key function of synaptotagmin-1 is to penetrate cell membranes. This work sheds light on fundamental mechanisms of neurotransmitter release. PMID:26311762

  20. Alterations in hippocampal excitability, synaptic transmission and synaptic plasticity in a neurodevelopmental model of schizophrenia.

    PubMed

    Sanderson, Thomas M; Cotel, Marie-Caroline; O'Neill, Michael J; Tricklebank, Mark D; Collingridge, Graham L; Sher, Emanuele

    2012-03-01

    The risk of developing schizophrenia has been linked to perturbations in embryonic development, but the physiological alterations that result from such insults are incompletely understood. Here, we have investigated aspects of hippocampal physiology in a proposed neurodevelopmental model of schizophrenia, induced during gestation in rats by injection of the antimitotic agent methylazoxymethanol acetate (MAM) at embryonic day 17 (MAM(E17)). We observed a reduction in synaptic innervation and synaptic transmission in the dorsal hippocampus of MAM(E17) treated rats, accompanied by a pronounced increase in CA1 pyramidal neuron excitability. Pharmacological investigations suggested that a deficit in GABAergic inhibition could account for the increase in excitability; furthermore, some aspects of the hyper-excitability could be normalised by the GABA(A) receptor (GABA(A)R) potentiator diazepam. Despite these alterations, two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) could be readily induced. In contrast, there was a substantial deficit in the reversal of LTP, depotentiation. These findings suggest that delivering neurodevelopmental insults at E17 may offer insights into some of the physiological alterations that underlie behavioural and cognitive symptoms observed in schizophrenia.

  1. Synaptic regulation of affective behaviors; role of BDNF

    PubMed Central

    Ninan, Ipe

    2013-01-01

    Brain derived neurotrophic factor (BDNF), a neurotrophin essential for nervous system development and synaptic plasticity, has been found to have a significant influence on affective behaviors. The notion that an impairment in BDNF signaling might be involved in affective disorders is originated primarily from the opposing effects of antidepressants and stress on BDNF signaling. Antidepressants enhance BDNF signaling and synaptic plasticity. On the other hand, negative environmental factors such as severe stress suppress BDNF signaling, impair synaptic activity and increase susceptibility to affective disorders. Postmortem studies provided strong support for decreased BDNF signaling in depressive disorders. Remarkably, studies in humans with a single nucleotide polymorphism in the BDNF gene, the BDNF Val66Met which affects regulated release of BDNF, showed profound deficits in hippocampal and prefrontal cortical (PFC) plasticity and cognitive behaviors. BDNF regulates synaptic mechanisms responsible for various cognitive processes including attenuation of aversive memories, a key process in the regulation of affective behaviors. The unique role of BDNF in cognitive and affective behaviors suggests that cognitive deficits due to altered BDNF signaling might underlie affective disorders. Understanding how BDNF modulates synapses in neural circuits relevant to affective behaviors, particularly the medial prefrontal cortical (mPFC)-hippocampus-amygdala pathway, and its interaction with development, sex, and environmental risk factors might shed light on potential therapeutic targets for affective disorders. PMID:23747574

  2. 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

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

    NASA Astrophysics Data System (ADS)

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

    2003-09-01

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

  4. 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

  5. Sex differences of excitatory synaptic transmission in RA projection neurons of adult zebra finches.

    PubMed

    Wang, Songhua; Meng, Wei; Liu, Shaoyi; Liao, Congshu; Huang, Qingyao; Li, Dongfeng

    2014-10-17

    Zebra finches are ideal animals to investigate sex difference in songbirds. Only males can sing. The brain nuclei controlling song learning and production in males are considerably larger than in females. The robust nucleus of the arcopallium (RA) is a premotor nucleus, playing a key role in controlling singing. RA receives denser synapse inputs in males than in females. Sex differences of excitatory synaptic transmission in the RA projection neurons (PNs) have not been reported. In the present study, using whole-cell voltage-clamp recording, spontaneous EPSCs (sEPSCs) and miniature EPSCs (mEPSCs) of RA PNs in the intact males and females were recorded. The average frequency and amplitude of sEPSCs/mEPSCs in the intact males were higher than females. The half-width and decay time of sEPSCs/mEPSCs in the intact males were longer than females. In order to verify whether these sex differences related to sex steroids, males were castrated. The average frequency of sEPSCs/mEPSCs in castrated males was lower than intact males and was similar to in females; the amplitude was not changed after castrating. These results demonstrate the sexually dimorphic of the excitatory synaptic transmission in the RA PNs, the RA PNs in males receive more excitatory synaptic transmission and these sex differences were partly affected by sex hormones. These findings contribute to further illuminate the neural mechanisms under the sexually dimorphism in song production of adult zebra finches.

  6. Changes in synaptic transmission produced by hydrogen peroxide.

    PubMed

    Colton, C A; Colton, J S; Gilbert, D L

    1986-01-01

    The effect of hydrogen peroxide (H2O2) on excitatory and inhibitory synaptic transmission was studied at the lobster neuromuscular junction. H2O2 produced a dose dependent decrease in the amplitude of the junction potential (Vejp). This decrease was due to changes in both presynaptic transmitter release and the postsynaptic response to the neurotransmitter. Observed presynaptic changes due to exposure to H2O2 were a decrease in the amount of transmitter released, that is, quantal content, as well as a decrease in the fast facilitation, that is, the amplitude increase of successive excitatory junction potentials at a rate of 3 Hz. To discern postsynaptic changes, glutamate, the putative excitatory neurotransmitter for this preparation was applied directly to the bathing medium in order to bypass the presynaptic release process. H2O2 produced a decreased response of the glutamate receptor/ionophore. The action of H2O2 was not selective to excitatory (glutamate-mediated) transmission because inhibitory (GABA-mediated) transmission was also depressed by H2O2. This effect was primarily presynaptic since H2O2 produced no change in the postsynaptic response to applied GABA.

  7. Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.

    PubMed

    Karayannis, T; Au, E; Patel, J C; Kruglikov, I; Markx, S; Delorme, R; Héron, D; Salomon, D; Glessner, J; Restituito, S; Gordon, A; Rodriguez-Murillo, L; Roy, N C; Gogos, J A; Rudy, B; Rice, M E; Karayiorgou, M; Hakonarson, H; Keren, B; Huguet, G; Bourgeron, T; Hoeffer, C; Tsien, R W; Peles, E; Fishell, G

    2014-07-10

    Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.

  8. Leptin potentiates GABAergic synaptic transmission in the developing rodent hippocampus

    PubMed Central

    Guimond, Damien; Diabira, Diabe; Porcher, Christophe; Bader, Francesca; Ferrand, Nadine; Zhu, Mingyan; Appleyard, Suzanne M.; Wayman, Gary A.; Gaiarsa, Jean-Luc

    2014-01-01

    It is becoming increasingly clear that leptin is not only a hormone regulating energy homeostasis but also a neurotrophic factor impacting a number of brain regions, including the hippocampus. Although leptin promotes the development of GABAergic transmission in the hypothalamus, little is known about its action on the GABAergic system in the hippocampus. Here we show that leptin modulates GABAergic transmission onto developing CA3 pyramidal cells of newborn rats. Specifically, leptin induces a long-lasting potentiation (LLP-GABAA) of miniature GABAA receptor-mediated postsynaptic current (GABAA-PSC) frequency. Leptin also increases the amplitude of evoked GABAA-PSCs in a subset of neurons along with a decrease in the coefficient of variation and no change in the paired-pulse ratio, pointing to an increased recruitment of functional synapses. Adding pharmacological blockers to the recording pipette showed that the leptin-induced LLP-GABAA requires postsynaptic calcium released from internal stores, as well as postsynaptic MAPK/ERK kinases 1 and/or 2 (MEK1/2), phosphoinositide 3 kinase (PI3K) and calcium-calmodulin kinase kinase (CaMKK). Finally, study of CA3 pyramidal cells in leptin-deficient ob/ob mice revealed a reduction in the basal frequency of miniature GABAA-PSCs compared to wild type littermates. In addition, presynaptic GAD65 immunostaining was reduced in the CA3 stratum pyramidale of mutant animals, both results converging to suggest a decreased number of functional GABAergic synapses in ob/ob mice. Overall, these results show that leptin potentiates and promotes the development of GABAergic synaptic transmission in the developing hippocampus likely via an increase in the number of functional synapses, and provide insights into the intracellular pathways mediating this effect. This study further extends the scope of leptin's neurotrophic action to a key regulator of hippocampal development and function, namely GABAergic transmission. PMID:25177272

  9. Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events.

    PubMed

    Popek, Mariusz; Bobula, Bartosz; Sowa, Joanna; Hess, Grzegorz; Polowy, Rafał; Filipkowski, Robert Kuba; Frontczak-Baniewicz, Małgorzata; Zabłocka, Barbara; Albrecht, Jan; Zielińska, Magdalena

    2017-01-23

    Neurological symptoms of acute liver failure (ALF) reflect decreased excitatory transmission, but the status of ALF-affected excitatory synapse has not been characterized in detail. We studied the effects of ALF in mouse on synaptic transmission and plasticity ex vivo and its relation to distribution of (i) synaptic vesicles (sv) and (ii) functional synaptic proteins within the synapse. ALF-competent neurological and biochemical changes were induced in mice with azoxymethane (AOM). Electrophysiological characteristics (long-term potentiation, whole-cell recording) as well as synapse ultrastructure were evaluated in the cerebral cortex. Also, sv were quantified in the presynaptic zone by electron microscopy. Finally, presynaptic proteins in the membrane-enriched (P2) and cytosolic (S2) fractions of cortical homogenates were quantitated by Western blot. Slices derived from symptomatic AOM mice presented a set of electrophysiological correlates of impaired transmitter release including decreased field potentials (FPs), increased paired-pulse facilitation (PPF), and decreased frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs/mEPSCs) accompanied by reduction of the spontaneous transmitter release-driving protein, vti1A. Additionally, an increased number of sv per synapse and a decrease of P2 content and/or P2/S2 ratio for sv-associated proteins, i.e. synaptophysin, synaptotagmin, and Munc18-1, were found, in spite of decreased content of the sv-docking protein, syntaxin-1. Slices from AOM-treated asymptomatic mice showed impaired long-term potentiation (LTP) and increased PPF but no changes in transmitter release or presynaptic protein composition. Our findings demonstrate that a decrease of synaptic transmission in symptomatic ALF is associated with inefficient recruitment of sv proteins and/or impaired sv trafficking to transmitter release sites.

  10. 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

  11. Mechanical feedback amplification in Drosophila hearing is independent of synaptic transmission.

    PubMed

    Kamikouchi, Azusa; Albert, Jörg T; Göpfert, Martin C

    2010-02-01

    Vertebrate inner-ear hair cells use mechanical feedback to amplify sound-induced vibrations. The gain of this 'cochlear amplifier' is centrally controlled via efferent fibres that, making synaptic contacts with the hair cells, modulate the feedback gain. The sensory neurons of the Drosophila ear likewise employ mechanical feedback to assist sound-evoked vibrations, yet whether this neuron-based feedback is also subject to efferent control has remained uncertain. We show here that the function of Drosophila auditory neurons is independent of efferent modulation, and that no synaptic transmission is needed to control the gain of mechanical feedback amplification. Immunohistochemical, mechanical and electrophysiological analyses revealed that the Drosophila auditory organ lacks peripheral synapses and efferent innervations, and that blocking synaptic transmission in a pan-neural manner does not affect the afferent electrical activity of the sensory neurons or the mechanical feedback gain. Hence, unlike the cochlear amplifier of vertebrates, mechanical feedback amplification in Drosophila is not associated with an efferent control system but seems to be a purely local process that is solely controlled peripherally within the ear itself.

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

    PubMed

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

    2017-03-01

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

  13. Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain.

    PubMed

    Watson, Jake F; Ho, Hinze; Greger, Ingo H

    2017-03-14

    AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and are selectively recruited during activity-dependent plasticity to increase synaptic strength. A prerequisite for faithful signal transmission is the positioning and clustering of AMPARs at postsynaptic sites. The mechanisms underlying this positioning have largely been ascribed to the receptor cytoplasmic C-termini and to AMPAR-associated auxiliary subunits, both interacting with the postsynaptic scaffold. Here, using mouse organotypic hippocampal slices, we show that the extracellular AMPAR N-terminal domain (NTD), which projects midway into the synaptic cleft, plays a fundamental role in this process. This highly sequence-diverse domain mediates synaptic anchoring in a subunit-selective manner. Receptors lacking the NTD exhibit increased mobility in synapses, depress synaptic transmission and are unable to sustain long-term potentiation (LTP). Thus, synaptic transmission and the expression of LTP are dependent upon an AMPAR anchoring mechanism that is driven by the NTD.

  14. Transient Enhancement of Inhibitory Synaptic Transmission in Hippocampal CA1 Pyramidal Neurons after Cerebral Ischemia

    PubMed Central

    Liang, Rui; Pang, Zhi-Ping; Deng, Ping; Xu, Zao C.

    2009-01-01

    Pyramidal neurons in hippocampal CA1 regions are highly sensitive to cerebral ischemia. Alterations of excitatory and inhibitory synaptic transmission may contribute to the ischemia-induced neuronal degeneration. However, little is known about the changes of GABAergic synaptic transmission in the hippocampus following reperfusion. We examined the GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal neurons 12 hours and 24 hours after transient forebrain ischemia. The amplitudes of evoked IPSCs (eIPSCs) were increased significantly 12 hours after ischemia and returned to control levels 24 hours following reperfusion. The potentiation of eIPSCs was accompanied by an increase of miniature IPSCs (mIPSCs) amplitude, and an enhanced response to exogenous application of GABA, indicating the involvement of postsynaptic mechanisms. Furthermore, there was no obvious change of the paired-pulse ratio (PPR) of eIPSCs and the frequency of mIPSCs, suggesting that the potentiation of eIPSCs might not be due to the increased presynaptic release. Blockade of adenosine A1 receptors led to a decrease of eIPSCs amplitude in post-ischemic neurons but not in control neurons, without affecting the frequency of mIPSCs and the PPR of eIPSCs. Thus, tonic activation of adenosine A1 receptors might, at least in part, contribute to the enhancement of inhibitory synaptic transmission in CA1 neurons after forebrain ischemia. The transient enhancement of inhibitory neurotransmission might temporarily protect CA1 pyramidal neurons, and delay the process of neuronal death after cerebral ischemia. PMID:19258028

  15. 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.

  16. Thermal preconditioning and heat-shock protein 72 preserve synaptic transmission during thermal stress.

    PubMed

    Kelty, Jonathan D; Noseworthy, Peter A; Feder, Martin E; Robertson, R Meldrum; Ramirez, Jan-Marino

    2002-01-01

    As with other tissues, exposing the mammalian CNS to nonlethal heat stress (i.e., thermal preconditioning) increases levels of heat-shock proteins (Hsps) such as Hsp70 and enhances the viability of neurons under subsequent stress. Using a medullary slice preparation from a neonatal mouse, including the site of the neural network that generates respiratory rhythm (the pre-Bötzinger complex), we show that thermal preconditioning has an additional fundamental effect, protection of synaptic function. Relative to 30 degrees C baseline, initial thermal stress (40 degrees C) greatly increased the frequency of synaptic currents recorded without pharmacological manipulation by approximately 17-fold (p < 0.01) and of miniature postsynaptic currents (mPSCs) elicited by GABA (20-fold) glutamate (10-fold), and glycine (36-fold). Thermal preconditioning (15 min at 40 degrees C) eliminated the increase in frequency of overall synaptic transmission during acute thermal stress and greatly attenuated the frequency increases of GABAergic, glutamatergic, and glycinergic mPSCs (for each, p < 0.05). Moreover, without thermal preconditioning, incubation of slices in solution containing inducible Hsp70 (Hsp72) mimicked the effect of thermal preconditioning on the stress-induced release of neurotransmitter. That preconditioning and exogenous Hsp72 can affect and preserve normal physiological function has important therapeutic implications.

  17. 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

  18. 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

  19. 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

    strongly affected but often showing significant changes only by 4 months. We thus demonstrate that, in a mouse model of rising amyloid-β, the initial deposition of plaques does not occur until several months after the first amyloid-β becomes detectable but coincides with a rapid acceleration in the rise of amyloid-β levels and the amyloid-β42:amyloid-β40 ratio. Prior to acceleration, however, there is already a pronounced synaptic dysfunction, reflected as changes in synaptic transmission and altered gene expression, indicating that restoring synaptic function early in the disease progression may represent the earliest possible target for intervention in the onset of Alzheimer’s disease. PMID:25981962

  20. 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

    affected but often showing significant changes only by 4 months. We thus demonstrate that, in a mouse model of rising amyloid-β, the initial deposition of plaques does not occur until several months after the first amyloid-β becomes detectable but coincides with a rapid acceleration in the rise of amyloid-β levels and the amyloid-β42:amyloid-β40 ratio. Prior to acceleration, however, there is already a pronounced synaptic dysfunction, reflected as changes in synaptic transmission and altered gene expression, indicating that restoring synaptic function early in the disease progression may represent the earliest possible target for intervention in the onset of Alzheimer's disease.

  1. Regulators of synaptic transmission: roles in the pathogenesis and treatment of epilepsy.

    PubMed

    Casillas-Espinosa, Pablo M; Powell, Kim L; O'Brien, Terence J

    2012-12-01

    Synaptic transmission is the communication between a presynaptic and a postsynaptic neuron, and the subsequent processing of the signal. These processes are complex and highly regulated, reflecting their importance in normal brain functioning and homeostasis. Sustaining synaptic transmission depends on the continuing cycle of synaptic vesicle formation, release, and endocytosis, which requires proteins such as dynamin, syndapin, synapsin, and synaptic vesicle protein 2A. Synaptic transmission is regulated by diverse mechanisms, including presynaptic modulators of synaptic vesicle formation and release, postsynaptic receptors and signaling, and modulators of neurotransmission. Neurotransmitters released presynaptically can bind to their postsynaptic receptors, the inhibitory γ-aminobutyric acid (GABA)ergic receptors or the excitatory glutamate receptors. Once released, glutamate activates a variety of postsynaptic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), kainate, and metabotropic receptors. The activation of the receptors triggers downstream signaling cascades generating a vast array of effects, which can be modulated by a numerous auxiliary regulatory subunits. Moreover, different neuropeptides such as neuropeptide Y, brain-derived neurotrophic factor (BDNF), somatostatin, ghrelin, and galanin, act as regulators of diverse synaptic functions and along with the classic neurotransmitters. Abnormalities in the regulation of synaptic transmission play a critical role in the pathogenesis of numerous brain diseases, including epilepsy. This review focuses on the different mechanisms involved in the regulation of synaptic transmission, which may play a role in the pathogenesis of epilepsy: the presynaptic modulators of synaptic vesicle formation and release, postsynaptic receptors, and modulators of neurotransmission, including the mechanism by which drugs can modulate the frequency and severity of

  2. Synapsin-dependent reserve pool of synaptic vesicles supports replenishment of the readily releasable pool under intense synaptic transmission.

    PubMed

    Vasileva, Mariya; Horstmann, Heinz; Geumann, Constanze; Gitler, Daniel; Kuner, Thomas

    2012-10-01

    Synapsins are abundant synaptic vesicle (SV)-associated proteins thought to mediate synaptic vesicle mobility and clustering at most synapses. We used synapsin triple knock-out (TKO) mice to examine the morphological and functional consequences of deleting all synapsin isoforms at the calyx of Held, a giant glutamatergic synapse located in the auditory brain stem. Quantitative three-dimensional (3D) immunohistochemistry of entire calyces showed lower amounts of the synaptic vesicle protein vGluT1 while the level of the active zone marker bassoon was unchanged in TKO terminals. Examination of brain lysates by ELISA revealed a strong reduction in abundance of several synaptic vesicle proteins, while proteins of the active zone cytomatrix or postsynaptic density were unaffected. Serial section scanning electron microscopy of large 3D-reconstructed segments confirmed a decrease in the number of SVs to approximately 50% in TKO calyces. Short-term depression tested at stimulus frequencies ranging from 10 to 300 Hz was accelerated only at frequencies above 100 Hz and the time course of recovery from depression was slowed in calyces lacking synapsins. These results reveal that in wild-type synapses, the synapsin-dependent reserve pool contributes to the replenishment of the readily releasable pool (RRP), although accounting only for a small fraction of the SVs that enter the RRP. In conclusion, our results suggest that synapsins may be required for normal synaptic vesicle biogenesis, trafficking and immobilization of synaptic vesicles, yet they are not essential for sustained high-frequency synaptic transmission at the calyx terminal.

  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. 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

  5. Glutamate-AMPAR interaction in a model of synaptic transmission.

    PubMed

    Ventriglia, Francesco; Di Maio, Vito

    2013-11-06

    Over the last several years we have investigated the excitatory synaptic response by means of a mathematical model based on a detailed description of the synapse geometry, the Brownian motion of Glutamate molecules and their binding to postsynaptic receptors. Recently, the basic model has been modified for the numbers, the size and the 3D structure of receptors according to new data from the literature. Some results of simulations performed with the updated model are shown here. They were aimed to study the synaptic response in relation to the binding probability, to the probable height of the receptors in the synaptic cleft, and to the space-time distribution of Glutamate/Receptor collisions. A first series of simulations permitted to determine a possible range of values for the binding probability of Glutamate to receptors. Other simulations, investigating the changes induced on the synaptic response by the variations of the height of AMPA receptors in synaptic cleft, allowed to identify the height producing the higher amplitude peak of the mEPSCs. Finally, two new statistical descriptors for analyzing the synaptic response were presented. The first is based on the study of the space distribution of the number of Glutamate/Receptor collisions. Simulations investigating the effects of an increasing eccentricity of the releasing vesicle allowed assessing this method. The second one considers the inter-collision times between Glutamate molecules and binding sites. The results of some of the last simulations demonstrated its capacity to highlight the subtleties and the randomness underlying the activation of the receptors. This article is part of a Special Issue entitled Neural Coding 2012.

  6. 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

  7. 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.

  8. Neonatal Propofol and Etomidate Exposure Enhance Inhibitory Synaptic Transmission in Hippocampal Cornus Ammonis 1 Pyramidal Neurons

    PubMed Central

    Zhang, Jia-Qiang; Xu, Wan-Ying; Xu, Chang-Qing

    2016-01-01

    Background: Propofol and etomidate are the most important intravenous general anesthetics in the current clinical use and that mediate gamma-aminobutyric acid's (GABAergic) synaptic transmission. However, their long-term effects on GABAergic synaptic transmission induced by neonatal propofol or etomidate exposure remain unclear. We investigated the long-term GABAergic neurotransmission alterations, following neonatal propofol and etomidate administration. Methods: Sprague-Dawley rat pups at postnatal days 4–6 were underwent 6-h-long propofol-induced or 5-h-long etomidate-induced anesthesia. We performed whole-cell patch-clamp recording from pyramidal cells in the cornus ammonis 1 area of acute hippocampal slices of postnatal 80–90 days. Spontaneous and miniature inhibitory GABAergic currents (spontaneous inhibitory postsynaptic currents [sIPSCs] and miniature inhibitory postsynaptic currents [mIPSCs]) and their kinetic characters were measured. The glutamatergic tonic effect on inhibitory transmission and the effect of bumetanide on neonatal propofol exposure were also examined. Results: Neonatal propofol exposure significantly increased the frequency of mIPSCs (from 1.87 ± 0.35 Hz to 3.43 ± 0.51 Hz, P < 0.05) and did not affect the amplitude of mIPSCs and sIPSCs. Both propofol and etomidate slowed the decay time of mIPSCs kinetics (168.39 ± 27.91 ms and 267.02 ± 100.08 ms vs. 68.18 ± 12.43 ms; P < 0.05). Bumetanide significantly blocked the frequency increase and reversed the kinetic alteration of mIPSCs induced by neonatal propofol exposure (3.01 ± 0.45 Hz and 94.30 ± 32.56 ms). Conclusions: Neonatal propofol and etomidate exposure has long-term effects on inhibitory GABAergic transmission. Propofol might act at pre- and post-synaptic GABA receptor A (GABAA) receptors within GABAergic synapses and impairs the glutamatergic tonic input to GABAergic synapses; etomidate might act at the postsynaptic site. PMID:27824005

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

    PubMed

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

    2012-05-02

    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.

  10. 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

  11. 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.

  12. Running Opposes the Effects of Social Isolation on Synaptic Plasticity and Transmission in a Rat Model of Depression

    PubMed Central

    Gómez-Galán, Marta; Femenía, Teresa; Åberg, Elin; Graae, Lisette; Van Eeckhaut, Ann; Smolders, Ilse; Brené, Stefan; Lindskog, Maria

    2016-01-01

    Stress, such as social isolation, is a well-known risk factor for depression, most probably in combination with predisposing genetic factors. Physical exercise on the other hand, is depicted as a wonder-treatment that makes you healthier, happier and live longer. However, the published results on the effects of exercise are ambiguous, especially when it comes to neuropsychiatric disorders. Here we combine a paradigm of social isolation with a genetic rat model of depression, the Flinders Sensitive Line (FSL), already known to have glutamatergic synaptic alterations. Compared to group-housed FSL rats, we found that social isolation further affects synaptic plasticity and increases basal synaptic transmission in hippocampal CA1 pyramidal neurons. These functional synaptic alterations co-exist with changes in hippocampal protein expression levels: social isolation in FSL rats reduce expression of the glial glutamate transporter GLT-1, and increase expression of the GluA2 AMPA-receptor subunit. We further show that physical exercise in form of voluntary running prevents the stress-induced synaptic effects but do not restore the endogenous mechanisms of depression already present in the FSL rat. PMID:27764188

  13. Tetraspanin 6: A novel regulator of hippocampal synaptic transmission and long term plasticity

    PubMed Central

    Salas, Isabel H.; Callaerts-Vegh, Zsuzsanna; Arranz, Amaia M.; Guix, Francesc X.; D’Hooge, Rudi; Esteban, José A.

    2017-01-01

    Tetraspanins (Tspan) are transmembrane proteins with important scaffold and signalling functions. Deletions of Tetraspanin 6 (Tspan6) gene, a member of the tetraspanin family, have been reported in patients with Epilepsy Female-restricted with Mental Retardation (EFMR). Interestingly, mutations in Tspan7, highly homologous to Tspan6, are associated with X-linked intellectual disability, suggesting that these two proteins are important for cognition. Considering recent evidences showing that Tspan7 plays a key role in synapse development and AMPAR trafficking, we initiated the study of Tspan6 in synaptic function using a Tspan6 knock out mouse model. Here we report that hippocampal field recordings from Tspan6 knock out mice show an enhanced basal synaptic transmission and impaired long term potentiation (LTP). A normal paired-pulse facilitation response suggests that Tspan6 affects the properties of the postsynaptic rather than the presynaptic terminal. However, no changes in spine morphology or postsynaptic markers could be detected in Tspan6 KO mice compared with wild types. In addition, Tspan6 KO mice show normal locomotor behaviour and no defects in hippocampus-dependent memory tests. PMID:28207852

  14. Nicotinic modulation of glutamatergic synaptic transmission in region CA3 of the hippocampus.

    PubMed

    Giocomo, Lisa M; Hasselmo, Michael E

    2005-09-01

    Cholinergic modulation of synaptic transmission in the hippocampus appears to be involved in learning, memory and attentional processes. In brain slice preparations of hippocampal region CA3, we have explored the effect of nicotine on the afferent connections of stratum lacunosum moleculare (SLM) vs. the intrinsic connections of stratum radiatum (SR). Nicotine application had a lamina-selective effect, causing changes in synaptic transmission only in SLM. The nicotinic effect in SLM was characterized by a transient decrease in synaptic potential size followed by a longer period of enhancement of synaptic transmission. The effect was blocked by gamma-aminobutyric acid (GABA)ergic antagonists, indicating the role of GABAergic interneurons in the observed nicotinic effect. The biphasic nature of the nicotinic effect could be due to a difference in receptor subtypes, as supported by the effects of the nicotinic antagonists mecamylamine and methyllycaconitine. Nicotinic modulation of glutamatergic synaptic transmission could complement muscarinic suppression of intrinsic connections, amplifying incoming information and providing a physiological mechanism for the memory-enhancing effect of nicotine.

  15. Antibody-mediated Impairment and Homeostatic Plasticity of Autonomic Ganglionic Synaptic Transmission

    PubMed Central

    Wang, Zhengbei; Low, Phillip A.; Vernino, Steven

    2010-01-01

    Antibodies against ganglionic acetylcholine receptors (AChR) are implicated as the cause of autoimmune autonomic ganglionopathy (AAG). To characterize ganglionic neurotransmission in an animal model of AAG, evoked and spontaneous excitatory post-synaptic potentials (EPSP) were recorded from neurons in isolated mouse superior cervical ganglia (SCG). In vitro exposure of ganglia to IgG from AAG patients progressively inhibited synaptic transmission. After passive transfer of antibody to mice, evoked EPSP amplitude decreased, and some neurons showed no synaptic responses. EPSP amplitude recovered by day seven despite persistence of ganglionic AChR antibody in the mouse serum. There was a more persistent (at least 14 day) reduction in miniature EPSP amplitude consistent with antibody-mediated reduction in post-synaptic AChR. Although the quantal size was reduced, a progressive increase in the frequency of spontaneous synaptic events occurred, suggesting a compensatory increase in presynaptic efficacy. The quantal size returned to baseline by 21 days while the frequency remained increased for at least four weeks. Ganglionic AChR antibodies cause an impairment of autonomic ganglionic synaptic transmission. Homeostatic plasticity in autonomic neurotransmission could help explain the spontaneous clinical recovery seen in some AAG patients and may also play an important role in regulating normal autonomic reflexes. PMID:20044994

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

    PubMed

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

    2014-03-01

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

  17. Synaptic transmission: inhibition of neurotransmitter release by botulinum toxins.

    PubMed

    Dolly, Oliver

    2003-01-01

    Botulinum toxin type A, a protein long used in the successful treatment of various dystonias, has a complex mechanism of action that results in muscle relaxation. At the neuromuscular junction, the presynaptic nerve ending is packed with synaptic vesicles filled with acetylcholine, and clustered at the tip of the folds of the postsynaptic muscle membrane are the acetylcholine receptors. Synaptic vesicles fuse with the membrane in response to an elevation of intraneuronal calcium concentration and undergo release of their transmitter by exocytosis. Intracellular proteins that contribute to the fusion of the vesicles with the plasma membrane during exocytosis include synaptosomal protein with a molecular weight of 25 kDa (SNAP-25); vesicle-associated membrane protein (VAMP), also known as synaptobrevin; and syntaxin. Through their proteolytic action on these proteins, botulinum toxins prevent exocytosis, thereby inhibiting the release of acetylcholine. There are 7 serotypes of this toxin-A, B, C1, D, E, F, and G-and each cleaves a different intracellular protein or the same target at distinct bonds. The separate cleavage sites in SNAP-25 for botulinum toxin types A and E contribute to their dissimilar durations of muscle relaxation. This report describes the molecular basis for the inhibition by botulinum toxins of neuroexocytosis and subsequent functional recovery at the neuromuscular junction.

  18. Increased glutamate synaptic transmission in the nucleus raphe magnus neurons from morphine-tolerant rats.

    PubMed

    Bie, Bihua; Pan, Zhizhong Z

    2005-02-09

    Currently, opioid-based drugs are the most effective pain relievers that are widely used in the treatment of pain. However, the analgesic efficacy of opioids is significantly limited by the development of tolerance after repeated opioid administration. Glutamate receptors have been reported to critically participate in the development and maintenance of opioid tolerance, but the underlying mechanisms remain unclear. Using whole-cell voltage-clamp recordings in brainstem slices, the present study investigated chronic morphine-induced adaptations in glutamatergic synaptic transmission in neurons of the nucleus raphe magnus (NRM), a key supraspinal relay for pain modulation and opioid analgesia. Chronic morphine significantly increased glutamate synaptic transmission exclusively in one class of NRM cells that contains mu-opioid receptors in a morphine-tolerant state. The adenylyl cyclase activator forskolin and the cAMP analog 8-bromo-cAMP mimicked the chronic morphine effect in control neurons and their potency in enhancing the glutamate synaptic current was significantly increased in neurons from morphine-tolerant rats. MDL12330a, an adenylyl cyclase inhibitor, and H89, a protein kinase A (PKA) inhibitor, reversed the increase in glutamate synaptic transmission induced by chronic morphine. In addition, PMA, a phorbol ester activator of protein kinase C (PKC), also showed an increased potency in enhancing the glutamate synaptic current in these morphine-tolerant cells. The PKC inhibitor GF109203X attenuated the chronic morphine effect. Taken together, these results suggest that chronic morphine increases presynaptic glutamate release in mu receptor-containing NRM neurons in a morphine-tolerant state, and that the increased glutamate synaptic transmission appears to involve an upregulation of both the cAMP/PKA pathway and the PKC pathway. This glutamate-mediated activation of these NRM neurons that are thought to facilitate spinal pain transmission may contribute to

  19. Chondroitin Sulfate Induces Depression of Synaptic Transmission and Modulation of Neuronal Plasticity in Rat Hippocampal Slices.

    PubMed

    Albiñana, Elisa; Gutierrez-Luengo, Javier; Hernández-Juarez, Natalia; Baraibar, Andrés M; Montell, Eulalia; Vergés, Josep; García, Antonio G; Hernández-Guijo, Jesus M

    2015-01-01

    It is currently known that in CNS the extracellular matrix is involved in synaptic stabilization and limitation of synaptic plasticity. However, it has been reported that the treatment with chondroitinase following injury allows the formation of new synapses and increased plasticity and functional recovery. So, we hypothesize that some components of extracellular matrix may modulate synaptic transmission. To test this hypothesis we evaluated the effects of chondroitin sulphate (CS) on excitatory synaptic transmission, cellular excitability, and neuronal plasticity using extracellular recordings in the CA1 area of rat hippocampal slices. CS caused a reversible depression of evoked field excitatory postsynaptic potentials in a concentration-dependent manner. CS also reduced the population spike amplitude evoked after orthodromic stimulation but not when the population spikes were antidromically evoked; in this last case a potentiation was observed. CS also enhanced paired-pulse facilitation and long-term potentiation. Our study provides evidence that CS, a major component of the brain perineuronal net and extracellular matrix, has a function beyond the structural one, namely, the modulation of synaptic transmission and neuronal plasticity in the hippocampus.

  20. Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain

    PubMed Central

    Watson, Jake F; Ho, Hinze; Greger, Ingo H

    2017-01-01

    AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and are selectively recruited during activity-dependent plasticity to increase synaptic strength. A prerequisite for faithful signal transmission is the positioning and clustering of AMPARs at postsynaptic sites. The mechanisms underlying this positioning have largely been ascribed to the receptor cytoplasmic C-termini and to AMPAR-associated auxiliary subunits, both interacting with the postsynaptic scaffold. Here, using mouse organotypic hippocampal slices, we show that the extracellular AMPAR N-terminal domain (NTD), which projects midway into the synaptic cleft, plays a fundamental role in this process. This highly sequence-diverse domain mediates synaptic anchoring in a subunit-selective manner. Receptors lacking the NTD exhibit increased mobility in synapses, depress synaptic transmission and are unable to sustain long-term potentiation (LTP). Thus, synaptic transmission and the expression of LTP are dependent upon an AMPAR anchoring mechanism that is driven by the NTD. DOI: http://dx.doi.org/10.7554/eLife.23024.001 PMID:28290985

  1. Chronic exposure to a 60-Hz electric field: effects on synaptic transmission and peripheral nerve function in the rat.

    PubMed

    Jaffe, R A; Laszewski, B L; Carr, D B; Phillips, R D

    1980-01-01

    Several reports have suggested that the nervous system can be affected by exposure to electric fields and that these effects may have detrimental health consequences for the exposed organism. The purpose of this study was to investigate the effects of chronic (30-day) exposure of rats to a 60Hz, 100-kV/m electric field on synaptic transmission and peripheral-nerve function. One hundred forty-four rats, housed in individual polycarbonate cages were exposed to uniform, vertical, 60-Hz electric fields in a system free of corona discharge and ozone formation and in which the animals did not receive spark discharges or other shocks during exposure. Following 30 days of exposure to the electric field, superior cervical sympathetic ganglia, vagus and sciatic nerves were removed from rats anesthetized with urethan, placed in a temperature-controlled chamber, and superfused with a modified mammalian Ringer's solution equilibrated with 95% O2 and 5% CO2. Several measures and tests were used to characterize synaptic transmission and peripheral-nerve function. These included amplitude, area, and configuration of the postsynaptic or whole-nerve compound-action potential; conduction velocity; accommodation; refractory period; strength-duration curves; conditioning-test (C-T) response, frequency response; post-tetanic response; and high-frequency-induced fatigue. The results of a series of neurophysiologic tests and measurements indicate that only synaptic transmission is significantly and consistently affected by chronic (30-day) exposure to a 60-Hz, 100-kV/m electric field. Specifically, and increase in synaptic excitability was detected in replicated measurements of the C-T response ratio. In addition, there are trends in other data that can be interpreted to suggest a generalized increase in neuronal excitability in exposed animals.

  2. Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS.

    PubMed

    Lessmann, V

    1998-11-01

    1. The protein family of the neurotrophins, consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and Neurotrophin-3, -4/5, and -6 (NT-3; NT-4/5; NT-6) is well known to enhance the survival and to stabilize the phenotype of different populations of neurons in the central and the peripheral nervous system. These effects are mediated via binding to specific tyrosine kinase receptors (Trks) and to the low-affinity p75 neurotrophin receptor. 2. The neurotrophins NGF, BDNF, and NT-3 and the BDNF and NT-3 selective receptors (TrkB, TrkC) are expressed at high levels in neurons of the basal forebrain, the hippocampus, and the neocortex of the mammalian brain. The expression and secretion of NGF and BDNF in these brain areas is regulated by (physiological levels of) neuronal activity. 3. Exogenous application of the neurotrophins to hippocampal and neocortical neurons can enhance excitatory glutamatergic synaptic transmission via activation of Trk receptors. In addition, long-term potentiation (a potential cellular correlate for learning and memory formation in mammals) in the rodent hippocampus depends on endogenous supply of neurons with BDNF. 4. Judged by the analysis of electrophysiological data, the BDNF- and NT-3-induced enhancement of glutamatergic synapses is mediated by increasing the efficacy of glutamate release from the presynaptic neuron. However, neurotrophin-dependent postsynaptic enhancement of NMDA (but not AMPA) receptor responsiveness has also been shown. 5. On the molecular level, neither the pre- nor the postsynaptic modulation of glutamatergic synapses by neurotrophins is well understood. However, neurotrophins were shown to acutely affect intraneuronal Ca2+ levels and to influence molecular components of the transmitter release machinery, which could underly the presynaptic modifications, whereas BDNF-induced phosphorylation of NMDA-type glutamate receptors could account for the postsynaptic effects. 6. Taken together

  3. New Tools for Targeted Disruption of Cholinergic Synaptic Transmission in Drosophila melanogaster

    PubMed Central

    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

  4. Functional properties of synaptic transmission in primary sense organs.

    PubMed

    Singer, Joshua H; Glowatzki, Elisabeth; Moser, Tobias; Strowbridge, Ben W; Bhandawat, Vikas; Sampath, Alapakkam P

    2009-10-14

    Sensory receptors transduce physical stimuli in the environment into neural signals that are interpreted by the brain. Although considerable attention has been given to how the sensitivity and dynamic range of sensory receptors is established, peripheral synaptic interactions improve the fidelity with which receptor output is transferred to the brain. For instance, synapses in the retina, cochlea, and primary olfactory system use mechanisms that fine-tune the responsiveness of postsynaptic neurons and the dynamics of exocytosis; these permit microcircuit interactions to encode efficiently the output of sensory receptors with the fidelity and dynamic range necessary to extract the salient features of the physical stimuli. The continuous matching of presynaptic and postsynaptic responsiveness highlight how the primary sensory organs have been optimized and can be modulated to resolve sparse sensory signals and to encode the entire range of receptor output.

  5. Activation of α7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Aß-mediated inhibition of LTP in the rat hippocampus.

    PubMed

    Ondrejcak, Tomas; Wang, Qinwen; Kew, James N C; Virley, David J; Upton, Neil; Anwyl, Roger; Rowan, Michael J

    2012-02-29

    Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid ß-protein (Aß). The α7 nicotinic acetylcholine receptor agonist "compound A" ((R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl))thiophene-2-carboxamide) induced a rapid-onset persistent enhancement of synaptic transmission in the dentate gyrus in vitro. Consistent with a requirement for activation of α7 nicotinic acetylcholine receptors, the type II α7-selective positive allosteric modulator PheTQS ((3aR, 4S, 9bS)-4-(4-methylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) potentiated, and the antagonist methyllycaconitine (MLA) prevented the persistent enhancement. Systemic injection of the agonist also induced a similar MLA-sensitive persistent enhancement of synaptic transmission in the CA1 area in vivo. Remarkably, although compound A did not affect control long-term potentiation (LTP) in vitro, it prevented the inhibition of LTP by Aß1-42 and this effect was inhibited by MLA. These findings strongly indicate that activation of α7 nicotinic acetylcholine receptors is sufficient to persistently enhance hippocampal synaptic transmission and to overcome the inhibition of LTP by Aß.

  6. Potentiation of Schaffer-Collateral CA1 Synaptic Transmission by eEF2K and p38 MAPK Mediated Mechanisms

    PubMed Central

    Weng, Weiguang; Chen, Ying; Wang, Man; Zhuang, Yinghan; Behnisch, Thomas

    2016-01-01

    The elongation factor 2 kinase (eEF2K), likewise known as CaMKIII, has been demonstrated to be involved in antidepressant responses of NMDA receptor antagonists. Even so, it remains open whether direct inhibition of eEF2K without altering up-stream or other signaling pathways affects hippocampal synaptic transmission and neuronal network synchrony. Inhibition of eEF2K by the selective and potent eEF2K inhibitor A-484954 induced a fast pre-synaptically mediated enhancement of synaptic transmission and synchronization of neural network activity. The eEF2K-inhibition mediated potentiation of synaptic transmission of hippocampal CA1 neurons is most notably independent of protein synthesis and does not rely on protein kinase C, protein kinase A or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase 1/2. Moreover, the strengthening of synaptic transmission in the response to the inhibition of eEF2K was strongly attenuated by the inhibition of p38 MAPK. In addition, we show the involvement of barium-sensitive and more specific the TWIK-related potassium-1 (TREK-1) channels in the eEF2K-inhibition mediated potentiation of synaptic transmission. These findings reveal a novel pathway of eEF2K mediated regulation of hippocampal synaptic transmission. Further research is required to study whether such compounds could be beneficial for the development of mood disorder treatments with a fast-acting antidepressant response. PMID:27826228

  7. Multiple roles for mTOR signaling in both glutamatergic and GABAergic synaptic transmission

    PubMed Central

    Weston, Matthew C.; Chen, Hongmei; Swann, John W.

    2012-01-01

    Summary The mammalian target of rapamycin (mTOR) signaling pathway in neurons integrates a variety of extracellular signals to produce appropriate translational responses. mTOR signaling is hyperactive in neurological syndromes in both humans and mouse models that are characterized by epilepsy, autism and cognitive disturbances. In addition, rapamycin, a clinically important immunosuppressant, is a specific and potent inhibitor of mTOR signaling. While mTOR is known to regulate growth and synaptic plasticity of glutamatergic neurons, its effects on basic parameters of synaptic transmission are less well studied, and its role in regulating GABAergic transmission is unexplored. We therefore performed an electrophysiological and morphological comparison of glutamatergic and GABAergic neurons in which mTOR signaling was either increased by loss of the repressor Pten or decreased by treatment with rapamycin. We found that hyperactive mTOR signaling increased evoked synaptic responses in both glutamatergic and GABAergic neurons by approximately 50%, due to an increase in the number of synaptic vesicles available for release, the number of synapses formed and the miniature event size. Prolonged (72 hours) rapamycin treatment prevented these abnormalities and also decreased synaptic transmission in wild-type glutamatergic, but not GABAergic, neurons. Further analyses suggested that hyperactivation of the mTOR pathway also impairs presynaptic function, possibly by interfering with vesicle fusion. Despite this presynaptic impairment, the net effect of Pten loss is enhanced synaptic transmission in both GABAergic and glutamatergic neurons, which has numerous implications – depending on where in the brain mutations of an mTOR suppressor gene takes place during development. PMID:22895726

  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. Substance P selectively modulates GABA(A) receptor-mediated synaptic transmission in striatal cholinergic interneurons.

    PubMed

    Govindaiah, G; Wang, Yanyan; Cox, Charles L

    2010-02-01

    Substance P (SP) is co-localized and co-released with gamma-amino butyric acid (GABA) from approximately 50% of GABAergic medium spiny neurons (MSNs) in the striatum. MSNs innervate several cellular targets including neighboring MSNs and cholinergic interneurons via collaterals. However, the functional role of SP release onto striatal interneurons is unknown. Here we examined SP-mediated actions on inhibitory synaptic transmission in cholinergic interneurons using whole-cell recordings in mouse corticostriatal slices. We found that SP selectively suppressed GABA(A) receptor-mediated inhibitory post-synaptic currents (IPSCs), but not excitatory post-synaptic currents (EPSCs) in cholinergic interneurons. In contrast, SP did not alter IPSCs in fast-spiking interneurons and MSNs. SP suppressed IPSC amplitude in a concentration-dependent and reversible manner, and the NK1 receptor antagonist RP67580 attenuated the SP-mediated suppression. In addition, RP67580 alone enhanced the evoked IPSC amplitude in cholinergic interneurons, suggesting an endogenous action of SP on regulation of inhibitory synaptic transmission. SP did not alter the paired-pulse ratio, but reduced the amplitudes of GABA(A) agonist muscimol-induced outward currents and miniature IPSCs in cholinergic interneurons, suggesting SP exerts its effects primarily at the post-synaptic site. Our results indicate that the physiological effects of SP are to enhance the activity of striatal cholinergic interneurons and provide a rationale for designing potential new antiparkinsonian agents.

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

    PubMed

    López-Hidalgo, Mónica; Salgado-Puga, Karla; Alvarado-Martínez, Reynaldo; Medina, Andrea Cristina; Prado-Alcalá, Roberto A; García-Colunga, Jesús

    2012-01-01

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

  11. Exogenous and endogenous cannabinoids control synaptic transmission in mice nucleus accumbens.

    PubMed

    Robbe, David; Alonso, Gerard; Manzoni, Oliver J

    2003-11-01

    Addictive drugs are thought to alter normal brain function and cause the remodeling of synaptic functions in areas important to memory and reward. Excitatory transmission to the nucleus accumbens (NAc) is involved in the actions of most drugs of abuse, including cannabis. We have explored the functions of the endocannabinoid system at the prefrontal cortex-NAc synapses. Immunocytochemistry showed cannabinoid receptor (CB1) expression on axonal terminals making contacts with NAc neurons. In NAc slices, synthetic cannabinoids inhibit spontaneous and evoked glutamate-mediated transmission through presynaptic activation of presynaptic K+ channels and GABA-mediated transmission most likely via a direct presynaptic action on the vesicular release machinery. How does synaptic activity lead to the production of endogenous cannabinoids (eCBs) in the NAc? More generally, do eCBs participate in long-term synaptic plasticity in the brain? We found that tetanic stimulation (mimicking naturally occurring frequencies) of prelimbic glutamatergic afferents induced a presynaptic LTD dependent on eCB and CB1 receptors (eCB-LTD). Induction of eCB-LTD required postsynaptic activation of mGlu5 receptors and a rise in postsynaptic Ca2+ from ryanodine-sensitive intracellular Ca2+ stores. This retrograde signaling cascade involved postsynaptic eCB release and activation of presynaptic CB1 receptors. In the NAc, eCB-LTD might be part of a negative feedback loop, reducing glutamatergic synaptic strength during sustained cortical activity. The fact that this new form of LTD was occluded by an exogenous cannabinoid suggested that cannabis derivatives, such as marijuana, may alter normal eCB-mediated synaptic plasticity. These data suggest a major role of the eCB system in long-term synaptic plasticity and give insights into how cannabis derivatives, such as marijuana, alter normal eCB functions in the brain reward system.

  12. 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

  13. Deletion of CB2 cannabinoid receptors reduces synaptic transmission and long-term potentiation in the mouse hippocampus.

    PubMed

    Li, Yong; Kim, Jimok

    2016-03-01

    The effects of cannabinoids are mostly mediated by two types of cannabinoid receptors--CB1 receptors in the nervous system and CB2 receptors in the immune system. However, CB2 cannabinoid receptors have recently been discovered in the brain and also implicated in neurophysiological functions. The deletion of CB2 receptors in mice induces long-term memory deficits and schizophrenia-like behaviors, implying that endogenous activity of CB2 receptors might be involved in neuropsychiatric effects. Little is known about the cellular mechanisms by which physiological activation of CB2 receptors modulates neuronal functions. We aimed to determine how deletion of CB2 receptors in mice affects synaptic transmission and plasticity. Electrophysiological and morphological studies indicated that CB2 receptor knockout resulted in decreases in excitatory synaptic transmission, long-term potentiation, and dendritic spine density in the hippocampus. Our data imply that endogenous activity of CB2 receptors might contribute to the maintenance of synaptic functions and the expression of normal long-term potentiation. This study provides insights into the role of CB2 cannabinoid receptors in regulating cognitive functions such as long-term memory.

  14. Specific functions of synaptically localized potassium channels in synaptic transmission at the neocortical GABAergic fast-spiking cell synapse.

    PubMed

    Goldberg, Ethan M; Watanabe, Shigeo; Chang, Su Ying; Joho, Rolf H; Huang, Z Josh; Leonard, Christopher S; Rudy, Bernardo

    2005-05-25

    Potassium (K+) channel subunits of the Kv3 subfamily (Kv3.1-Kv3.4) display a positively shifted voltage dependence of activation and fast activation/deactivation kinetics when compared with other voltage-gated K+ channels, features that confer on Kv3 channels the ability to accelerate the repolarization of the action potential (AP) efficiently and specifically. In the cortex, the Kv3.1 and Kv3.2 proteins are expressed prominently in a subset of GABAergic interneurons known as fast-spiking (FS) cells and in fact are a significant determinant of the fast-spiking discharge pattern. However, in addition to expression at FS cell somata, Kv3.1 and Kv3.2 proteins also are expressed prominently at FS cell terminals, suggesting roles for Kv3 channels in neurotransmitter release. We investigated the effect of 1.0 mM tetraethylammonium (TEA; which blocks Kv3 channels) on inhibitory synaptic currents recorded in layer II/III neocortical pyramidal cells. Spike-evoked GABA release by FS cells was enhanced nearly twofold by 1.0 mM TEA, with a decrease in the paired pulse ratio (PPR), effects not reproduced by blockade of the non-Kv3 subfamily K+ channels also blocked by low concentrations of TEA. Moreover, in Kv3.1/Kv3.2 double knock-out (DKO) mice, the large effects of TEA were absent, spike-evoked GABA release was larger, and the PPR was lower than in wild-type mice. Together, these results suggest specific roles for Kv3 channels at FS cell terminals that are distinct from those of Kv1 and large-conductance Ca2+-activated K+ channels (also present at the FS cell synapse). We propose that at FS cell terminals synaptically localized Kv3 channels keep APs brief, limiting Ca2+ influx and hence release probability, thereby influencing synaptic depression at a synapse designed for sustained high-frequency synaptic transmission.

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

    PubMed

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

    2015-01-01

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

  16. Kismet Positively Regulates Glutamate Receptor Localization and Synaptic Transmission at the Drosophila Neuromuscular Junction

    PubMed Central

    Ghosh, Rupa; Vegesna, Srikar; Safi, Ramia; Bao, Hong; Zhang, Bing; Marenda, Daniel R.; Liebl, Faith L. W.

    2014-01-01

    The Drosophila neuromuscular junction (NMJ) is a glutamatergic synapse that is structurally and functionally similar to mammalian glutamatergic synapses. These synapses can, as a result of changes in activity, alter the strength of their connections via processes that require chromatin remodeling and changes in gene expression. The chromodomain helicase DNA binding (CHD) protein, Kismet (Kis), is expressed in both motor neuron nuclei and postsynaptic muscle nuclei of the Drosophila larvae. Here, we show that Kis is important for motor neuron synaptic morphology, the localization and clustering of postsynaptic glutamate receptors, larval motor behavior, and synaptic transmission. Our data suggest that Kis is part of the machinery that modulates the development and function of the NMJ. Kis is the homolog to human CHD7, which is mutated in CHARGE syndrome. Thus, our data suggest novel avenues of investigation for synaptic defects associated with CHARGE syndrome. PMID:25412171

  17. Action-potential-independent GABAergic tone mediated by nicotinic stimulation of immature striatal miniature synaptic transmission.

    PubMed

    Liu, Zhi; Otsu, Yo; Vasuta, Cristina; Nawa, Hiroyuki; Murphy, Timothy H

    2007-08-01

    Stimulation of presynaptic nicotinic acetylcholine receptors (nAChRs) increases the frequency of miniature excitatory synaptic activity (mEPSCs) to a point where they can promote cell firing in hippocampal CA3 neurons. We have evaluated whether nicotine regulation of miniature synaptic activity can be extended to inhibitory transmission onto striatal medium spiny projection neurons (MSNs) in acute brain slices. Bath application of micromolar nicotine typically induced 12-fold increases in the frequency of miniature inhibitory synaptic currents (mIPSCs). Little effect was observed on the amplitude of mIPSCs or mEPSCs under these conditions. Nicotine stimulation of mIPSCs was dependent on entry of extracellular calcium because removal of calcium from perfusate was able to block its action. To assess the potential physiological significance of the nicotine-stimulated increase in mIPSC frequency, we also examined the nicotine effect on evoked IPSCs (eIPSCs). eIPSCs were markedly attenuated by nicotine. This effect could be attributed to two potential mechanisms: transmitter depletion due to extremely high mIPSC rates and/or a reduction in presynaptic excitability associated with nicotinic depolarization. Treatment with low concentrations of K(+) was able to in part mimic nicotine's stimulatory effect on mIPSCs and inhibitory effect on eIPSCs. Current-clamp recordings confirmed a direct depolarizing action of nicotine that could dampen eIPSC activity leading to a switch to striatal inhibitory synaptic transmission mediated by tonic mIPSCs.

  18. 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

  19. Transgenic inhibition of synaptic transmission reveals role of CA3 output in hippocampal learning.

    PubMed

    Nakashiba, Toshiaki; Young, Jennie Z; McHugh, Thomas J; Buhl, Derek L; Tonegawa, Susumu

    2008-02-29

    The hippocampus is an area of the brain involved in learning and memory. It contains parallel excitatory pathways referred to as the trisynaptic pathway (which carries information as follows: entorhinal cortex --> dentate gyrus --> CA3 --> CA1 --> entorhinal cortex) and the monosynaptic pathway (entorhinal cortex --> CA1 --> entorhinal cortex). We developed a generally applicable tetanus toxin-based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the trisynaptic pathway while preserving transmission in the monosynaptic pathway. We found that synaptic output from CA3 in the trisynaptic pathway is dispensable and the short monosynaptic pathway is sufficient for incremental spatial learning. In contrast, the full trisynaptic pathway containing CA3 is required for rapid one-trial contextual learning, for pattern completion-based memory recall, and for spatial tuning of CA1 cells.

  20. Snx14 Regulates Neuronal Excitability, Promotes Synaptic Transmission, and Is Imprinted in the Brain of Mice

    PubMed Central

    Huang, Hsien-Sung; Yoon, Bong-June; Brooks, Sherian; Bakal, Robert; Berrios, Janet; Larsen, Rylan S.; Wallace, Michael L.; Han, Ji Eun; Chung, Eui Hwan; Zylka, Mark J.; Philpot, Benjamin D.

    2014-01-01

    Genomic imprinting describes an epigenetic process through which genes can be expressed in a parent-of-origin-specific manner. The monoallelic expression of imprinted genes renders them particularly susceptible to disease causing mutations. A large proportion of imprinted genes are expressed in the brain, but little is known about their functions. Indeed, it has proven difficult to identify cell type-specific imprinted genes due to the heterogeneity of cell types within the brain. Here we used laser capture microdissection of visual cortical neurons and found evidence that sorting nexin 14 (Snx14) is a neuronally imprinted gene in mice. SNX14 protein levels are high in the brain and progressively increase during neuronal development and maturation. Snx14 knockdown reduces intrinsic excitability and severely impairs both excitatory and inhibitory synaptic transmission. These data reveal a role for monoallelic Snx14 expression in maintaining normal neuronal excitability and synaptic transmission. PMID:24859318

  1. 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

  2. LAP proteins are localized at the post-synaptic membrane of neuromuscular junctions and appear to modulate synaptic morphology and transmission.

    PubMed

    Kravic, Bojana; Huraskin, Danyil; Frick, Alexander D; Jung, Jasmin; Redai, Veronika; Palmisano, Ralf; Marchetto, Sylvie; Borg, Jean-Paul; Mei, Lin; Hashemolhosseini, Said

    2016-11-01

    Erbin, Lano, Scribble, and Densin-180 belong to LAP (leucine-rich repeats and PDZ domain) adaptor proteins involved in cell signaling pathways. Previously, we identified Erbin, Lano, and Scribble, but not Densin-180, in muscle cells, where they are involved in regulating the aggregation of nicotinic acetylcholine receptors in vitro. Here, we analyzed their cellular localization at the neuromuscular junction (NMJ) in skeletal muscles of mice. Erbin, Lano, and Scribble were significantly accumulated at NMJs and localized in different synaptic cells. Moreover, we used mouse mutants to analyze the role of Erbin at the NMJ. We used two Erbin mutant mouse strains that either completely lack Erbin protein (Erbin(null/null) ) or express a truncated Erbin mutant where the carboxy-terminal PDZ domain is replaced by β-galactosidase (Erbin(ΔC/ΔC) ) thereby abolishing its interaction with ErbB receptor tyrosine kinases. Neither the lack of the PDZ domain of Erbin, nor its complete absence interfered with the general localization of LAP proteins at NMJs, but Lano and Scribble transcript levels were up-regulated in homozygous Erbin-null muscles. Furthermore, grip strength was reduced and neural transmission impaired in homozygous aged Erbin-null but not Erbin-ΔC mice. Erbin-null skeletal muscles did not reveal any conspicuous impairment of the muscle fiber. Localization of other NMJ marker proteins was not affected either. Quantitative 3D morphometry showed that NMJs of Erbin-null muscles were significantly smaller and fragmented in the soleus. We speculate that Erbin, Lano, and Scribble act at the post-synaptic membrane of NMJs in a concerted fashion to regulate nicotinic acetylcholine receptors cluster morphology and neural transmission. Cover Image for this issue: doi: 10.1111/jnc.13340.

  3. 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...

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

    PubMed

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

    2005-11-01

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

  5. Effects of rates of spontaneous synaptic vesicle secretions in inner hair cells on information transmission in an auditory nerve fiber model.

    PubMed

    Kumsa, Parichat; Mino, Hiroyuki

    2012-01-01

    In this article, we investigate how the rates of spontaneous synaptic vesicle secretions affect information transmission of the spike trains in response to the inner hair cell (IHC) synaptic currents in an auditory nerve fiber (ANF) model through computer simulations. The IHC synaptic currents were modeled by a filtered inhomogeneous Poisson process modulated with sinusoidal functions, while the stochastic ion channel model was incorporated into each node of Ranvier in the ANF model with spiral ganglion. The information rates were estimated from the entropies of the inter-spike intervals of the spike trains to evaluate information transmission in the ANF model. The results show that the information rates increased, reached a maximum, and then decreased as the rate of spontaneous secretion increased, implying a resonance phenomenon dependent on the rate of spontaneous IHC synaptic secretions. In conclusion, this phenomenon similar to the regular stochastic resonance may be observed due to that spontaneous IHC synaptic secretions may act as an origin of fluctuation or noise, and these findings may play a key role in the design of better auditory prostheses.

  6. Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions

    PubMed Central

    Liu, Chien-Cheng; Gao, Yong-Jing; Luo, Hao; Berta, Temugin; Xu, Zhen-Zhong; Ji, Ru-Rong; Tan, Ping-Heng

    2016-01-01

    It is well known that interferons (IFNs), such as type-I IFN (IFN-α) and type-II IFN (IFN-γ) are produced by immune cells to elicit antiviral effects. IFNs are also produced by glial cells in the CNS to regulate brain functions. As a proinflammatory cytokine, IFN-γ drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-α in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-α/β receptor (type-I IFN receptor) was expressed by primary afferent terminals in the superficial dorsal horn that co-expressed the neuropeptide CGRP. In the spinal cord IFN-α was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-α suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-α also inhibited nociceptive transmission by reducing capsaicin-induced internalization of NK-1 and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial dorsal horn neurons. Finally, spinal (intrathecal) administration of IFN-α reduced inflammatory pain and increased pain threshold in naïve rats, whereas removal of endogenous IFN-α by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-α, produced by astrocytes, inhibits nociceptive transmission in the spinal cord. PMID:27670299

  7. Effects of diazepam on glutamatergic synaptic transmission in the hippocampal CA1 area of rats with traumatic brain injury

    PubMed Central

    Cao, Lei; Bie, Xiaohua; Huo, Su; Du, Jubao; Liu, Lin; Song, Weiqun

    2014-01-01

    The activity of the Schaffer collaterals of hippocampal CA3 neurons and hippocampal CA1 neurons has been shown to increase after fluid percussion injury. Diazepam can inhibit the hyperexcitability of rat hippocampal neurons after injury, but the mechanism by which it affects excitatory synaptic transmission remains poorly understood. Our results showed that diazepam treatment significantly increased the slope of input-output curves in rat neurons after fluid percussion injury. Diazepam significantly decreased the numbers of spikes evoked by super stimuli in the presence of 15 μmol/L bicuculline, indicating the existence of inhibitory pathways in the injured rat hippocampus. Diazepam effectively increased the paired-pulse facilitation ratio in the hippocampal CA1 region following fluid percussion injury, reduced miniature excitatory postsynaptic potentials, decreased action-potential-dependent glutamine release, and reversed spontaneous glutamine release. These data suggest that diazepam could decrease the fluid percussion injury-induced enhancement of excitatory synaptic transmission in the rat hippocampal CA1 area. PMID:25558239

  8. Both pre- and post-synaptic alterations contribute to aberrant cholinergic transmission in superior cervical ganglia of APP(-/-) mice.

    PubMed

    Cai, Zhao-Lin; Zhang, Jia-Jia; Chen, Ming; Wang, Jin-Zhao; Xiao, Peng; Yang, Li; Long, Cheng

    2016-11-01

    Though amyloid precursor protein (APP) can potentially be cleaved to generate the pathological amyloid β peptide (Aβ), APP itself plays an important role in regulating neuronal activity. APP deficiency causes functional impairment in cholinergic synaptic transmission and cognitive performance. However, the mechanisms underlying altered cholinergic synaptic transmission in APP knock-out mice (APP(-/-)) are poorly understood. In this study, we conducted in vivo extracellular recording to investigate cholinergic compound action potentials (CAPs) of the superior cervical ganglion (SCG) in APP(-/-) and littermate wild-type (WT) mice. Our results demonstrate that APP not only regulates presynaptic activity, but also affects postsynaptic function at cholinergic synapses in SCG. APP deficiency reduces the number of vesicles in presynaptic terminalsand attenuatesthe amplitude of CAPs, likely due to dysfunction of high-affinity choline transporters. Pharmacological and biochemical examination showed that postsynaptic responsesmediated by α4β2 and α7 nicotinic acetylcholine receptors are reduced in the absence of APP. Our research provides evidences on how APP regulates cholinergic function and therefore may help to identify potential therapeutic targets to treat cholinergic dysfunction associated with Alzheimer's disease pathogenesis.

  9. Excitatory synaptic transmission and network activity are depressed following mechanical injury in cortical neurons

    PubMed Central

    Goforth, Paulette B.; Ren, Jianhua; Schwartz, Benjamin S.

    2011-01-01

    In vitro and in vivo traumatic brain injury (TBI) alter the function and expression of glutamate receptors, yet the combined effect of these alterations on cortical excitatory synaptic transmission is unclear. We examined the effect of in vitro mechanical injury on excitatory synaptic function in cultured cortical neurons by assaying synaptically driven intracellular free calcium ([Ca2+]i) oscillations in small neuronal networks as well as spontaneous and miniature excitatory postsynaptic currents (mEPSCs). We show that injury decreased the incidence and frequency of spontaneous neuronal [Ca2+]i oscillations for at least 2 days post-injury. The amplitude of the oscillations was reduced immediately and 2 days post-injury, although a transient rebound at 4 h post-injury was observed due to increased activity of N-methyl-d-aspartate (NMDARs) and calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (CP-AMPARs). Increased CP-AMPAR function was abolished by the inhibition of protein synthesis. In parallel, mEPSC amplitude decreased immediately, 4 h, and 2 days post-injury, with a transient increase in the contribution of synaptic CP-AMPARs observed at 4 h post-injury. Decreased mEPSC amplitude was evident after injury, even if NMDARs and CP-AMPARs were blocked pharmacologically, suggesting the decrease reflected alterations in synaptic Glur2-containing, calcium-impermeable AMPARs. Despite the transient increase in CP-AMPAR activity that we observed, the overriding effect of mechanical injury was long-term depression of excitatory neurotransmission that would be expected to contribute to the cognitive deficits of TBI. PMID:21346214

  10. Excitatory synaptic transmission and network activity are depressed following mechanical injury in cortical neurons.

    PubMed

    Goforth, Paulette B; Ren, Jianhua; Schwartz, Benjamin S; Satin, Leslie S

    2011-05-01

    In vitro and in vivo traumatic brain injury (TBI) alter the function and expression of glutamate receptors, yet the combined effect of these alterations on cortical excitatory synaptic transmission is unclear. We examined the effect of in vitro mechanical injury on excitatory synaptic function in cultured cortical neurons by assaying synaptically driven intracellular free calcium ([Ca(2+)](i)) oscillations in small neuronal networks as well as spontaneous and miniature excitatory postsynaptic currents (mEPSCs). We show that injury decreased the incidence and frequency of spontaneous neuronal [Ca(2+)](i) oscillations for at least 2 days post-injury. The amplitude of the oscillations was reduced immediately and 2 days post-injury, although a transient rebound at 4 h post-injury was observed due to increased activity of N-methyl-d-aspartate (NMDARs) and calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (CP-AMPARs). Increased CP-AMPAR function was abolished by the inhibition of protein synthesis. In parallel, mEPSC amplitude decreased immediately, 4 h, and 2 days post-injury, with a transient increase in the contribution of synaptic CP-AMPARs observed at 4 h post-injury. Decreased mEPSC amplitude was evident after injury, even if NMDARs and CP-AMPARs were blocked pharmacologically, suggesting the decrease reflected alterations in synaptic Glur2-containing, calcium-impermeable AMPARs. Despite the transient increase in CP-AMPAR activity that we observed, the overriding effect of mechanical injury was long-term depression of excitatory neurotransmission that would be expected to contribute to the cognitive deficits of TBI.

  11. 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

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

    PubMed

    Van Hook, Matthew J; Thoreson, Wallace B

    2015-09-01

    Differences in synaptic transmission between rod and cone photoreceptors contribute to different response kinetics in rod- versus cone-dominated visual pathways. We examined Ca(2+) 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 IC l(Ca) confirmed that endogenous Ca(2+) 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 [Ca(2+)] 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 Ca(2+) 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 Ca(2+) buffering. However, weak Ca(2+) buffering speeded Ca(2+)/calmodulin (CaM)-dependent replenishment of vesicles to ribbons in both rods and cones, thereby enhancing sustained release. In rods, weak Ca(2+) buffering also amplified sustained release by enhancing CICR and CICR-stimulated release of vesicles at nonribbon sites. By contrast, elevating [Ca(2+)] at nonribbon sites in cones with weak Ca(2+) buffering and by inhibiting Ca(2+) extrusion did not trigger additional release, consistent with the notion that exocytosis from cones occurs exclusively at ribbons. The presence of weak endogenous Ca(2+) buffering in rods and cones facilitates slow, sustained exocytosis by enhancing Ca(2+)/CaM-dependent replenishment of ribbons in both rods and cones and by stimulating nonribbon release triggered by CICR in rods.

  13. 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

  14. Activation of TRPA1 channel facilitates excitatory synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord.

    PubMed

    Kosugi, Masafumi; Nakatsuka, Terumasa; Fujita, Tsugumi; Kuroda, Yasuo; Kumamoto, Eiichi

    2007-04-18

    TRPA1 is expressed in primary sensory neurons and hair cells, and it is proposed to be activated by cold stimuli, mechanical stimuli, or pungent ingredients. However, its role in regulating synaptic transmission has never been documented yet. In the present study, we examined whether activation of the TRPA1 channels affects synaptic transmission in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. A chief ingredient of mustard oil, allyl isothiocyanate (AITC), superfused for 2 min markedly increased the frequency and amplitude of spontaneous EPSCs (sEPSCs), which was accompanied by an inward current. Similar actions were produced by cinnamaldehyde and allicin. The AITC-induced increases in sEPSC frequency and amplitude were resistant to tetrodotoxin (TTX) and La3+, whereas being significantly reduced in extent in a Ca2+-free bath solution. In the presence of glutamate receptor antagonists CNQX and AP5, AITC did not generate any synaptic activities. The AITC-induced increases in sEPSC frequency and amplitude were reduced by ruthenium red, whereas being unaffected by capsazepine. AITC also increased the frequency and amplitude of spontaneous inhibitory postsynaptic currents; this AITC action was abolished in the presence of TTX or glutamate receptor antagonists. These results indicate that TRPA1 appears to be localized not only at presynaptic terminals on SG neurons to enhance glutamate release, but also in terminals of primary afferents innervating onto spinal inhibitory interneurons, which make synapses with SG neurons. This central modulation of sensory signals may be associated with physiological and pathological pain sensations.

  15. Role of Heterogeneous Macromolecular Crowding and Geometrical Irregularity at Central Excitatory Synapses in Shaping Synaptic Transmission

    PubMed Central

    Gupta, Rahul; Reneaux, Melissa; Karmeshu

    2016-01-01

    Besides the geometrical tortousity due to the extrasynaptic structures, macromolecular crowding and geometrical irregularities constituting the cleft composition at central excitatory synapses has a major and direct role in retarding the glutamate diffusion within the cleft space. However, the cleft composition may not only coarsely reduce the overall diffusivity of the glutamate but may also lead to substantial spatial variation in the diffusivity across the cleft space. Decrease in the overall diffusivity of the glutamate may have straightforward consequences to the glutamate transients in the cleft. However, how spatial variation in the diffusivity may further affect glutamate transients is an intriguing aspect. Therefore, to understand the role of cleft heterogeneity, the present study adopts a novel approach of glutamate diffusion which considers a gamma statistical distribution of the diffusion coefficient of glutamate (Dglut) across the cleft space, such that its moments discernibly capture the dual impacts of the cleft composition, and further applies the framework of superstatistics. The findings reveal a power law behavior in the glutamate transients, akin to the long-range anomalous subdiffusion, which leads to slower decay profile of cleft glutamate at higher intensity of cleft heterogeneity. Moreover, increase in the cleft heterogeneity is seen to eventually cause slower-rising excitatory postsynaptic currents with higher amplitudes, lesser noise, and prolonged duration of charge transfer across the postsynaptic membrane. Further, with regard to the conventional standard diffusion approach, the study suggests that the effective Dglut essentially derives from the median of the Dglut distribution and does not necessarily need to be the mean Dglut. Together, the findings indicate a strong implication of cleft heterogeneity to the metabolically cost-effective tuning of synaptic response during the phenomenon of plasticity at individual synapses and also

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

    PubMed Central

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

    2014-01-01

    Unapposed hemichannels (HCs) formed by hexamers of gap junction proteins are now known to be involved in various cellular processes under both physiological and pathological conditions. On the other hand, less is known regarding how differences in the molecular composition of HCs impact electrical synaptic transmission between neurons when they form intercellular heterotypic gap junctions (GJs). Here we review data indicating that molecular differences between apposed HCs at electrical synapses are generally associated with rectification of electrical transmission. Furthermore, this association has been observed at both innexin and connexin (Cx) based electrical synapses. We discuss the possible molecular mechanisms underlying electrical rectification, as well as the potential contribution of intracellular soluble factors to this phenomenon. We conclude that asymmetries in molecular composition and sensitivity to cellular factors of each contributing hemichannel can profoundly influence the transmission of electrical signals, endowing electrical synapses with more complex functional properties. PMID:25360082

  17. 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

  18. The Features and Functions of Neuronal Assemblies: Possible Dependency on Mechanisms beyond Synaptic Transmission

    PubMed Central

    Badin, Antoine-Scott; Fermani, Francesco; Greenfield, Susan A.

    2017-01-01

    “Neuronal assemblies” are defined here as coalitions within the brain of millions of neurons extending in space up to 1–2 mm, and lasting for hundreds of milliseconds: as such they could potentially link bottom-up, micro-scale with top-down, macro-scale events. The perspective first compares the features in vitro versus in vivo of this underappreciated “meso-scale” level of brain processing, secondly considers the various diverse functions in which assemblies may play a pivotal part, and thirdly analyses whether the surprisingly spatially extensive and prolonged temporal properties of assemblies can be described exclusively in terms of classic synaptic transmission or whether additional, different types of signaling systems are likely to operate. Based on our own voltage-sensitive dye imaging (VSDI) data acquired in vitro we show how restriction to only one signaling process, i.e., synaptic transmission, is unlikely to be adequate for modeling the full profile of assemblies. Based on observations from VSDI with its protracted spatio-temporal scales, we suggest that two other, distinct processes are likely to play a significant role in assembly dynamics: “volume” transmission (the passive diffusion of diverse bioactive transmitters, hormones, and modulators), as well as electrotonic spread via gap junctions. We hypothesize that a combination of all three processes has the greatest potential for deriving a realistic model of assemblies and hence elucidating the various complex brain functions that they may mediate. PMID:28119576

  19. Circadian Rhythm in Inhibitory Synaptic Transmission in the Mouse Suprachiasmatic Nucleus

    PubMed Central

    Itri, Jason; Michel, Stephan; Waschek, James A.; Colwell, Christopher S.

    2008-01-01

    It is widely accepted that most suprachiasmatic nucleus (SCN) neurons express the neurotransmitter GABA and are likely to use this neurotransmitter to regulate excitability within the SCN. To evaluate the possibility that inhibitory synaptic transmission varies with a circadian rhythm within the mouse SCN, we used whole cell patch-clamp recording in an acute brain slice preparation to record GABA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs). We found that the sIPSC frequency in the dorsal SCN (dSCN) exhibited a TTX-sensitive daily rhythm that peaked during the late day and early night in mice held in a light:dark cycle. We next evaluated whether vasoactive intestinal peptide (VIP) was responsible for the observed rhythm in IPSC frequency. Pretreatment of SCN slices with VPAC1/VPAC2- or VPAC2-specific receptor antagonists prevented the increase in sIPSC frequency in the dSCN. The rhythm in sIPSC frequency was absent in VIP/peptide histidine isoleucine (PHI)-deficient mice. Finally, we were able to detect a rhythm in the frequency of inhibitory synaptic transmission in mice held in constant darkness that was also dependent on VIP and the VPAC2 receptor. Overall, these data demonstrate that there is a circadian rhythm in GABAergic transmission in the dorsal region of the mouse SCN and that the VIP is required for expression of this rhythm. PMID:14973316

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

    PubMed

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

    2015-12-25

    The present study was designed to investigate the inhibitory effects of intravenous general anesthetic propofol (0.1-3.0 mmol/L) on excitatory synaptic transmission in supraoptic nucleus (SON) neurons of rats, and to explore the underlying mechanisms by using intracellular recording technique and hypothalamic slice preparation. It was observed that stimulation of the dorsolateral region of SON could elicit the postsynaptic potentials (PSPs) in SON neurons. Of the 8 tested SON neurons, the PSPs of 7 (88%, 7/8) neurons were decreased by propofol in a concentration-dependent manner, in terms of the PSPs' amplitude (P < 0.01), area under curve, duration, half-width and 10%-90% decay time (P < 0.05). The PSPs were completely and reversibly abolished by 1.0 mmol/L propofol at 2 out of 7 tested cells. The depolarization responses induced by pressure ejection of exogenous glutamate were reversibly and concentration-dependently decreased by bath application of propofol. The PSPs and glutamate-induced responses recorded simultaneously were reversibly and concentration-dependently decreased by propofol, but 0.3 mmol/L propofol only abolished PSPs. The excitatory postsynaptic potentials (EPSPs) of 7 cells increased in the condition of picrotoxin (30 µmol/L, a GABA(A) receptor antagonist) pretreatment. On this basis, the inhibitory effects of propofol on EPSPs were decreased. These data indicate that the presynaptic and postsynaptic mechanisms may be both involved in the inhibitory effects of propofol on excitatory synaptic transmission in SON neurons. The inhibitory effects of propofol on excitatory synaptic transmission of SON neurons may be related to the activation of GABA(A) receptors, but at a high concentration, propofol may also act directly on glutamate receptors.

  1. GABA transporter 1 tunes GABAergic synaptic transmission at output neurons of the mouse neostriatum

    PubMed Central

    Kirmse, Knut; Dvorzhak, Anton; Kirischuk, Sergei; Grantyn, Rosemarie

    2008-01-01

    GABAergic medium-sized striatal output neurons (SONs) provide the principal output for the neostriatum. In vitro and in vivo data indicate that spike discharge of SONs is tightly controlled by effective synaptic inhibition. Although phasic GABAergic transmission critically depends on ambient GABA levels, the role of GABA transporters (GATs) in neostriatal GABAergic synaptic transmission is largely unknown. In the present study we aimed at elucidating the role of GAT-1 in the developing mouse neostriatum (postnatal day (P) 7–34). We recorded GABAergic postsynaptic currents (PSCs) using the whole-cell patch-clamp technique. Based on the effects of NO-711, a specific GAT-1 blocker, we demonstrate that GAT-1 is operative at this age and influences GABAergic synaptic transmission by presynaptic and postsynaptic mechanisms. Presynaptic GABABR-mediated suppression of GABA release was found to be functional at all ages tested; however, there was no evidence for persistent GABABR activity under control conditions, unless GAT-1 was blocked (P12–34). In addition, whereas no tonic GABAAR-mediated conductances were detected in SONs until P14, application of a specific GABAAR antagonist caused distinct tonic outward currents later in development (P19–34). In the presence of NO-711, tonic GABAAR-mediated currents were also observed at P7–14 and were dramatically increased at more mature stages. Furthermore, GAT-1 block reduced the median amplitude of GABAergic miniature PSCs indicating a decrease in quantal size. We conclude that in the murine neostriatum GAT-1 operates in a net uptake mode. It prevents the persistent activation of presynaptic GABABRs (P12–34) and prevents (P7–14) or reduces (P19–34) tonic postsynaptic GABAAR activity. PMID:18832421

  2. 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.

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

    PubMed Central

    Chen, Yuncai; Andres, Adrienne L.; Frotscher, Michael; Baram, Tallie Z.

    2012-01-01

    To enhance survival, an organism needs to remember—and learn from—threatening or stressful events. This fact necessitates the presence of mechanisms by which stress can influence synaptic transmission in brain regions, such as hippocampus, that subserve learning and memory. A major focus of this series of monographs is on the role and actions of adrenal-derived hormones, corticosteroids, and of brain-derived neurotransmitters, on synaptic function in the stressed hippocampus. Here we focus on the contribution of hippocampus-intrinsic, stress-activated CRH-CRH receptor signaling to the function and structure of hippocampal synapses. Corticotropin-releasing hormone (CRH) is expressed in interneurons of adult hippocampus, and is released from axon terminals during stress. The peptide exerts time- and dose-dependent effects on learning and memory via modulation of synaptic function and plasticity. Whereas physiological levels of CRH, acting over seconds to minutes, augment memory processes, exposure to presumed severe-stress levels of the peptide results in spine retraction and loss of synapses over more protracted time-frames. Loss of dendritic spines (and hence of synapses) takes place through actin cytoskeleton collapse downstream of CRHR1 receptors that reside within excitatory synapses on spine heads. Chronic exposure to stress levels of CRH may promote dying-back (atrophy) of spine-carrying dendrites. Thus, the acute effects of CRH may contribute to stress-induced adaptive mechanisms, whereas chronic or excessive exposure to the peptide may promote learning problems and premature cognitive decline. PMID:22514519

  4. 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.

  5. 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.

  6. Spontaneous network activity transiently depresses synaptic transmission in the embryonic chick spinal cord.

    PubMed

    Fedirchuk, B; Wenner, P; Whelan, P J; Ho, S; Tabak, J; O'Donovan, M J

    1999-03-15

    We examined the effects of spontaneous or evoked episodes of rhythmic activity on synaptic transmission in several spinal pathways of embryonic day 9-12 chick embryos. We compared the amplitude of synaptic potentials evoked by stimulation of the ventrolateral funiculus (VLF), the dorsal or ventral roots, before and after episodes of activity. With the exception of the short-latency responses evoked by dorsal root stimulation, the potentials were briefly potentiated and then reduced for several minutes after an episode of rhythmic activity. Their amplitude progressively recovered in the interval between successive episodes. The lack of post-episode depression in the short-latency component of the dorsal root evoked responses is probably attributable to the absence of firing in cut muscle afferents during an episode of activity. The post-episode depression of VLF-evoked potentials was mimicked by prolonged stimulation of the VLF, subthreshold for an episode of activity. By contrast, antidromically induced motoneuron firing and the accompanying calcium entry did not depress VLF-evoked potentials recorded from the stimulated ventral root. In addition, post-episode depression of VLF-evoked synaptic currents was observed in voltage-clamped spinal neurons. Collectively, these findings suggest that somatic postsynaptic activity and calcium entry are not required for the depression. We propose instead that the mechanism may involve a form of long-lasting activity-induced synaptic depression, possibly a combination of transmitter depletion and ligand-induced changes in the postsynaptic current accompanying transmitter release. This activity-dependent depression appears to be an important mechanism underlying the occurrence of spontaneous activity in developing spinal networks.

  7. Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors.

    PubMed

    Van Hook, Matthew J; Parmelee, Caitlyn M; Chen, Minghui; Cork, Karlene M; Curto, Carina; Thoreson, Wallace B

    2014-11-01

    At the first synapse in the vertebrate visual pathway, light-evoked changes in photoreceptor membrane potential alter the rate of glutamate release onto second-order retinal neurons. This process depends on the synaptic ribbon, a specialized structure found at various sensory synapses, to provide a supply of primed vesicles for release. Calcium (Ca(2+)) accelerates the replenishment of vesicles at cone ribbon synapses, but the mechanisms underlying this acceleration and its functional implications for vision are unknown. We studied vesicle replenishment using paired whole-cell recordings of cones and postsynaptic neurons in tiger salamander retinas and found that it involves two kinetic mechanisms, the faster of which was diminished by calmodulin (CaM) inhibitors. We developed an analytical model that can be applied to both conventional and ribbon synapses and showed that vesicle resupply is limited by a simple time constant, τ = 1/(Dρδs), where D is the vesicle diffusion coefficient, δ is the vesicle diameter, ρ is the vesicle density, and s is the probability of vesicle attachment. The combination of electrophysiological measurements, modeling, and total internal reflection fluorescence microscopy of single synaptic vesicles suggested that CaM speeds replenishment by enhancing vesicle attachment to the ribbon. Using electroretinogram and whole-cell recordings of light responses, we found that enhanced replenishment improves the ability of cone synapses to signal darkness after brief flashes of light and enhances the amplitude of responses to higher-frequency stimuli. By accelerating the resupply of vesicles to the ribbon, CaM extends the temporal range of synaptic transmission, allowing cones to transmit higher-frequency visual information to downstream neurons. Thus, the ability of the visual system to encode time-varying stimuli is shaped by the dynamics of vesicle replenishment at photoreceptor synaptic ribbons.

  8. Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion neurons by expression of exogenous calcium channels

    PubMed Central

    Mochida, Sumiko; Westenbroek, Ruth E.; Yokoyama, Charles T.; Itoh, Kanako; Catterall, William A.

    2003-01-01

    Fast cholinergic neurotransmission between superior cervical ganglion neurons (SCGNs) in cell culture is initiated by N-type Ca2+ currents through Cav2.2 channels. To test the ability of different Ca2+-channel subtypes to initiate synaptic transmission in these cells, SCGNs were injected with cDNAs encoding Cav1.2 channels, which conduct L-type currents, Cav2.1 channels, which conduct P/Q-type Ca2+ currents, and Cav2.3 channels, which conduct R-type Ca2+ currents. Exogenously expressed Cav2.1 channels were localized in nerve terminals, as assessed by immunocytochemistry with subtype-specific antibodies, and these channels effectively initiated synaptic transmission. Injection with cDNA encoding Cav2.3 channels yielded a lower level of presynaptic labeling and synaptic transmission, whereas injection with cDNA encoding Cav1.2 channels resulted in no presynaptic labeling and no synaptic transmission. Our results show that exogenously expressed Ca2+ channels can mediate synaptic transmission in SCGNs and that the specificity of reconstitution of neurotransmission (Cav2.1 > Cav2.3 ≫ Cav1.2) follows the same order as in neurons in vivo. The specificity of reconstitution of neurotransmission parallels the specificity of trafficking of these Cav channels to nerve terminals. PMID:12601155

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

    PubMed Central

    Yan, Shijun; Du, Fang; Yan, Shirley Shidu

    2016-01-01

    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 a de novo 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 (nonTg) 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 nonTg 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

  10. 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.

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

    PubMed

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

    1998-07-01

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

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

    PubMed

    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

    2012-06-01

    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.

  13. Membrane lipids tune synaptic transmission by direct modulation of presynaptic potassium channels.

    PubMed

    Carta, Mario; Lanore, Frederic; Rebola, Nelson; Szabo, Zsolt; Da Silva, Silvia Viana; Lourenço, Joana; Verraes, Agathe; Nadler, André; Schultz, Carsten; Blanchet, Christophe; Mulle, Christophe

    2014-02-19

    Voltage-gated potassium (Kv) channels are involved in action potential (AP) repolarization in excitable cells. Exogenous application of membrane-derived lipids, such as arachidonic acid (AA), regulates the gating of Kv channels. Whether membrane-derived lipids released under physiological conditions have an impact on neuronal coding through this mechanism is unknown. We show that AA released in an activity-dependent manner from postsynaptic hippocampal CA3 pyramidal cells acts as retrograde messenger, inducing a robust facilitation of mossy fiber (Mf) synaptic transmission over several minutes. AA acts by broadening presynaptic APs through the direct modulation of Kv channels. This form of short-term plasticity can be triggered when postsynaptic cell fires with physiologically relevant patterns and sets the threshold for the induction of the presynaptic form of long-term potentiation (LTP) at hippocampal Mf synapses. Hence, direct modulation of presynaptic Kv channels by activity-dependent release of lipids serves as a physiological mechanism for tuning synaptic transmission.

  14. Comparison of baroreceptive to other afferent synaptic transmission to the medial solitary tract nucleus.

    PubMed

    Andresen, Michael C; Peters, James H

    2008-11-01

    Cranial nerve visceral afferents enter the brain stem to synapse on neurons within the solitary tract nucleus (NTS). The broad heterogeneity of both visceral afferents and NTS neurons makes understanding afferent synaptic transmission particularly challenging. To study a specific subgroup of second-order neurons in medial NTS, we anterogradely labeled arterial baroreceptor afferents of the aortic depressor nerve (ADN) with lipophilic fluorescent tracer (i.e., ADN+) and measured synaptic responses to solitary tract (ST) activation recorded from dye-identified neurons in medial NTS in horizontal brain stem slices. Every ADN+ NTS neuron received constant-latency ST-evoked excitatory postsynaptic currents (EPSCs) (jitter < 192 micros, SD of latency). Stimulus-recruitment profiles showed single thresholds and no suprathreshold recruitment, findings consistent with EPSCs arising from a single, branched afferent axon. Frequency-dependent depression of ADN+ EPSCs averaged approximately 70% for five shocks at 50 Hz, but single-shock failure rates did not exceed 4%. Whether adjacent ADN- or those from unlabeled animals, other second-order NTS neurons (jitters < 200 micros) had ST transmission properties indistinguishable from ADN+. Capsaicin (CAP; 100 nM) blocked ST transmission in some neurons. CAP-sensitive ST-EPSCs were smaller and failed over five times more frequently than CAP-resistant responses, whether ADN+ or from unlabeled animals. Variance-mean analysis of ST-EPSCs suggested uniformly high probabilities for quantal glutamate release across second-order neurons. While amplitude differences may reflect different numbers of contacts, higher frequency-dependent failure rates in CAP-sensitive ST-EPSCs may arise from subtype-specific differences in afferent axon properties. Thus afferent transmission within medial NTS differed by axon class (e.g., CAP sensitive) but was indistinguishable by source of axon (e.g., baroreceptor vs. nonbaroreceptor).

  15. Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons.

    PubMed

    Eastwood, S L; Harrison, P J

    2005-03-01

    Synaptic protein gene expression is altered in schizophrenia. In the hippocampal formation there may be particular involvement of glutamatergic neurons and their synapses, but overall the profile remains unclear. In this in situ hybridization histochemistry (ISHH) study, we examined four informative synaptic protein transcripts: vesicular glutamate transporter (VGLUT) 1, VGLUT2, complexin I, and complexin II, in dorsolateral prefrontal cortex (DPFC), superior temporal cortex (STC), and hippocampal formation, in 13 subjects with schizophrenia and 18 controls. In these areas, VGLUT1 and complexin II are expressed primarily by excitatory neurons, whereas complexin I is mainly expressed by inhibitory neurons. In schizophrenia, VGLUT1 mRNA was decreased in hippocampal formation and DPFC, complexin II mRNA was reduced in DPFC and STC, and complexin I mRNA decreased in STC. Hippocampal VGLUT1 mRNA declined with age selectively in the schizophrenia group. VGLUT2 mRNA was not quantifiable due to its low level. The data provide additional evidence for a synaptic pathology in schizophrenia, in terms of a reduced expression of three synaptic protein genes. In the hippocampus, the loss of VGLUT1 mRNA supports data indicating that glutamatergic presynaptic deficits are prominent, whereas the pattern of results in temporal and frontal cortex suggests broadly similar changes may affect inhibitory and excitatory neurons. The impairment of synaptic transmission implied by the synaptic protein reductions may contribute to the dysfunction of cortical neural circuits that characterises the disorder.

  16. 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

  17. 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

  18. Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons.

    PubMed

    Cristino, Luigia; Busetto, Giuseppe; Imperatore, Roberta; Ferrandino, Ida; Palomba, Letizia; Silvestri, Cristoforo; Petrosino, Stefania; Orlando, Pierangelo; Bentivoglio, Marina; Mackie, Kenneth; Di Marzo, Vincenzo

    2013-06-11

    Acute or chronic alterations in energy status alter the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity to allow for the adaptation of energy metabolism to new homeostatic requirements. The impact of such changes on endocannabinoid and cannabinoid receptor type 1 (CB1)-mediated modulation of synaptic transmission and strength is not known, despite the fact that this signaling system is an important target for the development of new drugs against obesity. We investigated whether CB1-expressing excitatory vs. inhibitory inputs to orexin-A-containing neurons in the lateral hypothalamus are altered in obesity and how this modifies endocannabinoid control of these neurons. In lean mice, these inputs are mostly excitatory. By confocal and ultrastructural microscopic analyses, we observed that in leptin-knockout (ob/ob) obese mice, and in mice with diet-induced obesity, orexinergic neurons receive predominantly inhibitory CB1-expressing inputs and overexpress the biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol, which retrogradely inhibits synaptic transmission at CB1-expressing axon terminals. Patch-clamp recordings also showed increased CB1-sensitive inhibitory innervation of orexinergic neurons in ob/ob mice. These alterations are reversed by leptin administration, partly through activation of the mammalian target of rapamycin pathway in neuropeptide-Y-ergic neurons of the arcuate nucleus, and are accompanied by CB1-mediated enhancement of orexinergic innervation of target brain areas. We propose that enhanced inhibitory control of orexin-A neurons, and their CB1-mediated disinhibition, are a consequence of leptin signaling impairment in the arcuate nucleus. We also provide initial evidence of the participation of this phenomenon in hyperphagia and hormonal dysregulation in obesity.

  19. Dietary cholesterol concentration affects synaptic plasticity and dendrite spine morphology of rabbit hippocampal neurons.

    PubMed

    Wang, Desheng; Zheng, Wen

    2015-10-05

    Previous studies have shown dietary cholesterol can enhance learning but retard memory which may be partly due to increased cholesterol levels in hippocampus and reduced afterhyperpolarization (AHP) amplitude of hippocampal CA1 neurons. This study explored the dose-dependent effect of dietary cholesterol on synaptic plasticity of rabbit hippocampal CA1 neurons and spine morphology, the postsynaptic structures responsible for synaptic plasticity. Field potential recordings revealed a low concentration of dietary cholesterol increased long-term potentiation (LTP) expression while high concentrations produced a pronounced reduction in LTP expression. Dietary cholesterol facilitated basal synaptic transmission but did not influence presynaptic function. DiI staining showed dietary cholesterol induced alterations in dendrite spine morphology characterized by increased mushroom spine density and decreased thin spine density, two kinds of dendritic spines that may be linked to memory consolidation and learning acquisition. Dietary cholesterol also modulated the geometric measures of mushroom spines. Therefore, dietary cholesterol dose-dependently modulated both synaptic plasticity and dendrite spine morphologies of hippocampal CA1 neurons that could mediate learning and memory changes previously seen to result from feeding a cholesterol diet.

  20. synaptojanin1 Is Required for Temporal Fidelity of Synaptic Transmission in Hair Cells

    PubMed Central

    Mo, Weike; Brockerhoff, Susan E.; Nicolson, Teresa

    2009-01-01

    To faithfully encode mechanosensory information, auditory/vestibular hair cells utilize graded synaptic vesicle (SV) release at specialized ribbon synapses. The molecular basis of SV release and consequent recycling of membrane in hair cells has not been fully explored. Here, we report that comet, a gene identified in an ENU mutagenesis screen for zebrafish larvae with vestibular defects, encodes the lipid phosphatase Synaptojanin 1 (Synj1). Examination of mutant synj1 hair cells revealed basal blebbing near ribbons that was dependent on Cav1.3 calcium channel activity but not mechanotransduction. Synaptojanin has been previously implicated in SV recycling; therefore, we tested synaptic transmission at hair-cell synapses. Recordings of post-synaptic activity in synj1 mutants showed relatively normal spike rates when hair cells were mechanically stimulated for a short period of time at 20 Hz. In contrast, a sharp decline in the rate of firing occurred during prolonged stimulation at 20 Hz or stimulation at a higher frequency of 60 Hz. The decline in spike rate suggested that fewer vesicles were available for release. Consistent with this result, we observed that stimulated mutant hair cells had decreased numbers of tethered and reserve-pool vesicles in comparison to wild-type hair cells. Furthermore, stimulation at 60 Hz impaired phase locking of the postsynaptic activity to the mechanical stimulus. Following prolonged stimulation at 60 Hz, we also found that mutant synj1 hair cells displayed a striking delay in the recovery of spontaneous activity. Collectively, the data suggest that Synj1 is critical for retrieval of membrane in order to maintain the quantity, timing of fusion, and spontaneous release properties of SVs at hair-cell ribbon synapses. PMID:19424431

  1. Biphasic cholinergic synaptic transmission controls action potential activity in thalamic reticular nucleus neurons.

    PubMed

    Sun, Yan-Gang; Pita-Almenar, Juan D; Wu, Chia-Shan; Renger, John J; Uebele, Victor N; Lu, Hui-Chen; Beierlein, Michael

    2013-01-30

    Cholinergic neurons in the basal forebrain and the brainstem form extensive projections to a number of thalamic nuclei. Activation of cholinergic afferents during distinct behavioral states can regulate neuronal firing, transmitter release at glutamatergic and GABAergic synapses, and synchrony in thalamic networks, thereby controlling the flow of sensory information. These effects are thought to be mediated by slow and persistent increases in extracellular ACh levels, resulting in the modulation of populations of thalamic neurons over large temporal and spatial scales. However, the synaptic mechanisms underlying cholinergic signaling in the thalamus are not well understood. Here, we demonstrate highly reliable cholinergic transmission in the mouse thalamic reticular nucleus (TRN), a brain structure essential for sensory processing, arousal, and attention. We find that ACh release evoked by low-frequency stimulation leads to biphasic excitatory-inhibitory (E-I) postsynaptic responses, mediated by the activation of postsynaptic α4β2 nicotinic ACh receptors (nAChRs) and M2 muscarinic ACh receptors (mAChRs), respectively. In addition, ACh can bind to mAChRs expressed near cholinergic release sites, resulting in autoinhibition of release. We show that the activation of postsynaptic nAChRs by transmitter release from only a small number of individual axons is sufficient to trigger action potentials in TRN neurons. Furthermore, short trains of cholinergic synaptic inputs can powerfully entrain ongoing TRN neuronal activity. Our study demonstrates fast and precise synaptic E-I signaling mediated by ACh, suggesting novel computational mechanisms for the cholinergic control of neuronal activity in thalamic circuits.

  2. Synaptojanin1 is required for temporal fidelity of synaptic transmission in hair cells.

    PubMed

    Trapani, Josef G; Obholzer, Nikolaus; Mo, Weike; Brockerhoff, Susan E; Nicolson, Teresa

    2009-05-01

    To faithfully encode mechanosensory information, auditory/vestibular hair cells utilize graded synaptic vesicle (SV) release at specialized ribbon synapses. The molecular basis of SV release and consequent recycling of membrane in hair cells has not been fully explored. Here, we report that comet, a gene identified in an ENU mutagenesis screen for zebrafish larvae with vestibular defects, encodes the lipid phosphatase Synaptojanin 1 (Synj1). Examination of mutant synj1 hair cells revealed basal blebbing near ribbons that was dependent on Cav1.3 calcium channel activity but not mechanotransduction. Synaptojanin has been previously implicated in SV recycling; therefore, we tested synaptic transmission at hair-cell synapses. Recordings of post-synaptic activity in synj1 mutants showed relatively normal spike rates when hair cells were mechanically stimulated for a short period of time at 20 Hz. In contrast, a sharp decline in the rate of firing occurred during prolonged stimulation at 20 Hz or stimulation at a higher frequency of 60 Hz. The decline in spike rate suggested that fewer vesicles were available for release. Consistent with this result, we observed that stimulated mutant hair cells had decreased numbers of tethered and reserve-pool vesicles in comparison to wild-type hair cells. Furthermore, stimulation at 60 Hz impaired phase locking of the postsynaptic activity to the mechanical stimulus. Following prolonged stimulation at 60 Hz, we also found that mutant synj1 hair cells displayed a striking delay in the recovery of spontaneous activity. Collectively, the data suggest that Synj1 is critical for retrieval of membrane in order to maintain the quantity, timing of fusion, and spontaneous release properties of SVs at hair-cell ribbon synapses.

  3. Investigation of hippocampal synaptic transmission and plasticity in mice deficient in the actin-binding protein Drebrin

    PubMed Central

    Willmes, Claudia G.; Mack, Till G. A.; Ledderose, Julia; Schmitz, Dietmar; Wozny, Christian; Eickholt, Britta J.

    2017-01-01

    The dynamic regulation of the actin cytoskeleton plays a key role in controlling the structure and function of synapses. It is vital for activity-dependent modulation of synaptic transmission and long-term changes in synaptic morphology associated with memory consolidation. Several regulators of actin dynamics at the synapse have been identified, of which a salient one is the postsynaptic actin stabilising protein Drebrin (DBN). It has been suggested that DBN modulates neurotransmission and changes in dendritic spine morphology associated with synaptic plasticity. Given that a decrease in DBN levels is correlated with cognitive deficits associated with ageing and dementia, it was hypothesised that DBN protein abundance instructs the integrity and function of synapses. We created a novel DBN deficient mouse line. Analysis of gross brain and neuronal morphology revealed no phenotype in the absence of DBN. Electrophysiological recordings in acute hippocampal slices and primary hippocampal neuronal cultures showed that basal synaptic transmission, and both long-term and homeostatic synaptic plasticity were unchanged, suggesting that loss of DBN is not sufficient in inducing synapse dysfunction. We propose that the overall lack of changes in synaptic function and plasticity in DBN deficient mice may indicate robust compensatory mechanisms that safeguard cytoskeleton dynamics at the synapse. PMID:28198431

  4. 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

  5. Effects of 4-aminopyridine on synaptic transmission in the cat spinal cord.

    PubMed

    Jankowska, E; Lundberg, A; Rudomin, P; Sykova, E

    1982-05-20

    An analysis was made of effects of 0.1-1.0 mg/kg 4-aminopyridine (4-AP) i.v. on excitatory and inhibitory spinal reflex pathways in lightly anaesthetized or decerebrated cats. The effects appeared within the first minutes of the injection, reached maximum after about 10-15 min and remained stable during at least several hours. 4-AP enhanced the following synaptic actions on motoneurones: monosynaptic excitation from Ia afferents and descending tracts, disynaptic and polysynaptic excitation from group Ib, group II, cutaneous and high threshold muscle afferents, disynaptic inhibition from Ia and Ib afferents and recurrent and polysynaptic inhibition from different afferents. 4-AP also increased primary afferent depolarization and excitation of ascending tract cells by peripheral stimuli. In the case of the disynaptic inhibitory pathways it has been shown that 4-AP may enhance the excitation of the interposed interneurones but it also increases the action of these interneurones on the motoneurones; monosynaptic inhibition evoked in motoneurones by electrical stimulation of the axons of the inhibitory interneurones was used as a test response in these experiments. No indications were found of direct effects of 4-AP on excitability of afferent fibres or motoneurones to electrical stimuli. No systematic changes were either found in the membrane potential of motoneurones or in the duration of action potentials of these neurones or primary afferents. It is therefore concluded that small doses of 4-AP enhance synaptic transmission in the spinal cord by an action at a presynaptic level.

  6. 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

  7. Synaptic transmission parallels neuromodulation in a central food-intake circuit

    PubMed Central

    Schlegel, Philipp; Texada, Michael J; Miroschnikow, Anton; Schoofs, Andreas; Hückesfeld, Sebastian; Peters, Marc; Schneider-Mizell, Casey M; Lacin, Haluk; Li, Feng; Fetter, Richard D; Truman, James W; Cardona, Albert; Pankratz, Michael J

    2016-01-01

    NeuromedinU is a potent regulator of food intake and activity in mammals. In Drosophila, neurons producing the homologous neuropeptide hugin regulate feeding and locomotion in a similar manner. Here, we use EM-based reconstruction to generate the entire connectome of hugin-producing neurons in the Drosophila larval CNS. We demonstrate that hugin neurons use synaptic transmission in addition to peptidergic neuromodulation and identify acetylcholine as a key transmitter. Hugin neuropeptide and acetylcholine are both necessary for the regulatory effect on feeding. We further show that subtypes of hugin neurons connect chemosensory to endocrine system by combinations of synaptic and peptide-receptor connections. Targets include endocrine neurons producing DH44, a CRH-like peptide, and insulin-like peptides. Homologs of these peptides are likewise downstream of neuromedinU, revealing striking parallels in flies and mammals. We propose that hugin neurons are part of an ancient physiological control system that has been conserved at functional and molecular level. DOI: http://dx.doi.org/10.7554/eLife.16799.001 PMID:27845623

  8. Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation.

    PubMed

    Artola, A; Singer, W

    1993-11-01

    In many brain areas, including the cerebellar cortex, neocortex, hippocampus, striatum and nucleus accumbens, brief activation of an excitatory pathway can produce long-term depression (LTD) of synaptic transmission. In most preparations, induction of LTD has been shown to require a minimum level of postsynaptic depolarization and a rise in the intracellular Ca2+ concentration [Ca2+]i in the postsynaptic neurone. Thus, induction conditions resemble those described for the initiation of associative long-term potentiation (LTP). However, data from structures susceptible to both LTD and LTP suggest that a stronger depolarization and a greater increase in [Ca2+]i are required to induce LTP than to initiate LTD. The source of Ca2+ appears to be less critical for the differential induction of LTP and LTD than the amplitude of the Ca2+ surge, since the activation of voltage- and ligand-gated Ca2+ conductances as well as the release from intracellular stores have all been shown to contribute to both LTD and LTP induction. LTD is induceable even at inactive synapses if [Ca2+]i is raised to the appropriate level by antidromic or heterosynaptic activation, or by raising the extracellular Ca2+ concentration [Ca2+]o. These conditions suggest a rule (called here the ABS rule) for activity-dependent synaptic modifications that differs from the classical Hebb rule and that can account for both homosynaptic LTD and LTP as well as for heterosynaptic competition and associativity.

  9. Cocaine-evoked synaptic plasticity of excitatory transmission in the ventral tegmental area.

    PubMed

    Lüscher, Christian

    2013-05-01

    Cocaine leads to a strong euphoria, which is at the origin of its recreational use. Past the acute effects, the drug leaves traces in the brain that persist long after it has been cleared from the body. These traces eventually shape behavior such that drug use may become compulsive and addiction develops. Here we discuss cocaine-evoked synaptic plasticity of glutamatergic transmission onto dopamine (DA) neurons of the ventral tegmental area (VTA) as one of the earliest traces after a first injection of cocaine. We review the literature that has examined the induction requirements as well as the expression mechanism of this form of plasticity and ask the question about its functional significance.

  10. 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

  11. FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels.

    PubMed

    Deng, Pan-Yue; Rotman, Ziv; Blundon, Jay A; Cho, Yongcheol; Cui, Jianmin; Cavalli, Valeria; Zakharenko, Stanislav S; Klyachko, Vitaly A

    2013-02-20

    Loss of FMRP causes fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx, and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation independent and are mediated selectively by BK channels via interaction of FMRP with BK channel's regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology.

  12. 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

  13. Propagation of epileptiform activity can be independent of synaptic transmission, gap junctions, or diffusion and is consistent with electrical field transmission.

    PubMed

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

    2014-01-22

    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.

  14. Pb2+ via protein kinase C inhibits nicotinic cholinergic modulation of synaptic transmission in the hippocampus.

    PubMed

    Braga, Maria F M; Pereira, Edna F R; Mike, Arpad; Albuquerque, Edson X

    2004-11-01

    The present study was designed to investigate the effects of Pb(2+) on modulation of synaptic transmission by nicotinic receptors (nAChRs) in the rat hippocampus. To this end, inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) were recorded by means of the whole-cell mode of the patch-clamp technique from rat hippocampal neurons in culture. Acetylcholine (ACh, 1 mM; 1-s pulses) triggered GABA release via activation of alpha4beta2* and alpha7* nAChRs. It also triggered glutamate release via activation of alpha7* nAChRs. Pb(2+) (0.1 and 1 microM) blocked ACh-triggered transmitter release. Blockade by Pb(2+) of ACh-triggered IPSCs was partially reversible upon washing of the neurons. In contrast, even after 30- to 60-min washing, there was no reversibility of Pb(2+)-induced blockade of ACh-triggered EPSCs. The effects of Pb(2+) on GABA release triggered by activation of alpha7* and alpha4beta2* nACRs were mimicked by the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (1 microM) and blocked by the indolocarbazole Go 7874 (50 nM) and the bisindolylmaleimide Ro-31-8425 (150 nM), which are selective PKC inhibitors. After washing of fully functional neuronal networks that had been exposed for 5 min to Pb(2+), the irreversible inhibition by Pb(2+) of ACh-triggered glutamate release was partially overridden by a disinhibitory mechanism that is likely to involve alpha4beta2* nAChR activation in interneurons that synapse onto other interneurons synapsing onto pyramidal neurons. Long-lasting inhibition of alpha7* nAChR modulation of synaptic transmission may contribute to the persistent cognitive impairment that results from childhood Pb(2+) intoxication.

  15. Nicotinic modulation of network and synaptic transmission in the immature hippocampus investigated with genetically modified mice

    PubMed Central

    Le Magueresse, Corentin; Safiulina, Victoria; Changeux, Jean-Pierre; Cherubini, Enrico

    2006-01-01

    The hippocampus, a key structure in learning and memory processes, receives a powerful cholinergic innervation from the septum and contains nicotinic acetylcholine receptors (nAChRs). Early in postnatal development, activation of nAChRs by nicotine or endogenous acetylcholine contributes to enhance synaptic signalling. Here, the patch-clamp technique was used to assess the contribution of α7 and β2-containing (α7* and β2*) nAChRs to nicotine-elicited modulation of GABAergic and glutamatergic activity at the network and single-cell level in the immature hippocampus of wild-type (WT), α7−/− and β2−/− mice. We found that α7* and β2* nAChRs were sufficient to modulate nicotine-induced increase in frequency of spontaneously occurring giant depolarizing potentials (GDPs), which are generated at the network level by the synergistic action of glutamate and depolarizing GABA, and thought to play a crucial role in neuronal wiring. However, α7* but not β2* receptors were essential in nicotine-induced increase of interictal discharge frequency recorded after postnatal day 3 in the presence of bicuculline, when GABA shifted from the depolarizing to the hyperpolarizing direction. To correlate these observations with nicotine-elicited changes in synaptic transmission, we recorded spontaneous GABAergic and glutamatergic postsynaptic currents in pyramidal cells and interneurons localized in stratum oriens, stratum pyramidale and stratum radiatum, in slices obtained from WT and knock-out animals. We found that early in postnatal life α7* and β2* nAChRs exert a fine regional modulation of GABAergic and glutamatergic transmission that underlies nicotine-elicited changes in network synchronization. PMID:16901939

  16. 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

    2016-02-09

    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.

  17. 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.

  18. 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.

  19. Endogenous modulators of synaptic transmission: cannabinoid regulation in the supraoptic nucleus.

    PubMed

    McDonald, Neil A; Kuzmiski, J Brent; Naderi, Nima; Schwab, Yannick; Pittman, Quentin J

    2008-01-01

    The magnocellular neurons of the hypothalamic supraoptic nucleus (SON) are a major source of both systemic and central release of the neurohypophyseal peptides, oxytocin (OXT) and arginine-vasopressin (AVP). Both OXT and AVP are released from the somatodendritic compartment of magnocellular neurons and act within the SON to modulate the electrophysiological function of these cells. Cannabinoids (CBs) affect hormonal output and the SON may represent a neural substrate through which CBs exert specific physiological and behavioural effects. Dynamic modulation of synaptic inputs is a fundamental mechanism through which neuronal output is controlled. Dendritically released OXT acts on autoreceptors to generate endocannabinoids (eCBs) which modify both excitatory and inhibitory inputs to OXT neurons through actions on presynaptic CB receptors. As such, OXT and eCBs cooperate to shape the electrophysiological properties of magnocellular OXT neurons, regulating the physiological function of this nucleus. Further study of eCB signalling in the SON, including its interaction with AVP neurons, promises to extend our understanding of the synaptic regulation of SON physiological function.

  20. Exposure to Cocaine Regulates Inhibitory Synaptic Transmission in the Nucleus Accumbens

    PubMed Central

    Otaka, Mami; Ishikawa, Masago; Lee, Brian R.; Liu, Lei; Neumann, Peter A.; Cui, Ranji; Huang, Yanhua; Schlüter, Oliver M.; Dong, Yan

    2013-01-01

    Medium spiny neurons (MSNs) within the nucleus accumbens shell (NAc) function to gate and prioritize emotional/motivational arousals for behavioral output. The neuronal output NAc MSNs is mainly determined by the integration of membrane excitability and excitatory/inhibitory synaptic inputs. Whereas cocaine-induced alterations at excitatory synapses and membrane excitability have been extensively examined, the overall functional output of NAc MSNs following cocaine exposure still poorly defined because little is known about whether inhibitory synaptic input to these neurons is affected by cocaine. Here, our results demonstrate multidimensional alterations at inhibitory synapses in NAc neurons following cocaine self-administration in rats. Specifically, the amplitude of miniature (m) inhibitory postsynaptic currents (IPSCs) was decreased after 21-d withdrawal from 5-d cocaine self-administration. Upon re-exposure to cocaine after 21-day withdrawal, whereas the amplitude of mIPSCs remained down-regulated, the frequency became significantly higher. Furthermore, the reversal potential of IPSCs, which was not significantly altered during withdrawal, became more hyperpolarized upon cocaine re-exposure. Moreover, the relative weight of excitatory and inhibitory inputs to NAc MSNs was significantly decreased after 1-d cocaine withdrawal, increased after 21-d withdrawal, and returned to the basal level upon cocaine re-exposure after 21-d withdrawal. These results, taken together with previous results showing cocaine-induced adaptations at excitatory synapses and intrinsic membrane excitability of NAc MSNs, may provide a relatively thorough picture of the functional state of NAc MSNs following cocaine exposure. PMID:23595733

  1. Effect of conduction block at axon bifurcations on synaptic transmission to different postsynaptic neurones in the leech.

    PubMed Central

    Gu, X N

    1991-01-01

    1. The cutaneous receptive field of the medial pressure (mP) sensory neurone in the leech has been examined. The cell has one major receptive field and an anterior and a posterior minor receptive field, principally on lateral and dorsal skin. The two minor receptive fields are contiguous with the major receptive field and are innervated by fine anterior and posterior axons, but there is no overlap between major and minor receptive fields. 2. At low frequencies of stimulation of the minor receptive fields, conduction block takes place in the mP cell at the central branch point within the leech ganglion. 3. The mP cell synapses directly with many other cells in the leech ganglion, including the anterior pagoda (AP) cell, longitudinal (L) motoneurone and the annulus erector (AE) motoneurone, which were studied as a group of postsynaptic neurones. Conduction block in the mP cell affects its synaptic transmission to all three postsynaptic neurones, but the effect can be different in different postsynaptic neurones. Block at the central branch point for an impulse travelling along the anterior axon reduces transmission to the AE cell much more than to the AP or L cells, while block at the central branch for an impulse travelling along the posterior axon has the reverse effect. 4. The distribution of functional connections of the branches of the mP cell with each postsynaptic cell was studied. For this analysis, branches of the mP cell were selectively silenced either during conduction block or by laser microsurgery. Generally, nearly all of the functional connections with the L and AP cell are made by anterior branches of the mP cell while the connection with the AE cell was primarily made by posterior branches of the mP cell. 5. The possible sites of contact between the mP cell and postsynaptic cells were determined by injecting separate markers into the mP cell and a postsynaptic cell. In confirmation of physiology, the mP cell's posterior branches had few, if any

  2. 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

  3. Synaptic Transmission from Horizontal Cells to Cones Is Impaired by Loss of Connexin Hemichannels

    PubMed Central

    Klaassen, Lauw J.; Sun, Ziyi; Steijaert, Marvin N.; Bolte, Petra; Fahrenfort, Iris; Sjoerdsma, Trijntje; Klooster, Jan; Claassen, Yvonne; Shields, Colleen R.; Ten Eikelder, Huub M. M.; Janssen-Bienhold, Ulrike; Zoidl, Georg; McMahon, Douglas G.; Kamermans, Maarten

    2011-01-01

    long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina. PMID:21811399

  4. 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.

  5. Increased Excitability and Excitatory Synaptic Transmission During in Vitro Ischemia in the Neonatal Mouse Hippocampus

    PubMed Central

    Santina Zanelli, A; Karthik Rajasekaran, K; Denise Grosenbaugh, K; Kapur, Jaideep

    2015-01-01

    Objective The present study tested the hypothesis that exposure to in vitro hypoxia-ischemia alters membrane properties and excitability as well as excitatory synaptic transmission of CA1 pyramidal neurons in the neonatal mouse. Methods Experiments were conducted in hippocampal slices in P7-P9 C57Bl/6 mice using whole-cell patch clamp in current- and voltage-clamp mode. Passive (membrane potential Vm, input resistance (Rin) and active (action potential (AP) threshold and amplitude) membrane properties of CA1 pyramidal neurons were assessed at baseline, during 10 min in vitro ischemia (oxygen-glucose deprivation (OGD)) and during reoxygenation. Spontaneous and miniature excitatory post-synaptic currents (s and mEPSCs) were studied under similar conditions. Results OGD caused significant depolarization of CA1 pyramidal neurons as well as decrease in AP threshold and increase in AP amplitude. These changes were blocked by the application of tetrodotoxin, indicating Na+ channels involvement. Following 10 min of reoxygenation, significant membrane hyperpolarization was noted and it was associated with a decrease in Rin. AP threshold and amplitude returned to baseline during that stage. sEPSC and mEPSC frequency increased during both OGD and reoxygenation but their amplitude remained unchanged. Additionally, we found that OGD decreases Ih (hyperpolarization activated depolarizing current) in CA1 neurons from neonatal mice and this effect persists during reoxygenation. Significance These results indicate that in vitro ischemia leads to changes in membrane excitability mediated by sodium and potassium channels. Further, it results in enhanced neurotransmitter release from presynaptic terminals. These changes are likely to represent one of the mechanisms of hypoxia/ischemia-mediated seizures in the neonatal period. PMID:26404876

  6. Histamine H3 receptor-mediated inhibition of excitatory synaptic transmission in the rat dentate gyrus in vivo.

    PubMed

    Chang, M; Saito, H; Abe, K

    1998-07-01

    We investigated the effects of histamine H3-receptor ligands on hippocampal synaptic transmission by using anesthetized rats in vivo. The medial perforant path was stimulated, and the population excitatory postsynaptic potential (pEPSP) and population spike were recorded from the granule cell layer of the dentate gyrus. Intracerebroventricular injection of the H3-receptor agonist (R)-alpha-methylhistamine decreased both the pEPSP and population spike, while H3-receptor antagonists, clobenpropit and thioperamide, increased both the pEPSP and population spike. These results suggest that the histaminergic system plays a role in inhibition of hippocampal synaptic excitation via the H3 receptor.

  7. VIP enhances both pre- and postsynaptic GABAergic transmission to hippocampal interneurones leading to increased excitatory synaptic transmission to CA1 pyramidal cells.

    PubMed

    Cunha-Reis, Diana; Sebastião, Ana M; Wirkner, Kerstin; Illes, Peter; Ribeiro, Joaquim Alexandre

    2004-11-01

    Vasoactive intestinal peptide (VIP) is present in the hippocampus in three subtypes of GABAergic interneurones, two of which innervate preferentially other interneurones, responsible for pyramidal cell inhibition. We investigated how pre- and postsynaptic modulation of GABAergic transmission (to both pyramidal cells and interneurones) by VIP could influence excitatory synaptic transmission in the CA1 area of the hippocampus. VIP (0.1-100 nM) increased [(3)H]GABA release from hippocampal synaptosomes (maximum effect at 1 nM VIP; 63.8 +/- 4.0%) but did not change [(3)H]glutamate release. VIP (0.3-30 nM) enhanced synaptic transmission in hippocampal slices (maximum effect at 1 nM VIP; field excitatory postsynaptic potentials (epsp) slope: 23.7 +/- 1.1%; population spike amplitude: 20.3 +/- 1.7%). The action on field epsp slope was fully dependent on GABAergic transmission since it was absent in the presence of picrotoxin (50 microM) plus CGP55845 (1 microM). VIP (1 nM) did not change paired-pulse facilitation but increased paired-pulse inhibition in CA1 pyramidal cells (16.0 +/- 0.9%), reinforcing the involvement of GABAergic transmission in the action of VIP. VIP (1 nM) increased muscimol-evoked inhibitory currents by 36.4 +/- 8.7% in eight out of ten CA1 interneurones in the stratum radiatum. This suggests that VIP promotes increased inhibition of interneurones that control pyramidal cells, leading to disinhibition of synaptic transmission to pyramidal cell dendrites. In conclusion, concerted pre- and postsynaptic actions of VIP lead to disinhibition of pyramidal cell dendrites causing an enhancement of synaptic transmission.

  8. Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour

    PubMed Central

    Hernández-Hernández, Oscar; Guiraud-Dogan, Céline; Sicot, Géraldine; Huguet, Aline; Luilier, Sabrina; Steidl, Esther; Saenger, Stefanie; Marciniak, Elodie; Obriot, Hélène; Chevarin, Caroline; Nicole, Annie; Revillod, Lucile; Charizanis, Konstantinos; Lee, Kuang-Yung; Suzuki, Yasuhiro; Kimura, Takashi; Matsuura, Tohru; Cisneros, Bulmaro; Swanson, Maurice S.; Trovero, Fabrice; Buisson, Bruno; Bizot, Jean-Charles; Hamon, Michel; Humez, Sandrine; Bassez, Guillaume; Metzger, Friedrich; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève

    2013-01-01

    Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology. PMID:23404338

  9. Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour.

    PubMed

    Hernández-Hernández, Oscar; Guiraud-Dogan, Céline; Sicot, Géraldine; Huguet, Aline; Luilier, Sabrina; Steidl, Esther; Saenger, Stefanie; Marciniak, Elodie; Obriot, Hélène; Chevarin, Caroline; Nicole, Annie; Revillod, Lucile; Charizanis, Konstantinos; Lee, Kuang-Yung; Suzuki, Yasuhiro; Kimura, Takashi; Matsuura, Tohru; Cisneros, Bulmaro; Swanson, Maurice S; Trovero, Fabrice; Buisson, Bruno; Bizot, Jean-Charles; Hamon, Michel; Humez, Sandrine; Bassez, Guillaume; Metzger, Friedrich; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève; Gomes-Pereira, Mário

    2013-03-01

    Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology.

  10. A neurodegenerative disease affecting synaptic connections in Drosophila mutant for the tumor suppressor morphogen Patched

    PubMed Central

    Gazi, Michal; Shyamala, Baragur V.; Bhat, Krishna Moorthi

    2009-01-01

    The tumor-suppressor morphogen, Patched (Ptc), has extensive homology to the Niemann-Pick-C 1 (NPC1) protein. The NPC disease is a paediatric, progressive and fatal neurodegenerative disorder thought to be due to an abnormal accumulation of cholesterol in neurons. Here, we report that patched mutant adults develop a progressive neurodegenerative disease and their brain contains membranous and lamellar inclusions. There is also a significant reduction in the number of synaptic terminals in the brain of the mutant adults. Interestingly, feeding cholesterol to wild type flies generates inclusions in the brain, but does not cause the disease. However, feeding cholesterol to mutant flies increases synaptic connections and suppresses the disease. Our results suggest that sequestration of cholesterol in the mutant brain in the form of membranous material and inclusions affects available pool of cholesterol for cellular functions. This, in turn, negatively affects the synaptic number and contributes to the disease-state. Consistent with this, in ptc mutants there is a reduction in the pool of cholesterol esters, and cholesterol-mediated suppression of the disease accompanies an increase in cholesterol esters. We further show that Ptc does not function directly in this process since gain-of-function for Hedgehog also induces the same disease with a reduction in the level of cholesterol esters. We believe that loss of function for ptc causes neurodegeneration via two distinct ways: de-repression of genes that interfere with lipid trafficking, and de-repression of genes outside of the lipid trafficking; the functions of both classes of genes ultimately converge on synaptic connections. PMID:19635474

  11. Non-additive modulation of synaptic transmission by serotonin, adenosine, and cholinergic modulators in the sensory thalamus.

    PubMed

    Yang, Ya-Chin; Hu, Chun-Chang; Lai, Yi-Chen

    2015-01-01

    The thalamus relays sensory information to the cortex. Oscillatory activities of the thalamocortical network are modulated by monoamines, acetylcholine, and adenosine, and could be the key features characteristic of different vigilance states. Although the thalamus is almost always subject to the actions of more than just one neuromodulators, reports on the modulatory effect of coexisting neuromodulators on thalamic synaptic transmission are unexpectedly scarce. We found that, if present alone, monoamine or adenosine decreases retinothalamic synaptic strength and short-term depression, whereas cholinergic modulators generally enhance postsynaptic response to presynaptic activity. However, coexistence of different modulators tends to produce non-additive effect, not predictable based on the action of individual modulators. Acetylcholine, acting via nicotinic receptors, can interact with either serotonin or adenosine to abolish most short-term synaptic depression. Moreover, the coexistence of adenosine and monoamine, with or without acetylcholine, results in robustly decreased synaptic strength and transforms short-term synaptic depression to facilitation. These findings are consistent with a view that acetylcholine is essential for an "enriched" sensory flow through the thalamus, and the flow is trimmed down by concomitant monoamine or adenosine (presumably for the wakefulness and rapid-eye movement, or REM, sleep states, respectively). In contrast, concomitant adenosine and monoamine would lead to a markedly "deprived" (and high-pass filtered) sensory flow, and thus the dramatic decrease of monoamine may constitute the basic demarcation between non-REM and REM sleep. The collective actions of different neuromodulators on thalamic synaptic transmission thus could be indispensable for the understanding of network responsiveness in different vigilance states.

  12. Dysfunctional Astrocytic and Synaptic Regulation of Hypothalamic Glutamatergic Transmission in a Mouse Model of Early-Life Adversity: Relevance to Neurosteroids and Programming of the Stress Response

    PubMed Central

    Gunn, Benjamin G.; Cunningham, Linda; Cooper, Michelle A.; Corteen, Nicole L.; Seifi, Mohsen; Swinny, Jerome D.; Lambert, Jeremy J.

    2013-01-01

    Adverse early-life experiences, such as poor maternal care, program an abnormal stress response that may involve an altered balance between excitatory and inhibitory signals. Here, we explored how early-life stress (ELS) affects excitatory and inhibitory transmission in corticotrophin-releasing factor (CRF)-expressing dorsal-medial (mpd) neurons of the neonatal mouse hypothalamus. We report that ELS associates with enhanced excitatory glutamatergic transmission that is manifested as an increased frequency of synaptic events and increased extrasynaptic conductance, with the latter associated with dysfunctional astrocytic regulation of glutamate levels. The neurosteroid 5α-pregnan-3α-ol-20-one (5α3α-THPROG) is an endogenous, positive modulator of GABAA receptors (GABAARs) that is abundant during brain development and rises rapidly during acute stress, thereby enhancing inhibition to curtail stress-induced activation of the hypothalamic-pituitary-adrenocortical axis. In control mpd neurons, 5α3α-THPROG potently suppressed neuronal discharge, but this action was greatly compromised by prior ELS exposure. This neurosteroid insensitivity did not primarily result from perturbations of GABAergic inhibition, but rather arose functionally from the increased excitatory drive onto mpd neurons. Previous reports indicated that mice (dams) lacking the GABAAR δ subunit (δ0/0) exhibit altered maternal behavior. Intriguingly, δ0/0 offspring showed some hallmarks of abnormal maternal care that were further exacerbated by ELS. Moreover, in common with ELS, mpd neurons of δ0/0 pups exhibited increased synaptic and extrasynaptic glutamatergic transmission and consequently a blunted neurosteroid suppression of neuronal firing. This study reveals that increased synaptic and tonic glutamatergic transmission may be a common maladaptation to ELS, leading to enhanced excitation of CRF-releasing neurons, and identifies neurosteroids as putative early regulators of the stress

  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.

  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. Reduced ATP concentration as a basis for synaptic transmission failure during hypoxia in the in vitro guinea-pig hippocampus

    PubMed Central

    Lipton, Peter; Whittingham, Tim S.

    1982-01-01

    1. Experiments were performed to determine whether a decrease in tissue ATP contributes to the rapid failure of cerebral synaptic transmission during hypoxia. Transmission between the perforant path and the dentate granule cells in the in vitro hippocampus was studied. 2. Hippocampal slice ATP is decreased by ∼ 15% at the time that the evoked response begins to diminish in standard Krebs bicarbonate buffer. This is about 2 min after the onset of hypoxia. 3. When transmission failure is accelerated by increasing extracellular K+ from 4·4 to 13·4 mM, the evoked response begins to decay about 30 sec after exposure to hypoxia. There is no decrease in hippocampal slice ATP at this time. 4. However, ATP in the molecular layer (the synaptic region of the tissue) is decreased by ∼ 15% at the time the evoked response begins to decay in the slices exposed to elevated K+ concentration. 5. Exposing the hippocampal slice to 25 mM-creatine for 3 hr elevates molecular layer phosphocreatine fourfold. Synaptic transmission during hypoxia survives three times as long as it does in the absence of creatine. 6. In the creatine fortified medium, molecular layer ATP no longer declines within 30 sec of hypoxia. However the molecular layer ATP does decline within 90 sec of hypoxia, the time at which the evoked response begins to decay in this creatine-fortified buffer. 7. The results establish that ATP in the region of the active synapses is lowered when the first signs of electrophysiological failure appear during hypoxia. They also show that maintaining ATP for longer than normal during hypoxia is associated with a prolonged maintenance of the evoked response. They thus suggest that a decline in ATP is one factor causing hypoxic block of synaptic transmission. 8. It is further suggested that the very rapid failure of the electroencephalogram during anoxia may also result from a decline in ATP. PMID:6286944

  16. 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.

  17. Long-term potentiation of GABAergic synaptic transmission in neonatal rat hippocampus.

    PubMed

    Caillard, O; Ben-Ari, Y; Gaiarsa, J L

    1999-07-01

    1. The plasticity of GABAergic synapses was investigated in neonatal rat hippocampal slices obtained between postnatal days 3 and 6 using intracellular recording techniques. Ionotropic glutamate receptor antagonists were present throughout the experiments to isolate GABAA receptor-mediated postsynaptic potentials (GABAA PSPs) or currents (GABAA PSCs). 2. Repetitive depolarizing pulses (20 pulses, 0.5 s duration, at 0.1 Hz, each pulse generating 4-6 action potentials) induced a long-term potentiation in the slope and amplitude of the evoked GABAA PSPs and GABAA PSCs. 3. Long-term potentiation was prevented by intracellular injection of the calcium chelator BAPTA (50 mM), or when the voltage-dependent calcium channels blockers Ni2+ (50 microM) and nimodipine (10 microM) were bath applied. 4. Repetitive depolarizing pulses induced a persistent (over 1 h) increase in the frequency of spontaneous GABAA PSCs. 5. Repetitive depolarizing pulses induced a long-lasting increase in the frequency of miniature GABAA PSCs, without altering their amplitude or decay-time constant. 6. It is concluded that the postsynaptic activation of voltage-dependent calcium channels leads to a long-term potentiation of GABAergic synaptic transmission in neonatal rat hippocampus. This form of plasticity is expressed as an increase in the probability of GABA release or in the number of functional synapses, rather than as an upregulation of postsynaptic GABAA receptor numbers or conductance at functional synapses.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK channels

    PubMed Central

    Deng, Pan-Yue; Rotman, Ziv; Blundon, Jay A.; Cho, Yongcheol; Cui, Jianmin; Cavalli, Valeria; Zakharenko, Stanislav S.; Klyachko, Vitaly A.

    2013-01-01

    SUMMARY Loss of FMRP causes Fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx and elevated neurotransmitter release. The AP broadening defects caused by FMRP loss have a cell-autonomous presynaptic origin and can be acutely rescued in postnatal neurons. These presynaptic actions of FMRP are translation-independent and are mediated selectively by BK channels via interaction of FMRP with BK channel’s regulatory β4 subunits. Information-theoretical analysis demonstrates that loss of these FMRP functions causes marked dysregulation of synaptic information transmission. FMRP-dependent AP broadening is not limited to the hippocampus, but also occurs in cortical pyramidal neurons. Our results thus suggest major translation-independent presynaptic functions of FMRP that may have important implications for understanding FXS neuropathology. PMID:23439122

  3. Dynasore blocks evoked release while augmenting spontaneous synaptic transmission from primary visceral afferents.

    PubMed

    Hofmann, Mackenzie E; Andresen, Michael C

    2017-01-01

    The recycling of vesicle membrane fused during exocytosis is essential to maintaining neurotransmission. The GTPase dynamin is involved in pinching off membrane to complete endocytosis and can be inhibited by dynasore resulting in activity-dependent depletion of release-competent synaptic vesicles. In rat brainstem slices, we examined the effects of dynasore on three different modes of glutamate release-spontaneous, evoked, and asynchronous release-at solitary tract (ST) inputs to neurons in the nucleus of the solitary tract (NTS). Intermittent bursts of stimuli to the ST interspersed with pauses in stimulation allowed examination of these three modes in each neuron continuously. Application of 100 μM dynasore rapidly increased the spontaneous EPSC (sEPSC) frequency which was followed by inhibition of both ST-evoked EPSCs (ST-EPSC) as well as asynchronous EPSCs. The onset of ST-EPSC failures was not accompanied by amplitude reduction-a pattern more consistent with conduction block than reduced probability of vesicle release. Neither result suggested that dynasore interrupted endocytosis. The dynasore response profile resembled intense presynaptic TRPV1 activation. The TRPV1 antagonist capsazepine failed to prevent dynasore increases in sEPSC frequency but did prevent the block of the ST-EPSC. In contrast, the TRPV1 antagonist JNJ 17203212 prevented both actions of dynasore in neurons with TRPV1-expressing ST inputs. In a neuron lacking TRPV1-expressing ST inputs, however, dynasore promptly increased sEPSC rate followed by block of ST-evoked EPSCs. Together our results suggest that dynasore actions on ST-NTS transmission are TRPV1-independent and changes in glutamatergic transmission are not consistent with changes in vesicle recycling and endocytosis.

  4. Dynasore blocks evoked release while augmenting spontaneous synaptic transmission from primary visceral afferents

    PubMed Central

    Andresen, Michael C.

    2017-01-01

    The recycling of vesicle membrane fused during exocytosis is essential to maintaining neurotransmission. The GTPase dynamin is involved in pinching off membrane to complete endocytosis and can be inhibited by dynasore resulting in activity-dependent depletion of release-competent synaptic vesicles. In rat brainstem slices, we examined the effects of dynasore on three different modes of glutamate release–spontaneous, evoked, and asynchronous release–at solitary tract (ST) inputs to neurons in the nucleus of the solitary tract (NTS). Intermittent bursts of stimuli to the ST interspersed with pauses in stimulation allowed examination of these three modes in each neuron continuously. Application of 100 μM dynasore rapidly increased the spontaneous EPSC (sEPSC) frequency which was followed by inhibition of both ST-evoked EPSCs (ST-EPSC) as well as asynchronous EPSCs. The onset of ST-EPSC failures was not accompanied by amplitude reduction–a pattern more consistent with conduction block than reduced probability of vesicle release. Neither result suggested that dynasore interrupted endocytosis. The dynasore response profile resembled intense presynaptic TRPV1 activation. The TRPV1 antagonist capsazepine failed to prevent dynasore increases in sEPSC frequency but did prevent the block of the ST-EPSC. In contrast, the TRPV1 antagonist JNJ 17203212 prevented both actions of dynasore in neurons with TRPV1-expressing ST inputs. In a neuron lacking TRPV1-expressing ST inputs, however, dynasore promptly increased sEPSC rate followed by block of ST-evoked EPSCs. Together our results suggest that dynasore actions on ST-NTS transmission are TRPV1-independent and changes in glutamatergic transmission are not consistent with changes in vesicle recycling and endocytosis. PMID:28358887

  5. Slow synaptic transmission mediated by TRPV1 channels in CA3 interneurons of the hippocampus.

    PubMed

    Eguchi, Noriomi; Hishimoto, Akitoyo; Sora, Ichiro; Mori, Masahiro

    2016-03-11

    Metabotropic glutamate receptors (mGluRs) modulate various neuronal functions in the central nervous system. Many studies reported that mGluRs have linkages to neuronal disorders such as schizophrenia and autism related disorders, indicating that mGluRs are involved in critical functions of the neuronal circuits. To study this possibility further, we recorded mGluR-induced synaptic responses in the interneurons of the CA3 stratum radiatum using rat hippocampal organotypic slice cultures. Electrical stimulation in the CA3 pyramidal cell layer evoked a slow inward current in the interneurons at a holding potential of -70mV in the presence of antagonists for AMPA/kainate receptors, NMDA receptors, GABAA receptors and GABAB receptors. The slow inward current was blocked in the absence of extracellular calcium, suggesting that this was a synaptic response. The slow excitatory postsynaptic current (EPSC) reversed near 0mV, reflecting an increase in a non-selective cationic conductance. The slow EPSC is mediated by group I mGluRs, as it was blocked by AP3, a group I mGluR antagonist. Neither a calcium chelator BAPTA nor a phospholipase C (PLC) inhibitor U73122 affected the slow EPSC. La(3+), a general TRP channel blocker or capsazepine, a selective TRPV1 channel antagonist significantly suppressed the slow EPSC. DHPG, a selective group I mGluRs agonist induced an inward current, which was suppressed by capsazepine. These results indicate that in the interneurons of the hippocampal CA3 stratum radiatum group I mGluRs activate TRPV1 channels independently of PLC and intracellular Ca(2+), resulting in the slow EPSC in the interneurons.

  6. Regulation of synaptic transmission at the Caenorhabditis elegans M4 neuromuscular junction by an antagonistic relationship between two calcium channels.

    PubMed

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

    2014-11-04

    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 Ca(2+) 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.

  7. Acid-Sensing Ion Channels Activated by Evoked Released Protons Modulate Synaptic Transmission at the Mouse Calyx of Held Synapse.

    PubMed

    González-Inchauspe, Carlota; Urbano, Francisco J; Di Guilmi, Mariano N; Uchitel, Osvaldo D

    2017-03-08

    Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in neurodegenerative diseases. We found that these channels can be activated in neurons of the medial nucleus of the trapezoid body (MNTB) of the auditory system in the CNS. A drop in extracellular pH induces transient inward ASIC currents (IASICs) in postsynaptic MNTB neurons from wild-type mice. The inhibition of IASICs by psalmotoxin-1 (PcTx1) and the absence of these currents in knock-out mice for ASIC-1a subunit (ASIC1a(-/-)) suggest that homomeric ASIC-1as are mediating these currents in MNTB neurons. Furthermore, we detect ASIC1a-dependent currents during synaptic transmission, suggesting an acidification of the synaptic cleft due to the corelease of neurotransmitter and H(+) from synaptic vesicles. These currents are capable of eliciting action potentials in the absence of glutamatergic currents. A significant characteristic of these homomeric ASIC-1as is their permeability to Ca(2+) Activation of ASIC-1a in MNTB neurons by exogenous H(+) induces an increase in intracellular Ca(2+) Furthermore, the activation of postsynaptic ASIC-1as during high-frequency stimulation (HFS) of the presynaptic nerve terminal leads to a PcTx1-sensitive increase in intracellular Ca(2+) in MNTB neurons, which is independent of glutamate receptors and is absent in neurons from ASIC1a(-/-) mice. During HFS, the lack of functional ASICs in synaptic transmission results in an enhanced short-term depression of glutamatergic EPSCs. These results strongly support the hypothesis of protons as neurotransmitters and demonstrate that presynaptic released protons modulate synaptic transmission by activating ASIC-1as at the calyx of Held-MNTB synapse.SIGNIFICANCE STATEMENT The manuscript demonstrates that postsynaptic neurons of the medial nucleus of the trapezoid body at the mouse calyx of Held synapse express functional homomeric Acid-sensing ion channel-1a (ASIC-1as) that can be activated by protons

  8. 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

  9. 3D analysis of synaptic vesicle density and distribution after acute foot-shock stress by using serial section transmission electron microscopy.

    PubMed

    Khanmohammadi, M; Darkner, S; Nava, N; Nyengaard, J R; Wegener, G; Popoli, M; Sporring, J

    2017-01-01

    Behavioural stress has shown to strongly affect neurotransmission within the neocortex. In this study, we analysed the effect of an acute stress model on density and distribution of neurotransmitter-containing vesicles within medial prefrontal cortex. Serial section transmission electron microscopy was employed to compare two groups of male rats: (1) rats subjected to foot-shock stress and (2) rats with sham stress as control group. Two-dimensional (2D) density measures are common in microscopic images and are estimated by following a 2D path in-section. However, this method ignores the slant of the active zone and thickness of the section. In fact, the active zone is a surface in three-dimension (3D) and the 2D measures do not accurately reflect the geometric configuration unless the active zone is perpendicular to the sectioning angle. We investigated synaptic vesicle density as a function of distance from the active zone in 3D. We reconstructed a 3D dataset by estimating the thickness of all sections and by registering all the image sections into a common coordinate system. Finally, we estimated the density as the average number of vesicles per area and volume and modelled the synaptic vesicle distribution by fitting a one-dimensional parametrized distribution that took into account the location uncertainty due to section thickness. Our results showed a clear structural difference in synaptic vesicle density and distribution between stressed and control group with improved separation by 3D measures in comparison to the 2D measures. Our results showed that acute foot-shock stress exposure significantly affected both the spatial distribution and density of the synaptic vesicles within the presynaptic terminal.

  10. Histamine H3 receptor-mediated depression of synaptic transmission in the dentate gyrus of the rat in vitro.

    PubMed Central

    Brown, R E; Reymann, K G

    1996-01-01

    1. The effects of histamine on excitatory synaptic transmission in the dentate gyrus region of rat hippocampal slices were examined using extracellular and whole-cell patch-clamp recording techniques. The GABAA receptor antagonist picrotoxin (50 microM) was present in the bath in all experiments. 2. Histamine (0.7-70 microM) reversibly depressed field excitatory postsynaptic potentials (fEPSPs) or excitatory postsynaptic currents (EPSCs) recorded intracellularly by up to 30%. The presynaptic fibre volley and EPSC reversal potential were unaffected by histamine, as were responses following pressure ejection of the glutamate receptor agonist S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (S-AMPA) into the slice. 3. Histamine (7 microM) depressed equally the AMPA and N-methyl-D-aspartate (NMDA) components of the dual-component EPSC, recorded at -40 mV. 4. In addition to depressing synaptic transmission, histamine also reduced the magnitude of paired-pulse depression (PPD; 40 ms interpulse interval) of the medial perforant path EPSC. 5. Histamine depressed medial perforant path EPSCs more strongly than lateral perforant path EPSCs. Paired-pulse facilitation (PPF; 40 ms interpulse interval) in the lateral perforant path was enhanced by histamine. 6. The effects of histamine on synaptic transmission and PPD were mimicked by the selective H3 receptor agonist R-alpha-methylhistamine (0.1-10 microM) but not by the selective H2 receptor agonist dimaprit (10 microM). Similarly, the H3 receptor antagonist thioperamide (10 microM) blocked the effect of histamine whereas the H1 antagonist mepyramine (1 microM) and the H2 receptor antagonist cimetidine (50 microM) were ineffective. 7. Histamine actions on synaptic transmission and PPD were not occluded by application of the metabotropic glutamate agonist L-2-amino-4-phosphonobutyrate (AP4). 8. The results indicate that histamine depresses synaptic transmission in the dentate gyrus by binding to histamine H3 receptors

  11. 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

    2013-09-05

    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.

  12. GABAergic and glycinergic inhibitory synaptic transmission in the ventral cochlear nucleus studied in VGAT channelrhodopsin-2 mice.

    PubMed

    Xie, Ruili; Manis, Paul B

    2014-01-01

    Both glycine and GABA mediate inhibitory synaptic transmission in the ventral cochlear nucleus (VCN). In mice, the time course of glycinergic inhibition is slow in bushy cells and fast in multipolar (stellate) cells, and is proposed to contribute to the processing of temporal cues in both cell types. Much less is known about GABAergic synaptic transmission in this circuit. Electrical stimulation of the auditory nerve or the tuberculoventral pathway evokes little GABAergic synaptic current in brain slice preparations, and spontaneous GABAergic miniature synaptic currents occur infrequently. To investigate synaptic currents carried by GABA receptors in bushy and multipolar cells, we used transgenic mice in which channelrhodopsin-2 and EYFP is driven by the vesicular GABA transporter (VGAT-ChR2-EYFP) and is expressed in both GABAergic and glycinergic neurons. Light stimulation evoked action potentials in EYFP-expressing presynaptic cells, and evoked inhibitory postsynaptic potentials (IPSPs) in non-expressing bushy and planar multipolar cells. Less than 10% of the IPSP amplitude in bushy cells arose from GABAergic synapses, whereas 40% of the IPSP in multipolar neurons was GABAergic. In voltage clamp, glycinergic IPSCs were significantly slower in bushy neurons than in multipolar neurons, whereas there was little difference in the kinetics of the GABAergic IPSCs between two cell types. During prolonged stimulation, the ratio of steady state vs. peak IPSC amplitude was significantly lower for glycinergic IPSCs. Surprisingly, the reversal potentials of GABAergic IPSCs were negative to those of glycinergic IPSCs in both bushy and multipolar neurons. In the absence of receptor blockers, repetitive light stimulation was only able to effectively evoke IPSCs up to 20 Hz in both bushy and multipolar neurons. We conclude that local GABAergic release within the VCN can differentially influence bushy and multipolar cells.

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

    PubMed

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

    2015-06-17

    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 Ca(2+)/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.

  14. GABAergic and glycinergic inhibitory synaptic transmission in the ventral cochlear nucleus studied in VGAT channelrhodopsin-2 mice

    PubMed Central

    Xie, Ruili; Manis, Paul B.

    2014-01-01

    Both glycine and GABA mediate inhibitory synaptic transmission in the ventral cochlear nucleus (VCN). In mice, the time course of glycinergic inhibition is slow in bushy cells and fast in multipolar (stellate) cells, and is proposed to contribute to the processing of temporal cues in both cell types. Much less is known about GABAergic synaptic transmission in this circuit. Electrical stimulation of the auditory nerve or the tuberculoventral pathway evokes little GABAergic synaptic current in brain slice preparations, and spontaneous GABAergic miniature synaptic currents occur infrequently. To investigate synaptic currents carried by GABA receptors in bushy and multipolar cells, we used transgenic mice in which channelrhodopsin-2 and EYFP is driven by the vesicular GABA transporter (VGAT-ChR2-EYFP) and is expressed in both GABAergic and glycinergic neurons. Light stimulation evoked action potentials in EYFP-expressing presynaptic cells, and evoked inhibitory postsynaptic potentials (IPSPs) in non-expressing bushy and planar multipolar cells. Less than 10% of the IPSP amplitude in bushy cells arose from GABAergic synapses, whereas 40% of the IPSP in multipolar neurons was GABAergic. In voltage clamp, glycinergic IPSCs were significantly slower in bushy neurons than in multipolar neurons, whereas there was little difference in the kinetics of the GABAergic IPSCs between two cell types. During prolonged stimulation, the ratio of steady state vs. peak IPSC amplitude was significantly lower for glycinergic IPSCs. Surprisingly, the reversal potentials of GABAergic IPSCs were negative to those of glycinergic IPSCs in both bushy and multipolar neurons. In the absence of receptor blockers, repetitive light stimulation was only able to effectively evoke IPSCs up to 20 Hz in both bushy and multipolar neurons. We conclude that local GABAergic release within the VCN can differentially influence bushy and multipolar cells. PMID:25104925

  15. Impaired neural transmission and synaptic plasticity in superior cervical ganglia from β-amyloid rat model of Alzheimer's disease.

    PubMed

    Alzoubi, K H; Alhaider, I A; Tran, T T; Mosely, A; Alkadhi, K K

    2011-06-01

    Basal synaptic transmission and activity-dependent synaptic plasticity were evaluated in superior cervical sympathetic ganglia (SCG) of amyloid-β rat model of Alzheimer's disease (Aβ rat) using electrophysiological and molecular techniques. Rats were administered Aβ peptides (a mixture of 1:1 Aβ1-40 and Aβ1-42) by chronic intracerebroventricular infusion via 14-day mini-osmotic pumps (300 pmol/day). Control rats received Aβ40-1 (inactive reverse peptide: 300 pmol/day). Ganglionic compound action potentials were recorded before (basal) and after repetitive stimulation. In isolated SCG, ganglionic long-term potentiation (gLTP) was generated by a brief train of stimuli (20Hz for 20s) and ganglionic long-term depression (gLTD) was produced with trains of paired pulses. The input/output (I/O) curves of ganglia from Aβ rats showed a marked downward shift along all stimulus intensities, compared to those of ganglia from control animals, indicating impaired basal synaptic transmission. In addition, repetitive stimulation induced robust gLTP and gLTD in ganglia isolated from control animals, but, the same protocols failed to induce gLTP or gLTD in ganglia from Aβ rats indicating impairment of activity-dependent synaptic plasticity in these animals. Western blotting of SCG homogenate from Aβ rats revealed reduction in the ratio of phosphorylated-/total-CaMKII and in calcineurin protein levels. Although other mechanisms could be involved, these changes in signaling molecules could represent an important molecular mechanism linked to the failure to express synaptic plasticity in Aβ rat ganglia. Results of the current study could explain some of the peripheral nervous system manifestations of Alzheimer's disease.

  16. Prenatal melamine exposure impairs spatial cognition and hippocampal synaptic plasticity by presynaptic and postsynaptic inhibition of glutamatergic transmission in adolescent offspring.

    PubMed

    An, Lei; Sun, Wei

    2017-03-05

    Our previous studies showed that prenatal melamine exposure (PME) could impair spatial cognition and hippocampal long-term potentiation (LTP). More importantly, the synaptic dysfunction induced by PME was associated with the probability of presynaptic glutamate release. Considering the crucial role of the other form of synaptic plasticity, long-term depression (LTD), in some types of learning and memory process, the aim of present study was to investigate if the hippocampal LTD and cognitive flexibility were affected. And then we attempted to explore the underlying mechanism. The animal model was produced by melamine exposure throughout gestational period with 400mg/kg bodyweight, the male offspring rats were used in the study. Morris water maze (MWM) test was performed, and then LTD was recorded from Schaffer collaterals to CA1 region in the hippocampus. Behavioral test showed that learning, reference memory and re-acquisition learning abilities were impaired significantly by PME. The field excitatory postsynaptic potentials (fEPSPs) slopes of LTD were significantly higher after PME. Furthermore, the data of whole-cell patch-clamp experiments showed that PME markedly diminished the frequencies of spontaneous EPSCs (sEPSCs) and simultaneously reduced the amplitude of sEPSCs. In conclusion, PME inhibited glutamate transmission presynaptically and postsynaptically which could contribute importantly to the depressed hippocampal synaptic plasticity and further induced cognitive deficits in MWM tests.

  17. Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats

    PubMed Central

    Petruska, Jeffrey C.; Kitay, Brandon; Boyce, Vanessa S.; Kaspar, Brian; Pearse, Damien; Gage, Fred H.; Mendell, Lorne M.

    2010-01-01

    We examined whether elevating levels of neurotrophin-3 (NT-3) in the spinal cord and dorsal root ganglion (DRG) would alter connections made by muscle spindle afferent fibers on motoneurons. Adeno-associated virus (AAV) serotypes AAV1, AAV2 and AAV5, selected for their tropism profile, were engineered with the NT-3 gene and administered to the medial gastrocnemius muscle in adult rats. ELISA studies in muscle, DRG and spinal cord revealed that NT-3 concentration in all tissues peaked about 3 months after a single viral injection; after 6 months NT-3 concentration returned to normal values. Intracellular recording in triceps surae motoneurons revealed complex electrophysiological changes. Moderate elevation in cord NT-3 resulted in diminished segmental excitatory postsynaptic potential (EPSP) amplitude, perhaps as a result of the observed decrease in motoneuron input resistance. With further elevation in NT-3 expression, the decline in EPSP amplitude was reversed indicating that NT-3 at higher concentration could increase EPSP amplitude. No correlation was observed between EPSP amplitude and NT-3 concentration in the DRG. Treatment with control viruses could elevate NT-3 levels minimally resulting in measurable electrophysiological effects, perhaps as a result of inflammation associated with injection. EPSPs elicited by stimulation of the ventrolateral funiculus underwent a consistent decline in amplitude independent of NT-3 level. These novel correlations between modified NT-3 expression and single-cell electrophysiological parameters indicate that intramuscular administration of AAV(NT-3) can exert long lasting effects on synaptic transmission to motoneurons. This approach to neurotrophin delivery could be useful in modifying spinal function after injury. PMID:20849530

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

    PubMed

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

    2015-01-01

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

  19. Implementing the cellular mechanisms of synaptic transmission in a neural mass model of the thalamo-cortical circuitry

    PubMed Central

    Bhattacharya, Basabdatta S.

    2013-01-01

    A novel direction to existing neural mass modeling technique is proposed where the commonly used “alpha function” for representing synaptic transmission is replaced by a kinetic framework of neurotransmitter and receptor dynamics. The aim is to underpin neuro-transmission dynamics associated with abnormal brain rhythms commonly observed in neurological and psychiatric disorders. An existing thalamocortical neural mass model is modified by using the kinetic framework for modeling synaptic transmission mediated by glutamatergic and GABA (gamma-aminobutyric-acid)-ergic receptors. The model output is compared qualitatively with existing literature on in vitro experimental studies of ferret thalamic slices, as well as on single-neuron-level model based studies of neuro-receptor and transmitter dynamics in the thalamocortical tissue. The results are consistent with these studies: the activation of ligand-gated GABA receptors is essential for generation of spindle waves in the model, while blocking this pathway leads to low-frequency synchronized oscillations such as observed in slow-wave sleep; the frequency of spindle oscillations increase with increased levels of post-synaptic membrane conductance for AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid) receptors, and blocking this pathway effects a quiescent model output. In terms of computational efficiency, the simulation time is improved by a factor of 10 compared to a similar neural mass model based on alpha functions. This implies a dramatic improvement in computational resources for large-scale network simulation using this model. Thus, the model provides a platform for correlating high-level brain oscillatory activity with low-level synaptic attributes, and makes a significant contribution toward advancements in current neural mass modeling paradigm as a potential computational tool to better the understanding of brain oscillations in sickness and in health. PMID:23847522

  20. Prenatal caffeine intake differently affects synaptic proteins during fetal brain development.

    PubMed

    Mioranzza, Sabrina; Nunes, Fernanda; Marques, Daniela M; Fioreze, Gabriela T; Rocha, Andréia S; Botton, Paulo Henrique S; Costa, Marcelo S; Porciúncula, Lisiane O

    2014-08-01

    Caffeine is the psychostimulant most consumed worldwide. However, little is known about its effects during fetal brain development. In this study, adult female Wistar rats received caffeine in drinking water (0.1, 0.3 and 1.0 g/L) during the active cycle in weekdays, two weeks before mating and throughout pregnancy. Cerebral cortex and hippocampus from embryonic stages 18 or 20 (E18 or E20, respectively) were collected for immunodetection of the following synaptic proteins: brain-derived neurotrophic factor (BDNF), TrkB receptor, Sonic Hedgehog (Shh), Growth Associated Protein 43 (GAP-43) and Synaptosomal-associated Protein 25 (SNAP-25). Besides, the estimation of NeuN-stained nuclei (mature neurons) and non-neuronal nuclei was verified in both brain regions and embryonic periods. Caffeine (1.0 g/L) decreased the body weight of embryos at E20. Cortical BDNF at E18 was decreased by caffeine (1.0 g/L), while it increased at E20, with no major effects on TrkB receptors. In the hippocampus, caffeine decreased TrkB receptor only at E18, with no effects on BDNF. Moderate and high doses of caffeine promoted an increase in Shh in both brain regions at E18, and in the hippocampus at E20. Caffeine (0.3g/L) decreased GAP-43 only in the hippocampus at E18. The NeuN-stained nuclei increased in the cortex at E20 by lower dose and in the hippocampus at E18 by moderate dose. Our data revealed that caffeine transitorily affect synaptic proteins during fetal brain development. The increased number of NeuN-stained nuclei by prenatal caffeine suggests a possible acceleration of the telencephalon maturation. Although some modifications in the synaptic proteins were transient, our data suggest that caffeine even in lower doses may alter the fetal brain development.

  1. 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.

  2. Dopaminergic enhancement of excitatory synaptic transmission in layer II entorhinal neurons is dependent on D₁-like receptor-mediated signaling.

    PubMed

    Glovaci, I; Caruana, D A; Chapman, C A

    2014-01-31

    The modulatory neurotransmitter dopamine induces concentration-dependent changes in synaptic transmission in the entorhinal cortex, in which high concentrations of dopamine suppress evoked excitatory postsynaptic potentials (EPSPs) and lower concentrations induce an acute synaptic facilitation. Whole-cell current-clamp recordings were used to investigate the dopaminergic facilitation of synaptic responses in layer II neurons of the rat lateral entorhinal cortex. A constant bath application of 1 μM dopamine resulted in a consistent facilitation of EPSPs evoked in layer II fan cells by layer I stimulation; the size of the facilitation was more variable in pyramidal neurons, and synaptic responses in a small group of multiform neurons were not modulated by dopamine. Isolated inhibitory synaptic responses were not affected by dopamine, and the facilitation of EPSPs was not associated with a change in paired-pulse facilitation ratio. Voltage-clamp recordings of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor-mediated excitatory postsynaptic currents (EPSCs) were facilitated by dopamine, but N-methyl-D-aspartate receptor-mediated currents were not. Bath application of the dopamine D₁-like receptor blocker SCH23390 (50 μM), but not the D₂-like receptor blocker sulpiride (50 μM), prevented the facilitation, indicating that it is dependent upon D₁-like receptor activation. Dopamine D₁ receptors lead to activation of protein kinase A (PKA), and including the PKA inhibitor H-89 or KT 5720 in the recording pipette solution prevented the facilitation of EPSCs. PKA-dependent phosphorylation of inhibitor 1 or the dopamine- and cAMP-regulated protein phosphatase (DARPP-32) can lead to a facilitation of AMPA receptor responses by inhibiting the activity of protein phosphatase 1 (PP1) that reduces dephosphorylation of AMPA receptors, and we found here that inhibition of PP1 occluded the facilitatory effect of dopamine. The dopamine

  3. 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

  4. Mechanisms of hydrogen sulfide (H2S) action on synaptic transmission at the mouse neuromuscular junction.

    PubMed

    Gerasimova, E; Lebedeva, J; Yakovlev, A; Zefirov, A; Giniatullin, R; Sitdikova, G

    2015-09-10

    Hydrogen sulfide (H2S) is a widespread gasotransmitter also known as a powerful neuroprotective agent in the central nervous system. However, the action of H2S in peripheral synapses is much less studied. In the current project we studied the modulatory effects of the H2S donor sodium hydrosulfide (NaHS) on synaptic transmission in the mouse neuromuscular junction using microelectrode technique. Using focal recordings of presynaptic response and evoked transmitter release we have shown that NaHS (300 μM) increased evoked end-plate currents (EPCs) without changes of presynaptic waveforms which indicated the absence of NaHS effects on sodium and potassium currents of motor nerve endings. Using intracellular recordings it was shown that NaHS increased the frequency of miniature end-plate potentials (MEPPs) without changing their amplitudes indicating a pure presynaptic effect. Furthermore, NaHS increased the amplitude of end-plate potentials (EPPs) without influencing the resting membrane potential of muscle fibers. L-cysteine, a substrate of H2S synthesis induced, similar to NaHS, an increase of EPC amplitudes whereas inhibitors of H2S synthesis (β-cyano-L-alanine and aminooxyacetic acid) had the opposite effect. Inhibition of adenylate cyclase using MDL 12,330A hydrochloride (MDL 12,330A) or elevation of cAMP level with 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (pCPT-cAMP) completely prevented the facilitatory action of NaHS indicating involvement of the cAMP signaling cascade. The facilitatory effect of NaHS was significantly diminished when intracellular calcium (Ca(2+)) was buffered by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis acetoxymethyl ester (BAPTA-AM) and ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid acetoxymethyl ester (EGTA-AM). Activation of ryanodine receptors by caffeine or ryanodine increased acetylcholine release and prevented further action of NaHS on transmitter release, likely due to

  5. Temperature sensitivity of graded synaptic transmission in the lobster stomatogastric ganglion.

    PubMed

    Johnson, B R; Peck, J H; Harris-Warrick, R M

    1991-03-01

    We examined the temperature sensitivity of graded chemical synaptic strength within the pyloric circuit of the spiny lobster stomatogastric ganglion. Cooling from 20.4 degrees C to 11.3 degrees C reduced the graded synaptic potential (GSP) amplitude at all six pyloric synapses tested. Cooling appeared to reduce the slope of the linear part of the input-output curve at three of these synapses, and did not significantly alter the threshold for transmitter release at any synapses. Pairs of neurons with a presynaptic pyloric dilator (PD) cell showed reductions in graded synaptic strength at 16.5 degrees C but those with presynaptic lateral pyloric (LP) or ventral dilator (VD) cells did not. A generalized decrease in input resistance is not responsible for the reduced GSP amplitude upon cooling, as determined by input resistance, action potential amplitude and electrical coupling measurements. We conclude that cooling reduces graded chemical strength by a direct synaptic action. Since the PD and VD cells use the same transmitter and act on some of the same postsynaptic cells, their differential sensitivity to cooling further suggests a presynaptic site of action. The temperature range used in our experiments encompasses the range that the animal normally encounters in nature. Thus, the relative importance of graded synaptic interactions in generating the pyloric motor rhythm may vary with transient changes in temperature.

  6. Ethanol inhibits epileptiform activity and NMDA receptor-mediated synaptic transmission in rat amygdaloid slices

    SciTech Connect

    Gean, P.W. )

    1992-02-26

    The effect of ethanol on the epileptiform activity induced by Mg{sup ++}-free solution was studied in rat amygdalar slices using intracellular recording techniques. The spontaneous and evoked epileptiform discharges consisting of an initial burst followed by afterdischarges were observed 20-30 min after switching to Mg{sup ++}-free medium. Superfusion with ethanol reversibly reduced the duration of spontaneous and evoked bursting discharges in a concentration-dependent manner. Synaptic response mediated by N-methyl-D-aspartate (NMDA) receptor activation was isolated by application of a solution containing the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and either in Mg{sup ++}-free solution or in the presence of 50 {mu}M bicuculline. Application of ethanol reversibly suppressed the duration of NMDA receptor-mediated synaptic response. These results suggest that intoxicating concentrations of ethanol possess anticonvulsant activity through blocking the NMDA receptor-mediated synaptic excitation.

  7. 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

  8. Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain.

    PubMed

    Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru

    2013-01-01

    In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca(2+) indicator in the MBs, we investigated synaptic transmission and plasticity at the AL-MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca(2+) responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca(2+) responses were mediated through Drosophila NMDA receptors (dNRs). AL-MB synaptic transmission was enhanced more than 2 h after the simultaneous 'associative-stimulation' of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL-MB synapses but not at the AFV-MB synapses. AL-MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL-MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL-MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL-MB LTE might be a relevant cellular model for olfactory memory.

  9. Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain

    PubMed Central

    Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru

    2013-01-01

    In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca2+ indicator in the MBs, we investigated synaptic transmission and plasticity at the AL–MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca2+ responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca2+ responses were mediated through Drosophila NMDA receptors (dNRs). AL–MB synaptic transmission was enhanced more than 2 h after the simultaneous ‘associative-stimulation’ of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL–MB synapses but not at the AFV–MB synapses. AL–MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL–MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL–MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL–MB LTE might be a relevant cellular model for olfactory memory. PMID:23027817

  10. [Changes in the kinetics of quanta secretion-effective mechanism of synaptic transmission modulation].

    PubMed

    Bukharaeva, É A; Nikol'skiĭ, E E

    2010-08-01

    It is widely accepted that the leading presynaptic mechanisms underlying the synaptic plasticity involve changes of the number of neurotransmitter quanta released by one nerve pulse (the quantal content of postsynaptic response) and of the size of a single quantum. In addition, the existence of one more effective though previously ignored mechanism of modulation of synaptic plasticity was suggested related to the change in the time course (kinetics) of secretion of single neurotransmitter quanta forming the multiquantal response. This article reviews current data (including the authors' own results) on the kinetics of evoked neurotransmitter quanta secretion from motor nerve endings in peripheral synapses, mechanisms of their modulation and methods of quantitative analysis.

  11. Developmental enhancement of alpha2-adrenoceptor-mediated suppression of inhibitory synaptic transmission onto mouse cerebellar Purkinje cells.

    PubMed

    Hirono, M; Matsunaga, W; Chimura, T; Obata, K

    2008-09-22

    Noradrenaline (NA) modulates glutamatergic and GABAergic transmission in various areas of the brain. It is reported that some alpha2-adrenoceptor subtypes are expressed in the cerebellar cortex and alpha2-adrenoceptors may play a role in motor coordination. Our previous study demonstrated that the selective alpha2-adrenoceptor agonist clonidine partially depresses spontaneous inhibitory postsynaptic currents (sIPSCs) in mouse cerebellar Purkinje cells (PCs). Here we found that the inhibitory effect of clonidine on sIPSCs was enhanced during postnatal development. The activation of alpha2-adrenoceptors by clonidine did not affect sIPSCs in PCs at postnatal days (P) 8-10, when PCs showed a few sIPSCs and interneurons in the molecular layer (MLIs) did not cause action potential (AP). In the second postnatal week, the frequency of sIPSCs increased temporarily and reached a plateau at P14. By contrast, MLIs began to fire at P11 with the firing rate gradually increasing thereafter and reaching a plateau at P21. In parallel with this rise in the rate of firing, the magnitude of the clonidine-mediated inhibition of sIPSCs increased during postnatal development. Furthermore, the magnitude of the clonidine-mediated firing suppression in MLIs, which seemed to be mediated by a reduction in amplitude of the hyperpolarization-activated nonselective cation current, I(h), was constant across development. Both alpha2A- and alpha2B-, but not alpha2C-, adrenoceptors were strongly expressed in MLIs at P13, and P31. Therefore, the developmental enhancement of the clonidine-mediated inhibition of sIPSCs is attributed to an age-dependent increase in AP-derived sIPSCs, which can be blocked by clonidine. Thus, presynaptic activation of alpha2-adrenoceptors inhibits cerebellar inhibitory synaptic transmission after the second postnatal week, leading to a restriction of NA signaling, which is mainly mediated by alpha1- and beta2-adrenoceptors in the adult cerebellar neuronal circuit.

  12. A subnanomolar concentration of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) pre-synaptically modulates glutamatergic transmission in the rat hippocampus acting through acetylcholine.

    PubMed

    Pecoraro, Valeria; Sardone, Lara Maria; Chisari, Mariangela; Licata, Flora; Li Volsi, Guido; Perciavalle, Vincenzo; Ciranna, Lucia; Costa, Lara

    2017-01-06

    The neuropeptide PACAP modulates synaptic transmission in the hippocampus exerting multiple effects through different receptor subtypes: the underlying mechanisms have not yet been completely elucidated. The neurotransmitter acetylcholine (ACh) also exerts a well-documented modulation of hippocampal synaptic transmission and plasticity. Since PACAP was shown to stimulate ACh release in the hippocampus, we tested whether PACAP acting through ACh might indirectly modulate glutamate-mediated synaptic transmission at a pre- and/or at a post-synaptic level. Using patch clamp on rat hippocampal slices, we tested PACAP effects on stimulation-evoked AMPA receptor-mediated excitatory post-synaptic currents (EPSCsAMPA) in the CA3-CA1 synapse and on spontaneous miniature EPSCs (mEPSCs) in CA1 pyramidal neurons. A subnanomolar dose of PACAP (0.5nM) decreased EPSCsAMPA amplitude, enhanced EPSC paired-pulse facilitation (PPF) and reduced mEPSC frequency, indicating a pre-synaptic decrease of glutamate release probability: these effects were abolished by simultaneous blockade of muscarinic and nicotinic ACh receptors, indicating the involvement of endogenous ACh. The effect of subnanomolar PACAP was abolished by a PAC1 receptor antagonist but not by a VPAC receptor blocker. At a higher concentration (10nM), PACAP inhibited EPSCsAMPA: this effect persisted in the presence of ACh receptor antagonists and did not involve any change in PPF or in mEPSC frequency, thus was not mediated by ACh and was exerted post- synaptically on CA1 pyramidal neurons. We suggest that a high-affinity PAC1 receptor pre-synaptically modulates hippocampal glutamatergic transmission acting through ACh. Therefore, administration of PACAP at very low doses might be envisaged in cognitive diseases with reduced cholinergic transmission.

  13. Drosophila cdk5 is needed for locomotive behavior and NMJ elaboration, but seems dispensable for synaptic transmission.

    PubMed

    Kissler, Alexander E; Pettersson, Nina; Frölich, Andreas; Sigrist, Stephan J; Suter, Beat

    2009-05-01

    Cyclin-dependent kinase 5 (Cdk5) functions in postmitotic neuronal cells and play roles in cell differentiation, cell migration, axonal guidance, and synaptic function. Here, we demonstrate that Drosophila cdk5 is dispensable for adult viability and fertility, a feature that allows us to study its physiological function in the whole animal model. For the adult, cdk5 is needed for proper locomotion and flight performance. Larvae lacking cdk5 in the presynaptic tissue display abnormal crawling motion, and their neuromuscular junctions (NMJ) are elongated and contain a higher number of boutons that are smaller. As a result of these two counteracting effects, the total synaptic area/NMJ is similar to wild type, leading to normal synaptic transmission, indicating that a compensatory mechanism is capable of correcting the problem caused by the lack of cdk5. futsch, the Drosophila MAP1B homolog, is also involved in NMJ morphogenesis, and analysis of the NMJ phenotype of the double mutant futsch(K68); cdk5(-) indicates that cdk5 is epistatic to futsch in this process.

  14. 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.

  15. Synaptic transmission from splanchnic nerves to the adrenal medulla of guinea-pigs.

    PubMed Central

    Holman, M E; Coleman, H A; Tonta, M A; Parkington, H C

    1994-01-01

    1. Membrane potentials were recorded with conventional intracellular microelectrodes from chromaffin cells in isolated, bisected adrenal glands from guinea-pigs. 2. All cells were electrically excitable and responded to depolarizing current with all-or-nothing action potentials that were blocked by tetrodotoxin. 3. Input resistance was 180 +/- 14 M omega and this was lower than that reported for isolated chromaffin cells using patch electrodes. 4. All cells responded to transmural stimulation with action potentials that arose from excitatory synaptic potentials in response to the excitation of one or more preganglionic fibres, many having strong synaptic action. Other fibres had weaker synaptic action but in all cases, maximal transmural stimulation caused depolarization well above threshold for action potential initiation. 5. Spontaneous excitatory synaptic potentials were observed whose frequency was greatly increased by repetitive stimulation at 10 or 30 Hz. 6. No evidence was found for the desensitization of nicotinic receptors in response to acetylcholine released from presynaptic nerve terminals. 7. These experiments show that there are many similarities between the responses to splanchnic nerve stimulation of guinea-pig chromaffin cells in situ and sympathetic ganglion cells from the same species. PMID:7965827

  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. Activation of transient receptor potential vanilloid 2-expressing primary afferents stimulates synaptic transmission in the deep dorsal horn of the rat spinal cord and elicits mechanical hyperalgesia.

    PubMed

    Petitjean, Hugues; Hugel, Sylvain; Barthas, Florent; Bohren, Yohann; Barrot, Michel; Yalcin, Ipek; Schlichter, Rémy

    2014-10-01

    Probenecid, an agonist of transient receptor vanilloid (TRPV) type 2, was used to evaluate the effects of TRPV2 activation on excitatory and inhibitory synaptic transmission in the dorsal horn (DH) of the rat spinal cord and on nociceptive reflexes induced by thermal heat and mechanical stimuli. The effects of probenecid were compared with those of capsaicin, a TRPV1 agonist. Calcium imaging experiments on rat dorsal root ganglion (DRG) and DH cultures indicated that functional TRPV2 and TRPV1 were expressed by essentially non-overlapping subpopulations of DRG neurons, but were absent from DH neurons and DH and DRG glial cells. Pretreatment of DRG cultures with small interfering RNAs against TRPV2 suppressed the responses to probenecid. Patch-clamp recordings from spinal cord slices showed that probenecid and capsaicin increased the frequencies of spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents in a subset of laminae III-V neurons. In contrast to capsaicin, probenecid failed to stimulate synaptic transmission in lamina II. Intrathecal or intraplantar injections of probenecid induced mechanical hyperalgesia/allodynia without affecting nociceptive heat responses. Capsaicin induced both mechanical hyperalgesia/allodynia and heat hyperalgesia. Activation of TRPV1 or TRPV2 in distinct sets of primary afferents increased the sEPSC frequencies in a largely common population of DH neurons in laminae III-V, and might underlie the development of mechanical hypersensitivity following probenecid or capsaicin treatment. However, only TRPV1-expressing afferents facilitated excitatory and/or inhibitory transmission in a subpopulation of lamina II neurons, and this phenomenon might be correlated with the induction of thermal heat hyperalgesia.

  18. Effects of prenatal protein malnutrition on kindling-induced alterations in dentate granule cell excitability. I. Synaptic transmission measures.

    PubMed

    Bronzino, J D; Austin-LaFrance, R J; Morgane, P J; Galler, J R

    1991-05-01

    The effects of prenatal protein malnutrition upon the efficacy of excitatory synaptic transmission at the level of the perforant path/dentate granule cell synapse were examined during development of perforant path kindling in chronically implanted adults rats. Rats born to dams fed a low protein (6% casein) or control protein (25% casein) diet were fostered to lactating dams fed the 25% casein diet 24 h after birth and were maintained on this diet throughout life following weaning. Beginning at 90-120 days of age, animals received daily kindling stimulations applied to the perforant path. Extracellular field potentials recorded from the granule cell layer of the dentate gyrus in response to single-pulse stimulation of the perforant path were analyzed to determine the effects of prenatal protein malnutrition on the efficacy of synaptic transmission during the kindling process. Measures used for these analyses included the EPSP slope, an indicator of the level of synaptic drive, the population spike amplitude which is a measure of postsynaptic activation and cellular firing, and the ratio of the population spike amplitude relative to the corresponding EPSP slope value, which was used to evaluate the overall efficacy of synaptic transmission. animals of the 6%/25% diet group were found to have significantly lower afterdischarge thresholds, yet required significantly more daily kindling stimulations to develop generalized motor convulsions (stage 5 seizure) than control animals. Examination of dentate field potentials obtained prior to kindling revealed no significant between group differences in measures of EPSP slope or population spike amplitude. Statistically significant increases in measures of both the population EPSP slope and population spike amplitude were observed in both diet groups 24 h after the first kindled afterdischarge. The degree of increase in both of these measures was significantly greater in animals of the 6%/25% group. Evaluation of input

  19. 5-HT(1A) and 5-HT(7) receptors differently modulate AMPA receptor-mediated hippocampal synaptic transmission.

    PubMed

    Costa, L; Trovato, C; Musumeci, S A; Catania, M V; Ciranna, L

    2012-04-01

    We have studied the effects of 5-HT(1A) and 5-HT(7) serotonin receptor activation in hippocampal CA3-CA1 synaptic transmission using patch clamp on mouse brain slices. Application of either 5-HT or 8-OH DPAT, a mixed 5-HT(1A)/5-HT(7) receptor agonist, inhibited AMPA receptor-mediated excitatory post synaptic currents (EPSCs); this effect was mimicked by the 5-HT(1A) receptor agonist 8-OH PIPAT and blocked by the 5-HT(1A) antagonist NAN-190. 8-OH DPAT increased paired-pulse facilitation and reduced the frequency of mEPSCs, indicating a presynaptic reduction of glutamate release probability. In another group of neurons, 8-OH DPAT enhanced EPSC amplitude but did not alter paired-pulse facilitation, suggesting a postsynaptic action; this effect persisted in the presence of NAN-190 and was blocked by the 5-HT(7) receptor antagonist SB-269970. To confirm that EPSC enhancement was mediated by 5-HT(7) receptors, we used the compound LP-44, which is considered a selective 5-HT(7) agonist. However, LP-44 reduced EPSC amplitude in most cells and instead increased EPSC amplitude in a subset of neurons, similarly to 8-OH DPAT. These effects were respectively antagonized by NAN-190 and by SB-269970, indicating that under our experimental condition LP-44 behaved as a mixed agonist. 8-OH DPAT also modulated the current evoked by exogenously applied AMPA, inducing either a reduction or an increase of amplitude in distinct neurons; these effects were respectively blocked by 5-HT(1A) and 5-HT(7) receptor antagonists, indicating that both receptors exert a postsynaptic action. Our results show that 5-HT(1A) receptors inhibit CA3-CA1 synaptic transmission acting both pre- and postsynaptically, whereas 5-HT(7) receptors enhance CA3-CA1 synaptic transmission acting exclusively at a postsynaptic site. We suggest that a selective pharmacological targeting of either subtype may be envisaged in pathological loss of hippocampal-dependent cognitive functions. In this respect, we underline the

  20. 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

  1. CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis.

    PubMed

    Uchitel, Osvaldo D; Inchauspe, Carlota González; Urbano, Francisco J; Di Guilmi, Mariano N

    2012-01-01

    Studies on the genetic forms of epilepsy, chronic pain, and migraine caused by mutations in ion channels have given crucial insights into the molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological disorders. In this review we focus on the role of mutated CaV2.1 (i.e., P/Q-type) voltage-activated Ca2+ channels, and on the ultimate consequences that mutations causing familial hemiplegic migraine type-1 (FHM1) have in neurotransmitter release. Transgenic mice harboring the human pathogenic FHM1 mutation R192Q or S218L (KI) have been used as models to study neurotransmission at several central and peripheral synapses. FHM1 KI mice are a powerful tool to explore presynaptic regulation associated with expression of CaV2.1 channels. Mutated CaV2.1 channels activate at more hyperpolarizing potentials and lead to a gain-of-function in synaptic transmission. This gain-of-function might underlie alterations in the excitatory/ inhibitory balance of synaptic transmission, favoring a persistent state of hyperexcitability in cortical neurons that would increase the susceptibility for cortical spreading depression (CSD), a mechanism believed to initiate the attacks of migraine with aura.

  2. Electrical synaptic transmission in developing zebrafish: properties and molecular composition of gap junctions at a central auditory synapse

    PubMed Central

    Yao, Cong; Vanderpool, Kimberly G.; Delfiner, Matthew; Eddy, Vanessa; Lucaci, Alexander G.; Soto-Riveros, Carolina; Yasumura, Thomas; Rash, John E.

    2014-01-01

    In contrast to the knowledge of chemical synapses, little is known regarding the properties of gap junction-mediated electrical synapses in developing zebrafish, which provide a valuable model to study neural function at the systems level. Identifiable “mixed” (electrical and chemical) auditory synaptic contacts known as “club endings” on Mauthner cells (2 large reticulospinal neurons involved in tail-flip escape responses) allow exploration of electrical transmission in fish. Here, we show that paralleling the development of auditory responses, electrical synapses at these contacts become anatomically identifiable at day 3 postfertilization, reaching a number of ∼6 between days 4 and 9. Furthermore, each terminal contains ∼18 gap junctions, representing between 2,000 and 3,000 connexon channels formed by the teleost homologs of mammalian connexin 36. Electrophysiological recordings revealed that gap junctions at each of these contacts are functional and that synaptic transmission has properties that are comparable with those of adult fish. Thus a surprisingly small number of mixed synapses are responsible for the acquisition of auditory responses by the Mauthner cells, and these are likely sufficient to support escape behaviors at early developmental stages. PMID:25080573

  3. Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior.

    PubMed

    Yamazaki, Maya; Le Pichon, Claire E; Jackson, Alexander C; Cerpas, Manuel; Sakimura, Kenji; Scearce-Levie, Kimberly; Nicoll, Roger A

    2015-01-27

    Transmembrane AMPA receptor regulatory proteins (TARPs) play an essential role in excitatory synaptic transmission throughout the central nervous system (CNS) and exhibit subtype-specific effects on AMPA receptor (AMPAR) trafficking, gating, and pharmacology. The function of TARPs has largely been determined through work on canonical type I TARPs such as stargazin (TARP γ-2), absent in the ataxic stargazer mouse. Little is known about the function of atypical type II TARPs, such as TARP γ-7, which exhibits variable effects on AMPAR function. Because γ-2 and γ-7 are both strongly expressed in multiple cell types in the cerebellum, we examined the relative contribution of γ-2 and γ-7 to both synaptic transmission in the cerebellum and motor behavior by using both the stargazer mouse and a γ-7 knockout (KO) mouse. We found that the loss of γ-7 alone had little effect on climbing fiber (cf) responses in Purkinje neurons (PCs), yet the additional loss of γ-2 all but abolished cf responses. In contrast, γ-7 failed to make a significant contribution to excitatory transmission in stellate cells and granule cells. In addition, we generated a PC-specific deletion of γ-2, with and without γ-7 KO background, to examine the relative contribution of γ-2 and γ-7 to PC-dependent motor behavior. Selective deletion of γ-2 in PCs had little effect on motor behavior, yet the additional loss of γ-7 resulted in a severe disruption in motor behavior. Thus, γ-7 is capable of supporting a component of excitatory transmission in PCs, sufficient to maintain essentially normal motor behavior, in the absence of γ-2.

  4. Regulation of Synaptic Transmission by Presynaptic CaMKII and BK channels

    PubMed Central

    Wang, Zhao-Wen

    2009-01-01

    Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the BK channel are enriched at the presynaptic nerve terminal, where CaMKII associates with synaptic vesicles whereas the BK channel colocalizes with voltage-sensitive Ca2+ channels (VSCCs) in the plasma membrane. Mounting evidence suggests that these two proteins play important roles in controlling neurotransmitter release. Presynaptic BK channels primarily serve as a negative regulator of neurotransmitter release. In contrast, presynaptic CaMKII either enhances or inhibits neurotransmitter release and synaptic plasticity depending on experimental/physiological conditions and properties of specific synapses. The different functions of presynaptic CaMKII appear to be mediated by distinct downstream proteins, including the BK channel. PMID:18759010

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

    PubMed

    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.

  7. 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

  8. Cholinergic suppression of excitatory synaptic transmission in layers II/III of the parasubiculum.

    PubMed

    Glasgow, S D; Glovaci, I; Karpowicz, L S; Chapman, C A

    2012-01-10

    Layer II of the parasubiculum (PaS) receives excitatory synaptic input from the CA1 region of the hippocampus and sends a major output to layer II of the medial and lateral entorhinal cortex. The PaS also receives heavy cholinergic innervation from the medial septum, which contributes to the generation of theta-frequency (4-12 Hz) electroencephalographic (EEG) activity. Cholinergic receptor activation exerts a wide range of effects in other areas of the hippocampal formation, including membrane depolarization, changes in neuronal excitability, and suppression of excitatory synaptic responses. The present study was aimed at determining how cholinergic receptor activation modulates excitatory synaptic input to the layer II/III neurons of the PaS in acute brain slices. Field excitatory postsynaptic potentials (fEPSPs) in layer II/III of the PaS were evoked by stimulation of either layer I afferents, or ascending inputs from layer V. Bath-application of the cholinergic agonist carbachol (0.5-10 μM) suppressed the amplitude of fEPSPs evoked by both superficial- and deep layer stimulation, and also enhanced paired-pulse facilitation. Constant bath-application of the GABA(A) antagonist bicuculline (10 μM) failed to eliminate the suppression, indicating that the cholinergic suppression of fEPSPs is not due to increased inhibitory tone. The muscarinic receptor antagonist atropine (1 μM) blocked the suppression of fEPSPs, and the selective M(1)-preferring receptor antagonist pirenzepine (1 μM), but not the M(2)-preferring antagonist methoctramine (1-5 μM), also significantly attenuated the suppression. Therefore, cholinergic receptor activation suppresses excitatory synaptic input to layer II/III neurons of the PaS, and this suppression is mediated in part by M(1) receptor activation.

  9. Adenosine effects on inhibitory synaptic transmission and excitation–inhibition balance in the rat neocortex

    PubMed Central

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

    2015-01-01

    Abstract Adenosine might be the most widespread neuromodulator in the brain: as a metabolite of ATP it is present in every neuron and glial cell. However, how adenosine affects operation of neurons and networks in the neocortex is poorly understood, mostly because modulation of inhibitory transmission by adenosine has been so little studied. To clarify adenosine's role at inhibitory synapses, and in excitation–inhibition balance in pyramidal neurons, we recorded pharmacologically isolated inhibitory responses, compound excitatory–inhibitory responses and spontaneous events in layer 2/3 pyramidal neurons in slices from rat visual cortex. We show that adenosine (1–150 μm) suppresses inhibitory transmission to these neurons in a concentration-dependent and reversible manner. The suppression was mediated by presynaptic A1 receptors (A1Rs) because it was blocked by a selective A1 antagonist, DPCPX, and associated with changes of release indices: paired-pulse ratio, inverse coefficient of variation and frequency of miniature events. At some synapses (12 out of 24) we found evidence for A2ARs: their blockade led to a small but significant increase of the magnitude of adenosine-mediated suppression. This effect of A2AR blockade was not observed when A1Rs were blocked, suggesting that A2ARs do not have their own effect on transmission, but can modulate the A1R-mediated suppression. At both excitatory and inhibitory synapses, the magnitude of A1R-mediated suppression and A2AR–A1R interaction expressed high variability, suggesting high heterogeneity of synapses in the sensitivity to adenosine. Adenosine could change the balance between excitation and inhibition at a set of inputs to a neuron bidirectionally, towards excitation or towards inhibition. On average, however, these bidirectional changes cancelled each other, and the overall balance of excitation and inhibition was maintained during application of adenosine. These results suggest that changes of adenosine

  10. The Role of GluK4 in Synaptic Plasticity and Affective Behavior in Mice

    NASA Astrophysics Data System (ADS)

    Catches, Justin Samuel

    Kainate receptors (KARs) are glutamate-gated ion channels that signal through both ionotropic and metabotropic pathways (Contractor et al., 2011). Combinations of five KAR subunits (GluK1-5) form tetrameric receptors with GluK1, GluK2, and GluK3 able to form functional homomeric channels. The high-affinity subunits, GluK4 and GluK5, do not form homomeric channels but modify the properties of heteromeric receptors. Expression of the GluK4 receptor subunit in the forebrain is restricted to the CA3 region of the hippocampus and dentate gyrus regions where KARs modulate synaptic plasticity. In this study, ablation of Grik4, which encodes GluK4, in mice reduced KAR synaptic currents and altered activation properties of postsynaptic receptors but left two forms of presynaptic short-term plasticity intact. Disruption of both Grik4 and Grik5 caused complete loss of the postsynaptic ionotropic KAR current and impaired presynaptic frequency facilitation. Additionally, KAR surface expression was altered at pre- and postsynaptic sites at the MF synapse. Despite the loss of ionotropic signaling, KAR-mediated inhibition of the slow afterhyperpolarization current, which is dependent on metabotropic signaling, was intact in CA3 neurons. Long-term potentiation at the MF-CA3 synapse was reduced, likely through a loss of KAR modulation of excitability of the presynaptic MF axons. Genetic variants in the human GRIK4 gene alter the susceptibility for affective disorders (Bloss and Hunter, 2010). We found that ablation of Grik4 in mice resulted in reduced anxiety and an antidepressant-like phenotype. In the elevated zero-maze, a test for anxiety and risk taking behavior, and in two anxiogenic tests, marble-burying and novelty-induced suppression of feeding, anxiety-like behavior was consistently reduced in knockout animals. In the forced swim, a test of learned helplessness used to determine depression-like behavior, knockout mice demonstrated significantly less immobility suggesting

  11. 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

  12. 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.

  13. 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.

  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.

  15. Structure and function of the amygdaloid NPY system: NPY Y2 receptors regulate excitatory and inhibitory synaptic transmission in the centromedial amygdala.

    PubMed

    Wood, J; Verma, D; Lach, G; Bonaventure, P; Herzog, H; Sperk, G; Tasan, R O

    2016-09-01

    The amygdala is essential for generating emotional-affective behaviors. It consists of several nuclei with highly selective, elaborate functions. In particular, the central extended amygdala, consisting of the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST) is an essential component actively controlling efferent connections to downstream effectors like hypothalamus and brain stem. Both, CEA and BNST contain high amounts of different neuropeptides that significantly contribute to synaptic transmission. Among these, neuropeptide Y (NPY) has emerged as an important anxiolytic and fear-reducing neuromodulator. Here, we characterized the expression, connectivity and electrophysiological function of NPY and Y2 receptors within the CEA. We identified several NPY-expressing neuronal populations, including somatostatin- and calretinin-expressing neurons. Furthermore, in the main intercalated nucleus, NPY is expressed primarily in dopamine D1 receptor-expressing neurons but also in interspersed somatostatin-expressing neurons. Interestingly, NPY neurons did not co-localize with the Y2 receptor. Retrograde tract tracing experiments revealed that NPY neurons reciprocally connect the CEA and BNST. Functionally, the Y2 receptor agonist PYY3-36, reduced both, inhibitory as well as excitatory synaptic transmission in the centromedial amygdala (CEm). However, we also provide evidence that lack of NPY or Y2 receptors results in increased GABA release specifically at inhibitory synapses in the CEm. Taken together, our findings suggest that NPY expressed by distinct populations of neurons can modulate afferent and efferent projections of the CEA via presynaptic Y2 receptors located at inhibitory and excitatory synapses.

  16. Presynaptic inhibition of synaptic transmission in the rat hippocampus by activation of muscarinic receptors: involvement of presynaptic calcium influx

    PubMed Central

    Qian, Jing; Saggau, Peter

    1997-01-01

    Modulation of presynaptic voltage-dependent calcium channels (VDCCs) by muscarinic receptors at the CA3–CA1 synapse of rat hippocampal slices was investigated by using the calcium indicator fura-2. Stimulation-evoked presynaptic calcium transients ([Capre]t) and field excitatory postsynaptic potentials (fe.p.s.ps) were simultaneously recorded. The relationship between presynaptic calcium influx and synaptic transmission was studied. Activation of muscarinic receptors inhibited [Capre]t, thereby reducing synaptic transmission. Carbachol (CCh, 10 μM) inhibited [Capre]t by 35% and reduced fe.p.s.p. by 85%. The inhibition was completely antagonized by 1 μM atropine. An approximate 4th power relationship was found between presynaptic calcium influx and postsynaptic responses. Application of the N-type VDCC-blocking peptide toxin ω-conotoxin GVIA (ω-CTx GVIA, 1 μM) inhibited [Capre]t and fe.p.s.ps by 21% and 49%, respectively, while the P/Q-type VDCC blocker ω-agatoxin IVA (ω-Aga IVA, 1 μM) reduced [Capre]t and fe.p.s.ps by 35% and 85%, respectively. Muscarinic receptor activation differentially inhibited distinct presynaptic VDCCs. ω-CTx GVIA-sensitive calcium channels were inhibited by muscarinic receptors, while ω-Aga IVA-sensitive channels were not. The percentage inhibition of ω-CTx GVIA-sensitive [Capre]t was about 63%. Muscarinic receptors inhibited presynaptic VDCCs in a way similar to adenosine (Ad) receptors. The percentage inhibition of ω-CTx GVIA-sensitive [Capre]t by Ad (100 μM) was about 59%. There was no significant inhibition of ω-Aga IVA-sensitive channels by Ad. The inhibitions of [Capre]t by CCh and Ad were mutually occlusive. These results indicate that inhibition of synaptic transmission by muscarinic receptors is mainly the consequence of a reduction of the [Capre]t due to inhibition of presynaptic VDCCs. PMID:9351508

  17. Endocannabinoid-Dependent Long-Term Potentiation of Synaptic Transmission at Rat Barrel Cortex.

    PubMed

    Maglio, Laura Eva; Noriega-Prieto, José Antonio; Maraver, Maria Jesús; Fernández de Sevilla, David

    2017-03-01

    Brain-derived neurotrophic factor (BDNF) plays a critical role in modulating plasticity in sensory cortices. Indeed, a BDNF-dependent long-term potentiation (LTP) at distal basal excitatory synapses of Layer 5 pyramidal neurons (L5PNs) has been demonstrated in disinhibited rat barrel cortex slices. Although it is well established that this LTP requires the pairing of excitatory postsynaptic potentials (PSPs) with Ca2+ spikes, its induction when synaptic inhibition is working remains unexplored. Here we show that low-frequency stimulation at basal dendrites of L5PNs is able to trigger a PSP followed by an action potential (AP) and a slow depolarization (termed PSP-Ca2+ response) in thalamocortical slices without blocking synaptic inhibition. We demonstrate that AP barrage-mediated release of endocannabinoids (eCBs) from the recorded L5PNs induces PSP-Ca2+ response facilitation and BDNF-dependent LTP. Indeed, this LTP requires the type 1 cannabinoid receptors activation, is prevented by postsynaptic intracellular 1,2-bis(2-aminophenoxy) ethane-N,N,N,N'-tetraacetic acid (BAPTA) or the anandamide membrane transporter inhibitor AM404, and only occurs in L5PNs neurons showing depolarization-induced suppression of inhibition. Additionally, electrical stimulation at the posteromedial thalamic nucleus induced similar response and LTP. These results reveal a novel form of eCB-dependent LTP at L5PNs that could be relevant in the processing of sensory information in the barrel cortex.

  18. Crossover inhibition in the retina: circuitry that compensates for nonlinear rectifying synaptic transmission.

    PubMed

    Molnar, Alyosha; Hsueh, Hain-Ann; Roska, Botond; Werblin, Frank S

    2009-12-01

    In the mammalian retina, complementary ON and OFF visual streams are formed at the bipolar cell dendrites, then carried to amacrine and ganglion cells via nonlinear excitatory synapses from bipolar cells. Bipolar, amacrine and ganglion cells also receive a nonlinear inhibitory input from amacrine cells. The most common form of such inhibition crosses over from the opposite visual stream: Amacrine cells carry ON inhibition to the OFF cells and carry OFF inhibition to the ON cells ("crossover inhibition"). Although these synapses are predominantly nonlinear, linear signal processing is required for computing many properties of the visual world such as average intensity across a receptive field. Linear signaling is also necessary for maintaining the distinction between brightness and contrast. It has long been known that a subset of retinal outputs provide exactly this sort of linear representation of the world; we show here that rectifying (nonlinear) synaptic currents, when combined thorough crossover inhibition can generate this linear signaling. Using simple mathematical models we show that for a large set of cases, repeated rounds of synaptic rectification without crossover inhibition can destroy information carried by those synapses. A similar circuit motif is employed in the electronics industry to compensate for transistor nonlinearities in analog circuits.

  19. 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

  20. Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex.

    PubMed

    Sakata, Kazuko; Woo, Newton H; Martinowich, Keri; Greene, Joshua S; Schloesser, Robert J; Shen, Liya; Lu, Bai

    2009-04-07

    Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression. BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven Bdnf transcription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from BDNF-KIV, but not wild-type littermates. These results demonstrate the importance of promoter IV-dependent Bdnf transcription in GABAergic function and reveal an unexpected regulation of STDP in the PFC by BDNF.

  1. 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

  2. A presynaptic locus for long-term potentiation of elementary synaptic transmission at mossy fiber synapses in culture.

    PubMed Central

    López-García, J C; Arancio, O; Kandel, E R; Baranes, D

    1996-01-01

    The complex circuitry of the CA3 region and the abundance of collateral connections has made it difficult to study the mossy fiber pathway in hippocampal slices and therefore to establish the site of expression of long-term potentiation at these synapses. Using a novel cell culture system, we have produced long-term potentiation of the elementary synaptic connections on single CA3 pyramidal neurons following tetanic stimulation of individual dentate gyrus granule cells. As is the case for the hippocampal slice, this potentiation was independent of N-methyl-D-aspartate receptor activation, was simulated by application of forskolin, and its induction did not require any modulatory input. The increase in synaptic strength was accompanied by a reduction in the number of failures of transmission and by an increase in the coefficient of variation of the responses and was prevented by presynaptic injection of an inhibitor of protein kinase A. These findings show that mossy fiber long-term potentiation has a presynaptic locus and that its expression is dependent on protein kinase A. PMID:8643468

  3. Bone marrow-derived mesenchymal stem cells promote neuronal networks with functional synaptic transmission after transplantation into mice with neurodegeneration.

    PubMed

    Bae, Jae-Sung; Han, Hyung Soo; Youn, Dong-Ho; Carter, Janet E; Modo, Michel; Schuchman, Edward H; Jin, Hee Kyung

    2007-05-01

    Recent studies have shown that bone marrow-derived MSCs (BM-MSCs) improve neurological deficits when transplanted into animal models of neurological disorders. However, the precise mechanism by which this occurs remains unknown. Herein we demonstrate that BM-MSCs are able to promote neuronal networks with functional synaptic transmission after transplantation into Niemann-Pick disease type C (NP-C) mouse cerebellum. To address the mechanism by which this occurs, we used gene microarray, whole-cell patch-clamp recordings, and immunohistochemistry to evaluate expression of neurotransmitter receptors on Purkinje neurons in the NP-C cerebellum. Gene microarray analysis revealed upregulation of genes involved in both excitatory and inhibitory neurotransmission encoding subunits of the ionotropic glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA) GluR4 and GABA(A) receptor beta2. We also demonstrated that BM-MSCs, when originated by fusion-like events with existing Purkinje neurons, develop into electrically active Purkinje neurons with functional synaptic formation. This study provides the first in vivo evidence that upregulation of neurotransmitter receptors may contribute to synapse formation via cell fusion-like processes after BM-MSC transplantation into mice with neurodegenerative disease. Disclosure of potential conflicts of interest is found at the end of this article.

  4. 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.

  5. Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala.

    PubMed

    Penzo, Mario A; Robert, Vincent; Li, Bo

    2014-02-12

    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.

  6. 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

  7. Effects of alcohol on the membrane excitability and synaptic transmission of medium spiny neurons in the nucleus accumbens

    PubMed Central

    Marty, Vincent N.; Spigelman, Igor

    2013-01-01

    Chronic and excessive alcohol drinking lead to alcohol dependence and loss of control over alcohol consumption, with serious detrimental health consequences. Chronic alcohol exposure followed by protracted withdrawal causes profound alterations in the brain reward system that leads to marked changes in reinforcement mechanisms and motivational state. These long-lasting neuroadaptations are thought to contribute to the development of cravings and relapse. The nucleus accumbens (NAcc), a central component of the brain reward system, plays a critical role in alcohol-induced neuroadaptive changes underlying alcohol-seeking behaviors. Here we review the findings that chronic alcohol exposure produces long-lasting neuroadaptive changes in various ion channels that govern intrinsic membrane properties and neuronal excitability, as well as excitatory and inhibitory synaptic transmission in the NAcc that underlie alcohol-seeking behavior during protracted withdrawal. PMID:22445807

  8. 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

  9. Reactive oxygen species mediate the potentiating effects of ATP on GABAergic synaptic transmission in the immature hippocampus.

    PubMed

    Safiulina, Victoria F; Afzalov, Ramil; Khiroug, Leonard; Cherubini, Enrico; Giniatullin, Rashid

    2006-08-18

    Reactive oxygen species (ROS) constitute important signaling molecules in the central nervous system. They regulate a number of different functions both under physiological conditions and under pathological conditions. Here we tested the hypothesis that in the immature hippocampus ATP, the most diffuse neurotransmitter in the brain, modulates synaptic transmission via ROS. We show that ATP, acting on metabotropic P2Y1 receptors, increased the frequency of GABA(A)-mediated spontaneous postsynaptic currents (SPSCs) in CA3 principal cells, an effect that was prevented by the antioxidant N-acetyl-cysteine or by catalase, an enzyme that breaks down H2O2. The effect of ATP on SPSCs was mimicked by H2O2 or by the pro-oxidant, Fe2+, which, through the Fentol reaction, catalyzes the conversion of H2O2 into highly reactive hydroxyl radicals. MRS-2179, a P2Y1 receptor antagonist, removed the facilitatory action of Fe2+ on SPSCs, suggesting that endogenous ATP acting on P2Y1 receptors is involved in Fe2+-induced modulation of synaptic transmission. Imaging ROS with the H2O2-sensitive dye DCF revealed that ATP induces generation of peroxide in astrocytes via activation of P2Y1 receptors coupled to intracellular calcium rise. Neither N-acetyl-cysteine nor catalase prevented Ca2+ transients induced by ATP in astrocytes. Since a single hippocampal astrocyte can contact many neurons, ATP-induced ROS signaling may control thousands of synapses. This may be crucial for information processing in the immature brain when GABAergic activity is essential for the proper wiring of the hippocampal network.

  10. Effects of prenatal paraquat and mancozeb exposure on amino acid synaptic transmission in developing mouse cerebellar cortex.

    PubMed

    Miranda-Contreras, Leticia; Dávila-Ovalles, Rosaura; Benítez-Díaz, Pedro; Peña-Contreras, Zulma; Palacios-Prü, Ernesto

    2005-11-07

    The goal of this study was to analyze the effects of prenatal exposure to the pesticides paraquat (PQ) and mancozeb (MZ) on the development of synaptic transmission in mouse cerebellar cortex. Pregnant NMRI mice were treated with either saline, 10 mg/kg PQ, 30 mg/kg MZ or the combination of PQ + MZ, between gestational days 12 (E12) and E20. Variation in the levels of amino acid neurotransmitters was determined by HPLC, between postnatal day 1 (P1) and P30. Motor coordination was assessed by locomotor activity evaluation of control and experimental pups at P14, P21 and P30. Significant reductions in the levels of excitatory neurotransmitters, aspartate and glutamate, were observed in PQ-, MZ- or combined PQ + MZ-exposed pups, with respect to control, during peak periods of excitatory innervation of Purkinje cells: between P2-P5 and P11-P15. However, at P30, lower aspartate contents, in contrast with increased glutamate levels, were detected in all experimental groups. During the first two postnatal weeks, delays in GABA and glycine ontogenesis were observed in PQ- and PQ + MZ-exposed pups, whereas notable decrements in GABA and glycine levels were seen in PQ + MZ-exposed animals. Decreased taurine contents were detected at P3 and P11 in PQ- and PQ + MZ-exposed mice. Pups in different experimental groups all showed hyperactivity at P14 and then exhibited reduced locomotor activity at P30. Taken together, our results indicate that prenatal exposure to either PQ or MZ or the combination of both could alter the chronology and magnitude of synaptic transmission in developing mouse cerebellar cortex.

  11. Actions of endomorphins on synaptic transmission of Adelta-fibers in spinal cord dorsal horn neurons.

    PubMed

    Yajiri, Y; Huang, L Y

    2000-01-01

    The effects of endogenous mu-opioid ligands, endomorphins, on Adelta-afferent-evoked excitatory postsynaptic currents (EPSCs) were studied in substantia gelatinosa neurons in spinal cord slices. Under voltage-clamp conditions, endomorphins blocked the evoked EPSCs in a dose-dependent manner. To determine if the block resulted from changes in transmitter release from glutamatergic synaptic terminals, the opioid actions on miniature excitatory postsynaptic currents (mEPSCs) were examined. Endomorphins (1 microM) reduced the frequency but not the amplitude of mEPSCs, suggesting that endomorphins directly act on presynaptic terminals. The effects of endomorphins on the unitary (quantal) properties of the evoked EPSCs were also studied. Endomorphins reduced unitary content without significantly changing unitary amplitude. These results suggest that in addition to presynaptic actions on interneurons, endomorphins also inhibit evoked EPSCs by reducing transmitter release from Adelta-afferent terminals.

  12. Glial cells modulate the synaptic transmission of NTS neurons sending projections to ventral medulla of Wistar rats

    PubMed Central

    Accorsi-Mendonça, Daniela; Zoccal, Daniel B; Bonagamba, Leni G H; Machado, Benedito H

    2013-01-01

    There is evidence that sympathoexcitatory and respiratory responses to chemoreflex activation involve ventrolateral medulla-projecting nucleus tractus solitarius (NTS) neurons (NTS-VLM neurons) and also that ATP modulates this neurotransmission. Here, we evaluated whether or not astrocytes is the source of endogenous ATP modulating the synaptic transmission in NTS-VLM neurons. Synaptic activities of putative astrocytes or NTS-VLM neurons were recorded using whole cell patch clamp. Tractus solitarius (TS) stimulation induced TS-evoked excitatory postsynaptic currents (TS-eEPSCs) in NTS-VLM neurons as well in NTS putative astrocytes, which were also identified by previous labeling. Fluoracetate (FAC), an inhibitor of glial metabolism, reduced TS-eEPSCs amplitude (−85.6 ± 16 vs. −39 ± 7.1 pA, n = 12) and sEPSCs frequency (2.8 ± 0.5 vs. 1.8 ± 0.46 Hz, n = 10) in recorded NTS-VLM neurons, indicating a gliomodulation of glutamatergic currents. To verify the involvement of endogenous ATP a purinergic antagonist was used, which reduced the TS-eEPSCs amplitude (−207 ± 50 vs. −149 ± 50 pA, n = 6), the sEPSCs frequency (1.19 ± 0.2 vs. 0.62 ± 0.11 Hz, n = 6), and increased the paired-pulse ratio (PPR) values (∼20%) in NTS-VLM neurons. Simultaneous perfusion of Pyridoxalphosphate-6-azophenyl-2′,5′-disulfonic acid (iso-PPADS) and FAC produced reduction in TS-eEPSCs similar to that observed with iso-PPADS or FAC alone, indicating that glial cells are the source of ATP released after TS stimulation. Extracellular ATP measurement showed that FAC reduced evoked and spontaneous ATP release. All together these data show that putative astrocytes are the source of endogenous ATP, which via activation of presynaptic P2X receptors, facilitates the evoked glutamate release and increases the synaptic transmission efficacy in the NTS-VLM neurons probably involved with the peripheral chemoreflex pathways. PMID:24303152

  13. Neurotrophin-3 potentiates excitatory GABAergic synaptic transmission in cultured developing hypothalamic neurones of the rat

    PubMed Central

    Gao, Xiao-Bing; van den Pol, A N

    1999-01-01

    Neurotrophin-3 (NT-3) supports the survival and differentiation of neurones in the central and peripheral nervous systems through a number of mechanisms that occur in a matter of hours or days. NT-3 may also have a more rapid mode of action that influences synaptic activity in mature neurones. In the present study, the effect of NT-3 on developing GABAergic synapses was investigated in 3- to 7-day-old cultures of rat hypothalamic neurones with whole-cell patch-clamp recording. NT-3 induced a substantial dose-dependent potentiation of the frequency of spontaneous postsynaptic currents (sPSCs; 160 %) in developing neurones during a period when GABA evoked inward (depolarizing) current, as determined with gramicidin-perforated patch recordings. The NT-3 effect was long lasting; continued enhancement was found > 30 min after NT-3 wash-out. NT-3 evoked a substantial 202 % increase in total GABA-mediated inward current, measured as the time-current integral. Action potential frequency was also increased by NT-3 (to 220 %). The frequency of GABA-mediated miniature postsynaptic currents in developing neurones in the presence of tetrodotoxin was potentiated (to 140 %) by NT-3 with no change in the mean amplitude, suggesting a presynaptic locus of the effect. In striking contrast to immature neurones, when more mature neurones were studied, NT-3 did not enhance the frequency of GABA-mediated spontaneous postsynaptic currents (sPSCs), but instead evoked a slight (16 %) decrease. The frequency of miniature post-synaptic currents was also slightly decreased (16 %) by the NT-3, with no change in amplitude. These results were recorded during a later period of neuronal maturity when GABA would evoke outward (hyperpolarizing) currents. NT-3 had no effect on the mean amplitude of GABA-evoked postsynaptic currents in either developing or mature neurones. Intracellular application of K252a, a non-selective tyrosine kinase inhibitor, did not block the NT-3 effect postsynaptically. In

  14. Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP

    PubMed Central

    Herring, Bruce E.; Nicoll, Roger A.

    2016-01-01

    The molecular mechanism underlying long-term potentiation (LTP) is critical for understanding learning and memory. CaMKII, a key kinase involved in LTP, is both necessary and sufficient for LTP induction. However, how CaMKII gives rise to LTP is currently unknown. Recent studies suggest that Rho GTPases are necessary for LTP. Rho GTPases are activated by Rho guanine exchange factors (RhoGEFs), but the RhoGEF(s) required for LTP also remain unknown. Here, using a combination of molecular, electrophysiological, and imaging techniques, we show that the RhoGEF Kalirin and its paralog Trio play critical and redundant roles in excitatory synapse structure and function. Furthermore, we show that CaMKII phosphorylation of Kalirin is sufficient to enhance synaptic AMPA receptor expression, and that preventing CaMKII signaling through Kalirin and Trio prevents LTP induction. Thus, our data identify Kalirin and Trio as the elusive targets of CaMKII phosphorylation responsible for AMPA receptor up-regulation during LTP. PMID:26858404

  15. Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP.

    PubMed

    Herring, Bruce E; Nicoll, Roger A

    2016-02-23

    The molecular mechanism underlying long-term potentiation (LTP) is critical for understanding learning and memory. CaMKII, a key kinase involved in LTP, is both necessary and sufficient for LTP induction. However, how CaMKII gives rise to LTP is currently unknown. Recent studies suggest that Rho GTPases are necessary for LTP. Rho GTPases are activated by Rho guanine exchange factors (RhoGEFs), but the RhoGEF(s) required for LTP also remain unknown. Here, using a combination of molecular, electrophysiological, and imaging techniques, we show that the RhoGEF Kalirin and its paralog Trio play critical and redundant roles in excitatory synapse structure and function. Furthermore, we show that CaMKII phosphorylation of Kalirin is sufficient to enhance synaptic AMPA receptor expression, and that preventing CaMKII signaling through Kalirin and Trio prevents LTP induction. Thus, our data identify Kalirin and Trio as the elusive targets of CaMKII phosphorylation responsible for AMPA receptor up-regulation during LTP.

  16. 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

  17. CB₂ cannabinoid receptors inhibit synaptic transmission when expressed in cultured autaptic neurons.

    PubMed

    Atwood, Brady K; Straiker, Alex; Mackie, Ken

    2012-09-01

    The role of CB₂ in the central nervous system, particularly in neurons, has generated much controversy. Fueling the controversy are imperfect tools, which have made conclusive identification of CB₂ expressing neurons problematic. Imprecise localization of CB₂ has made it difficult to determine its function in neurons. Here we avoid the localization controversy and directly address the question if CB₂ can modulate neurotransmission. CB₂ was expressed in excitatory hippocampal autaptic neurons obtained from CB₁ null mice. Whole-cell patch clamp recordings were made from these neurons to determine the effects of CB₂ on short-term synaptic plasticity. CB₂ expression restored depolarization induced suppression of excitation to these neurons, which was lost following genetic ablation of CB₁. The endocannabinoid 2-arachidonylglycerol (2-AG) mimicked the effects of depolarization in CB₂ expressing neurons. Interestingly, ongoing basal production of 2-AG resulted in constitutive activation of CB₂, causing a tonic inhibition of neurotransmission that was relieved by the CB₂ antagonist AM630 or the diacylglycerol lipase inhibitor RHC80267. Through immunocytochemistry and analysis of spontaneous EPSCs, paired pulse ratios and coefficients of variation we determined that CB₂ exerts its function at a presynaptic site of action, likely through inhibition of voltage gated calcium channels. Therefore CB₂ expressed in neurons effectively mimics the actions of CB₁. Thus neuronal CB₂ is well suited to integrate into conventional neuronal endocannabinoid signaling processes, with its specific role determined by its unique and highly inducible expression profile.

  18. Mossy fiber synaptic transmission: communication from the dentate gyrus to area CA3.

    PubMed

    Jaffe, David B; Gutiérrez, Rafael

    2007-01-01

    Communication between the dentate gyrus (DG) and area CA3 of the hippocampus proper is transmitted via axons of granule cells--the mossy fiber (MF) pathway. In this review we discuss and compare the properties of transmitter release from the MFs onto pyramidal neurons and interneurons. An examination of the anatomical connectivity from DG to CA3 reveals a surprising interplay between excitation and inhibition for this circuit. In this respect it is particularly relevant that the major targets of the MFs are interneurons and that the consequence of MF input into CA3 may be inhibitory or excitatory, conditionally dependent on the frequency of input and modulatory regulation. This is further complicated by the properties of transmitter release from the MFs where a large number of co-localized transmitters, including GABAergic inhibitory transmitter release, and the effects of presynaptic modulation finely tune transmitter release. A picture emerges that extends beyond the hypothesis that the MFs are simply "detonators" of CA3 pyramidal neurons; the properties of synaptic information flow from the DG have more subtle and complex influences on the CA3 network.

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

    PubMed

    Bannon, N M; Zhang, P; Ilin, V; Chistiakova, M; Volgushev, M

    2014-02-28

    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 the hippocampus and striatum, the heterogeneity of the effects of A1R and A2AR 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 excitatory postsynaptic potentials (EPSPs), miniature excitatory postsynaptic potentials (mEPSPs), and membrane properties. Adenosine reduced the amplitude of evoked EPSPs and excitatory postsynaptic currents (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 (8-cyclopentyl-1,3-dipropylxanthine), suggesting that activation of presynaptic A1Rs suppresses excitatory transmission by reducing release probability. Adenosine (20μM) hyperpolarized the cell membrane from -65.3±1.5 to -67.7±1.8mV, and reduced input resistance from 396.5±44.4 to 314.0±36.3MOhm (∼20%). These effects were also abolished by DPCPX, suggesting postsynaptic A1Rs. Application of the selective A2AR antagonist SCH-58261 (2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-a-mine) on the background of high adenosine concentrations revealed an additional decrease in EPSP amplitude. Moreover, application of the A2AR agonist CGS-21680 (4-[2-[[6-amino-9-(N-ethyl-β-d-ribofuranuronamidosyl)-9H

  20. Loss of neuronal GSK3β reduces dendritic spine stability and attenuates excitatory synaptic transmission via β-catenin

    PubMed Central

    Ochs, S M; Dorostkar, M M; Aramuni, G; Schön, C; Filser, S; Pöschl, J; Kremer, A; Van Leuven, F; Ovsepian, S V; Herms, J

    2015-01-01

    Central nervous glycogen synthase kinase 3β (GSK3β) is implicated in a number of neuropsychiatric diseases, such as bipolar disorder, depression, schizophrenia, fragile X syndrome or anxiety disorder. Many drugs employed to treat these conditions inhibit GSK3β either directly or indirectly. We studied how conditional knockout of GSK3β affected structural synaptic plasticity. Deletion of the GSK3β gene in a subset of cortical and hippocampal neurons in adult mice led to reduced spine density. In vivo imaging revealed that this was caused by a loss of persistent spines, whereas stabilization of newly formed spines was reduced. In electrophysiological recordings, these structural alterations correlated with a considerable drop in the frequency and amplitude of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-dependent miniature excitatory postsynaptic currents. Expression of constitutively active β-catenin caused reduction in spine density and electrophysiological alterations similar to GSK3β knockout, suggesting that the effects of GSK3β knockout were mediated by the accumulation of β-catenin. In summary, changes of dendritic spines, both in quantity and in morphology, are correlates of experience-dependent synaptic plasticity; thus, these results may help explain the mechanism of action of psychotropic drugs inhibiting GSK3β. PMID:24912492

  1. Sex differences in cerebellar synaptic transmission and sex-specific responses to autism-linked Gabrb3 mutations in mice

    PubMed Central

    Mercer, Audrey A; Palarz, Kristin J; Tabatadze, Nino; Woolley, Catherine S; Raman, Indira M

    2016-01-01

    Neurons of the cerebellar nuclei (CbN) transmit cerebellar signals to premotor areas. The cerebellum expresses several autism-linked genes, including GABRB3, which encodes GABAA receptor β3 subunits and is among the maternal alleles deleted in Angelman syndrome. We tested how this Gabrb3 m-/p+ mutation affects CbN physiology in mice, separating responses of males and females. Wild-type mice showed sex differences in synaptic excitation, inhibition, and intrinsic properties. Relative to females, CbN cells of males had smaller synaptically evoked mGluR1/5-dependent currents, slower Purkinje-mediated IPSCs, and lower spontaneous firing rates, but rotarod performances were indistinguishable. In mutant CbN cells, IPSC kinetics were unchanged, but mutant males, unlike females, showed enlarged mGluR1/5 responses and accelerated spontaneous firing. These changes appear compensatory, since mutant males but not females performed indistinguishably from wild-type siblings on the rotarod task. Thus, sex differences in cerebellar physiology produce similar behavioral output, but provide distinct baselines for responses to mutations. DOI: http://dx.doi.org/10.7554/eLife.07596.001 PMID:27077953

  2. Drosophila-Cdh1 (Rap/Fzr) a regulatory subunit of APC/C is required for synaptic morphology, synaptic transmission and locomotion.

    PubMed

    Wise, Alexandria; Schatoff, Emma; Flores, Julian; Hua, Shao-Ying; Ueda, Atsushi; Wu, Chun-Fang; Venkatesh, Tadmiri

    2013-11-01

    The assembly of functional synapses requires the orchestration of the synthesis and degradation of a multitude of proteins. Protein degradation and modification by the conserved ubiquitination pathway has emerged as a key cellular regulatory mechanism during nervous system development and function (Kwabe and Brose, 2011). The anaphase promoting complex/cyclosome (APC/C) is a multi-subunit ubiquitin ligase complex primarily characterized for its role in the regulation of mitosis (Peters, 2002). In recent years, a role for APC/C in nervous system development and function has been rapidly emerging (Stegmuller and Bonni, 2005; Li et al., 2008). In the mammalian central nervous system the activator subunit, APC/C-Cdh1, has been shown to be a regulator of axon growth and dendrite morphogenesis (Konishi et al., 2004). In the Drosophila peripheral nervous system (PNS), APC2, a ligase subunit of the APC/C complex has been shown to regulate synaptic bouton size and activity (van Roessel et al., 2004). To investigate the role of APC/C-Cdh1 at the synapse we examined loss-of-function mutants of Rap/Fzr (Retina aberrant in pattern/Fizzy related), a Drosophila homolog of the mammalian Cdh1 during the development of the larval neuromuscular junction in Drosophila. Our cell biological, ultrastructural, electrophysiological, and behavioral data showed that rap/fzr loss-of-function mutations lead to changes in synaptic structure and function as well as locomotion defects. Data presented here show changes in size and morphology of synaptic boutons, and, muscle tissue organization. Electrophysiological experiments show that loss-of-function mutants exhibit increased frequency of spontaneous miniature synaptic potentials, indicating a higher rate of spontaneous synaptic vesicle fusion events. In addition, larval locomotion and peristaltic movement were also impaired. These findings suggest a role for Drosophila APC/C-Cdh1 mediated ubiquitination in regulating synaptic morphology

  3. Cocaine-Induced Changes of Synaptic Transmission in the Striatum are Modulated by Adenosine A2A Receptors and Involve the Tyrosine Phosphatase STEP

    PubMed Central

    Chiodi, Valentina; Mallozzi, Cinzia; Ferrante, Antonella; Chen, Jiang F; Lombroso, Paul J; Di Stasi, Anna Maria Michela; Popoli, Patrizia; Domenici, Maria Rosaria

    2014-01-01

    The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum and mediate, at least in part, cocaine-induced psychomotor effects in vivo. Here we studied the synaptic mechanisms implicated in the pharmacological action of cocaine in the striatum and investigated the influence of A2ARs. We found that synaptic transmission was depressed in corticostriatal slices after perfusion with cocaine (10 μM). This effect was reduced by the A2AR antagonist ZM241385 and almost abolished in striatal A2AR-knockout mice (mice lacking A2ARs in striatal neurons, stA2ARKO). The effect of cocaine on synaptic transmission was also prevented by the protein tyrosine phosphatases (PTPs) inhibitor sodium orthovanadate (Na3VO4). In synaptosomes prepared from striatal slices, we found that the activity of striatal-enriched protein tyrosine phosphatase (STEP) was upregulated by cocaine, prevented by ZM241385, and absent in synaptosomes from stA2ARKO. The role played by STEP in cocaine modulation of synaptic transmission was investigated in whole-cell voltage clamp recordings from medium spiny neurons of the striatum. We found that TAT-STEP, a peptide that renders STEP enzymatically inactive, prevented cocaine-induced reduction in AMPA- and NMDA-mediated excitatory post-synaptic currents, whereas the control peptide, TAT-myc, had no effect. These results demonstrate that striatal A2ARs modulate cocaine-induced synaptic depression in the striatum and highlight the potential role of PTPs and specifically STEP in the effects of cocaine. PMID:23989619

  4. Cocaine-induced changes of synaptic transmission in the striatum are modulated by adenosine A2A receptors and involve the tyrosine phosphatase STEP.

    PubMed

    Chiodi, Valentina; Mallozzi, Cinzia; Ferrante, Antonella; Chen, Jiang F; Lombroso, Paul J; Di Stasi, Anna Maria Michela; Popoli, Patrizia; Domenici, Maria Rosaria

    2014-02-01

    The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum and mediate, at least in part, cocaine-induced psychomotor effects in vivo. Here we studied the synaptic mechanisms implicated in the pharmacological action of cocaine in the striatum and investigated the influence of A2ARs. We found that synaptic transmission was depressed in corticostriatal slices after perfusion with cocaine (10 μM). This effect was reduced by the A2AR antagonist ZM241385 and almost abolished in striatal A2AR-knockout mice (mice lacking A2ARs in striatal neurons, stA2ARKO). The effect of cocaine on synaptic transmission was also prevented by the protein tyrosine phosphatases (PTPs) inhibitor sodium orthovanadate (Na3VO4). In synaptosomes prepared from striatal slices, we found that the activity of striatal-enriched protein tyrosine phosphatase (STEP) was upregulated by cocaine, prevented by ZM241385, and absent in synaptosomes from stA2ARKO. The role played by STEP in cocaine modulation of synaptic transmission was investigated in whole-cell voltage clamp recordings from medium spiny neurons of the striatum. We found that TAT-STEP, a peptide that renders STEP enzymatically inactive, prevented cocaine-induced reduction in AMPA- and NMDA-mediated excitatory post-synaptic currents, whereas the control peptide, TAT-myc, had no effect. These results demonstrate that striatal A2ARs modulate cocaine-induced synaptic depression in the striatum and highlight the potential role of PTPs and specifically STEP in the effects of cocaine.

  5. 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

  6. Patterns of maternal transmission in bipolar affective disorder.

    PubMed

    McMahon, F J; Stine, O C; Meyers, D A; Simpson, S G; DePaulo, J R

    1995-06-01

    The mode of inheritance of bipolar affective disorder (BPAD) appears complex, and non-Mendelian models of inheritance have been postulated. Two non-Mendelian phenomena, genomic imprinting and mitochondrial inheritance, may contribute to the complex inheritance pattern seen in BPAD. Both imprinting and mitochondrial inheritance share the feature of differential expression of the phenotype, depending on the parent of origin. In this study we tested the hypothesis of a parent-of-origin effect on the transmission of BPAD. We examined the frequency and risk of affective disorder among relatives in a sample of 31 families ascertained through treated probands with BPAD and selected for the presence of affected phenotypes in only one parental lineage. Three specific comparisons were performed: (1) the observed frequency of transmitting mothers versus transmitting fathers; (2) the observed frequency and lifetime risk of BPAD among the maternal versus the paternal relatives of probands; and (3) the observed frequency and lifetime risk of BPAD for the offspring of affected mothers compared with the offspring of affected fathers. We observed a higher than expected frequency of affected mothers (P < .04), a 2.3-2.8-fold increased risk of illness for maternal relatives (P < .006), and a 1.3- 2.5-fold increased risk of illness for the offspring of affected mothers (P < .017). In seven enlarged pedigrees, fathers repeatedly failed to transmit the affected phenotype to daughters or sons. Taken together, these findings indicate a maternal effect in the transmission of BPAD susceptibility and suggest that molecular studies of mtDNA and imprinted DNA are warranted in patients with BPAD.

  7. A transient receptor potential-like channel mediates synaptic transmission in rod bipolar cells

    PubMed Central

    Shen, Yin; Heimel, J. Alexander; Kamermans, Maarten; Peachey, Neal S.; Gregg, Ronald G.; Nawy, Scott

    2009-01-01

    On bipolar cells are connected to photoreceptors via a sign-inverting synapse. At this synapse, glutamate binds to a metabotropic receptor which couples to the closure of a cation-selective transduction channel. The molecular identity of both the receptor and the G protein are known, but the identity of the transduction channel has remained elusive. Here we show that the transduction channel in mouse rod bipolar cells, a subtype of On bipolar cell, is likely to be a member of the TRP family of channels. To evoke a transduction current, the metabotropic receptor antagonist LY341495 was applied to the dendrites of cells that were bathed in a solution containing the mGluR6 agonists L-AP4 or glutamate. The transduction current was suppressed by ruthenium red and the TRPV1 antagonists capsazepine and SB-366791. Furthermore, focal application of the TRPV1 agonists capsaicin and anandamide evoked a transduction-like current. The capsaicin-evoked and endogenous transduction current displayed prominent outward rectification, a property of the TRPV1 channel. To test the possibility that the transduction channel is TRPV1, we measured rod bipolar cell function in the TRPV1-/-mouse. The ERG b-wave, a measure of On bipolar cell function, as well as the transduction current and the response to TRPV1 agonists were normal, arguing against a role for TRPV1. However, ERG measurements from mice lacking TRPM1 receptors, another TRP channel implicated in retinal function, revealed the absence of a b-wave. Our results suggest that a TRP-like channel, possibly TRPM1, is essential for synaptic function in On bipolar cells. PMID:19439586

  8. Activation of α₁-adrenoceptors enhances excitatory synaptic transmission via a pre- and postsynaptic protein kinase C-dependent mechanism in the medial prefrontal cortex of rats.

    PubMed

    Luo, Fei; Tang, Hua; Li, Bao-ming; Li, Si-hai

    2014-04-01

    The physiological effects of α₁-adrenoceptors (α₁-ARs) have been examined in many brain regions. However, little is known about the mechanism of modulation on synaptic transmission by α₁-ARs in the medial prefrontal cortex (mPFC). The present study investigated how α₁-AR activation regulates glutamatergic synaptic transmission in layer V/VI pyramidal cells of the rat mPFC. We found that the α₁-AR agonist phenylephrine (Phe) induced a significant enhancement of the amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs). The facilitation effect of Phe on the frequency of mEPSCs involved a presynaptic protein kinase C-dependent pathway. Phe produced a significant enhancement on the amplitude of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R)- and N-methyl-D-aspartic acid receptor (NMDA-R)-mediated evoked excitatory postsynaptic currents (eEPSCs). Phe enhanced inward currents evoked by puff application of glutamate or NMDA. The Phe-induced facilitation of AMPA-R- and NMDA-R-mediated eEPSCs required, in part, postsynaptic Gq , phospholipase C and PKC. These findings suggest that α₁-AR activation facilitates excitatory synaptic transmission in mPFC pyramidal cells via both pre- and post-synaptic PKC-dependent mechanisms.

  9. Mice lacking brain/kidney phosphate-activated glutaminase (GLS1) have impaired glutamatergic synaptic transmission, altered breathing, disorganized goal-directed behavior and die shortly after birth

    PubMed Central

    Masson, Justine; Darmon, Michèle; Conjard, Agnès; Chuhma, Nao; Ropert, Nicole; Thoby-Brisson, Muriel; Foutz, Arthur S.; Parrot, Sandrine; Miller, Gretchen M.; Jorisch, Renée; Polan, Jonathan; Hamon, Michel; Hen, René; Rayport, Stephen

    2009-01-01

    Neurotransmitter glutamate has been thought to derive mainly from glutamine via the action of glutaminase type 1 (GLS1). To address the importance of this pathway in glutamatergic transmission, we knocked out GLS1 in mice. The insertion of a STOP cassette by homologous recombination produced a null allele that blocked transcription, encoded no immunoreactive protein and abolished GLS1 enzymatic activity. Null mutants were slightly smaller, were deficient in goal-directed behavior, hypoventilated and died in the first post-natal day. No gross or microscopic defects were detected in peripheral organs or in the central nervous system. In cultured neurons from the null mutants, miniature EPSC amplitude and duration were normal; however, the amplitude of evoked EPSCs decayed more rapidly with sustained 10 Hz stimulation, consistent with an observed reduction in depolarization-evoked glutamate release. Because of this activity-dependent impairment in glutamatergic transmission, we surmised that respiratory networks, which require temporal summation of synaptic input, would be particularly affected. We found that the amplitude of inspirations was decreased in vivo, chemosensitivity to CO2 was severely altered, and the frequency of pacemaker activity recorded in the respiratory generator in the Pre-Bötzinger complex, a glutamatergic brainstem network that can be isolated in vitro, was increased. Our results show that while alternate pathways to GLS1 glutamate synthesis support baseline glutamatergic transmission, the GLS1 pathway is essential for maintaining the function of active synapses, and so the mutation is associated with impaired respiratory function, abnormal goal-directed behavior and neonatal demise. PMID:16641247

  10. 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.

  11. Activation of presynaptic kainate receptors suppresses GABAergic synaptic transmission in the rat globus pallidus

    PubMed Central

    Jin, Xiao-Tao; Smith, Yoland

    2007-01-01

    The globus pallidus (GP) plays a central integrative role in the basal ganglia circuitry. It receives strong GABAergic inputs from the striatum and significant glutamatergic afferents from the subthalamic nucleus (STN). The change in firing rate and pattern of GP neurons is a cardinal feature of Parkinson’s disease pathophysiology. Kainate receptor GluR6/7 subunits immunoreactivity is expressed presynaptically in GABAergic striatopallidal terminals (Kane-Jackson and Smith 2003; Jin et al., 2006), which provides a substrate for regulation of GABAergic transmission in GP. To test this hypothesis, we recorded GABAA-mediated inhibitory postsynaptic currents (IPSCs) in the GP following electrical stimulation of the striatum. Following blockade of AMPA and NMDA receptors with selective antagonists, bath application of kainate (KA) (0.3–3 μM) reduced significantly the amplitude of evoked IPSCs. This inhibition was associated with a significant increase in paired-pulse facilitation ratio and a reduction of the frequency, but not amplitude, of miniature IPSCs (mIPSCs), suggesting a presynaptic site of KA action. The KA effects on striatopallidal GABAergic transmission were blocked by the G-protein inhibitor, N-ethylmaleimide (NEM), or protein kinase C (PKC) inhibitor calphostin C. Our results demonstrate that KAR activation inhibits GABAergic transmission through a presynaptic G protein-coupled, PKC-dependent metabotropic mechanism in the rat GP. These findings open up the possibility for the development of kainate-mediated pharmacotherapies aim at decreasing the excessive and abnormally regulated inhibition of GP neurons in Parkinson’s disease. PMID:17881134

  12. Increased Excitatory Synaptic Transmission of Dentate Granule Neurons in Mice Lacking PSD-95-Interacting Adhesion Molecule Neph2/Kirrel3 during the Early Postnatal Period

    PubMed Central

    Roh, Junyeop D.; Choi, Su-Yeon; Cho, Yi Sul; Choi, Tae-Yong; Park, Jong-Sil; Cutforth, Tyler; Chung, Woosuk; Park, Hanwool; Lee, Dongsoo; Kim, Myeong-Heui; Lee, Yeunkum; Mo, Seojung; Rhee, Jeong-Seop; Kim, Hyun; Ko, Jaewon; Choi, Se-Young; Bae, Yong Chul; Shen, Kang; Kim, Eunjoon; Han, Kihoon

    2017-01-01

    Copy number variants and point mutations of NEPH2 (also called KIRREL3) gene encoding an immunoglobulin (Ig) superfamily adhesion molecule have been linked to autism spectrum disorders, intellectual disability and neurocognitive delay associated with Jacobsen syndrome, but the physiological roles of Neph2 in the mammalian brain remain largely unknown. Neph2 is highly expressed in the dentate granule (DG) neurons of the hippocampus and is localized in both dendrites and axons. It was recently shown that Neph2 is required for the formation of mossy fiber filopodia, the axon terminal structure of DG neurons forming synapses with GABAergic neurons of CA3. In contrast, however, it is unknown whether Neph2 also has any roles in the postsynaptic compartments of DG neurons. We here report that, through its C-terminal PDZ domain-binding motif, Neph2 directly interacts with postsynaptic density (PSD)-95, an abundant excitatory postsynaptic scaffolding protein. Moreover, Neph2 protein is detected in the brain PSD fraction and interacts with PSD-95 in synaptosomal lysates. Functionally, loss of Neph2 in mice leads to age-specific defects in the synaptic connectivity of DG neurons. Specifically, Neph2−/− mice show significantly increased spontaneous excitatory synaptic events in DG neurons at postnatal week 2 when the endogenous Neph2 protein expression peaks, but show normal excitatory synaptic transmission at postnatal week 3. The evoked excitatory synaptic transmission and synaptic plasticity of medial perforant pathway (MPP)-DG synapses are also normal in Neph2−/− mice at postnatal week 3, further confirming the age-specific synaptic defects. Together, our results provide some evidence for the postsynaptic function of Neph2 in DG neurons during the early postnatal period, which might be implicated in neurodevelopmental and cognitive disorders caused by NEPH2 mutations. PMID:28381988

  13. alpha7 nicotinic acetylcholine receptors and modulation of gabaergic synaptic transmission in the hippocampus.

    PubMed

    Alkondon, M; Braga, M F; Pereira, E F; Maelicke, A; Albuquerque, E X

    2000-03-30

    The present report provides new findings regarding modulation of gamma-aminobutyric acid (GABA) transmission by alpha7 nicotinic receptor activity in CA1 interneurons of rat hippocampal slices. Recordings were obtained from tight-seal cell-attached patches of the CA1 interneurons, and agonists were delivered to the neurons via a modified U-tube. Application for 6 s of the alpha7 nicotinic receptor-selective agonist choline (> or =1 mM) to all CA1 interneurons tested triggered action potentials that were detected as fast current transients. The activity triggered by choline terminated well before the end of the agonist pulse, was blocked by the alpha7 nicotinic receptor antagonist methyllycaconitine (50 nM) and was concentration dependent; the higher the concentration of choline the higher the frequency of events and the shorter the delay for detection of the first event. In 40% of the neurons tested, choline-triggered action potentials decreased in amplitude progressively until no more events could be detected despite the presence of the agonist. Primarily, this finding could be explained by Na(+)-channel inactivation associated with membrane depolarization induced by alpha7 nicotinic receptor activation. In 60% of the neurons, the amplitude of choline-induced action potentials was sustained at the intial level, but again the activity did not last as long as the agonist pulse, in this case apparently because of agonist-induced receptor desensitization. These results altogether demonstrate that agonists interacting with alpha7 nicotinic receptors, including the natural transmitter acetylcholine and its metabolite choline, influence GABAergic transmission, not only by activating these receptors, but also by controlling the rate of Na(+)-channel inactivation and/or by inducing receptor desensitization.

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

    PubMed

    Inchauspe, Carlota González; Pilati, Nadia; Di Guilmi, Mariano N; Urbano, Francisco J; Ferrari, Michel D; van den Maagdenberg, Arn M J M; Forsythe, Ian D; Uchitel, Osvaldo D

    2015-01-01

    CaV2.1 Ca(2+) channels play a key role in triggering neurotransmitter release and mediating synaptic transmission. Familial hemiplegic migraine type-1 (FHM-1) is caused by missense mutations in the CACNA1A gene that encodes the α1A pore-forming subunit of CaV2.1 Ca(2+) channels. We used knock-in (KI) transgenic mice harbouring the pathogenic FHM-1 mutation R192Q to study inhibitory and excitatory neurotransmission in the principle neurons of the lateral superior olive (LSO) in the auditory brainstem. We tested if the R192Q FHM-1 mutation differentially affects excitatory and inhibitory synaptic transmission, disturbing the normal balance between excitation and inhibition in this nucleus. Whole cell patch-clamp was used to measure neurotransmitter elicited excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in wild-type (WT) and R192Q KI mice. Our results showed that the FHM-1 mutation in CaV2.1 channels has multiple effects. Evoked EPSC amplitudes were smaller whereas evoked and miniature IPSC amplitudes were larger in R192Q KI compared to WT mice. In addition, in R192Q KI mice, the release probability was enhanced compared to WT, at both inhibitory (0.53 ± 0.02 vs. 0.44 ± 0.01, P = 2.10(-5), Student's t-test) and excitatory synapses (0.60 ± 0.03 vs. 0.45 ± 0.02, P = 4 10(-6), Student's t-test). Vesicle pool size was diminished in R192Q KI mice compared to WT mice (68 ± 6 vs 91 ± 7, P = 0.008, inhibitory; 104 ± 13 vs 335 ± 30, P = 10(-6), excitatory, Student's t-test). R192Q KI mice present enhanced short-term plasticity. Repetitive stimulation of the afferent axons caused short-term depression (STD) of E/IPSCs that recovered significantly faster in R192Q KI mice compared to WT. This supports the hypothesis of a gain-of-function of the CaV2.1 channels in R192Q KI mice, which alters the balance of excitatory/inhibitory inputs and could also have implications in the altered cortical excitability responsible for FHM

  15. Modulation of NMDA and AMPA-mediated synaptic transmission by CB1 receptors in frontal cortical pyramidal cells.

    PubMed

    Li, Qiang; Yan, Haidun; Wilson, Wilkie A; Swartzwelder, H Scott

    2010-06-25

    Although the endogenous cannabinoid system modulates a variety of physiological and pharmacological processes, the specific role of cannabinoid CB1 receptors in the modulation of glutamatergic neurotransmission and neural plasticity is not well understood. Using whole-cell patch clamp recording techniques, evoked or spontaneous excitatory postsynaptic currents (eEPSCs or sEPSCs) were recorded from visualized, layer II/III pyramidal cells in frontal cortical slices from rat brain. Bath application of the CB1 receptor agonist, WIN 55212-2 (WIN), reduced the amplitude of NMDA receptor-mediated EPSCs in a concentration-dependent manner. When co-applied with the specific CB1 antagonists, AM251 or AM281, WIN did not suppress NMDA receptor-mediated EPSCs. WIN also reduced the amplitude of evoked AMPA receptor-mediated EPSCs, an effect that was also reversed by AM251. Both the frequency and amplitude of spontaneous AMPA receptor-mediated EPSCs were significantly reduced by WIN. In contrast, WIN reduced the frequency, but not the amplitude of miniature EPSCs, suggesting that the suppression of glutamatergic activity by CB1 receptors in the frontal neocortex is mediated by a presynaptic mechanism. Taken together, these data indicate a critical role for endocannabinoid signaling in the regulation of excitatory synaptic transmission in frontal neocortex, and suggest a possible neuronal mechanism whereby THC regulates cortical function.

  16. Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission.

    PubMed Central

    Mehler, M F; Haas, K Z; Kessler, J A; Stanton, P K

    1992-01-01

    The gene at the Duchenne/Becker muscular dystrophy locus encodes dystrophin, a member of a protein superfamily that links the actin cytoskeleton to transmembrane plasmalemmal proteins. In mature skeletal myocytes, the absence of dystrophin is associated with decreased membrane stability, altered kinetics of several calcium channels, and increased intracellular calcium concentration. In the central nervous system, dystrophin is restricted to specific neuronal populations that show heightened susceptibility to excitotoxic damage and is localized in proximal dendrites and the neuronal somata. We report that CA1 pyramidal neurons in a hippocampal slice preparation from a dystrophin-deficient mouse genetic model of Duchenne muscular dystrophy (the mdx mouse) exhibit significant increased susceptibility to hypoxia-induced damage to synaptic transmission. This selective vulnerability was substantially ameliorated by pretreatment with diphenylhydantoin, an anticonvulsant that blocks both sodium-dependent action potentials and low-threshold transient calcium conductances. These findings suggest that dystrophin deficiency could predispose susceptible neuronal populations to cumulative hypoxic insults that may contribute to the development of cognitive deficits in Duchenne/Becker muscular dystrophy patients and that the effects of such periods of hypoxia may be pharmacologically remediable. PMID:1549609

  17. TH-9 (a theophylline derivative) induces long-lasting enhancement in excitatory synaptic transmission in the rat hippocampus that is occluded by frequency-dependent plasticity in vitro.

    PubMed

    Nashawi, H; Bartl, T; Bartl, P; Novotny, L; Oriowo, M A; Kombian, S B

    2012-09-18

    Dementia, especially Alzheimer's disease, is a rapidly increasing medical condition that presents with enormous challenge for treatment. It is characterized by impairment in memory and cognitive function often accompanied by changes in synaptic transmission and plasticity in relevant brain regions such as the hippocampus. We recently synthesized TH-9, a conjugate racetam-methylxanthine compound and tested if it had potential for enhancing synaptic function and possibly, plasticity, by examining its effect on hippocampal fast excitatory synaptic transmission and plasticity. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 hippocampal area of naïve juvenile male Sprague-Dawley rats using conventional electrophysiological recording techniques. TH-9 caused a concentration-dependent, long-lasting enhancement in fEPSPs. This effect was blocked by adenosine A1, acetylcholine (muscarinic and nicotinic) and glutamate (N-methyl-d-aspartate) receptor antagonists but not by a γ-aminobutyric acid receptor type B (GABA(B)) receptor antagonist. The TH-9 effect was also blocked by enhancing intracellular cyclic adenosine monophosphate and inhibiting protein kinase A. Pretreatment with TH-9 did not prevent the induction of long-term potentiation (LTP) or long-term depression (LTD). Conversely, induction of LTP or LTD completely occluded the ability of TH-9 to enhance fEPSPs. Thus, TH-9 utilizes cholinergic and adenosinergic mechanisms to cause long-lasting enhancement in fEPSPs which were occluded by LTP and LTD. TH-9 may therefore employ similar or convergent mechanisms with frequency-dependent synaptic plasticities to produce the observed long-lasting enhancement in synaptic transmission and may thus, have potential for use in improving memory.

  18. Inhibitory effects of dopamine on spinal synaptic transmission via dopamine D1-like receptors in neonatal rats

    PubMed Central

    Kawamoto, K; Otsuguro, K; Ishizuka, M; Ito, S

    2012-01-01

    BACKGROUND AND PURPOSE Dopamine released from the endings of descending dopaminergic nerve fibres in the spinal cord may be involved in modulating functions such as locomotion and nociception. Here, we examined the effects of dopamine on spinal synaptic transmissions in rats. EXPERIMENTAL APPROACH Spinal reflex potentials, monosynaptic reflex potential (MSR) and slow ventral root potential (sVRP), were measured in the isolated spinal cord of the neonatal rat. Dopamine release was measured by HPLC. KEY RESULTS Dopamine at lower concentrations (<1 µM) depressed sVRP, which is a C fibre-evoked polysynaptic response and believed to reflect nociceptive transmission. At higher concentrations (>1 µM), in addition to a potent sVRP depression, dopamine depolarized baseline potential and slightly depressed MSR. Depression of sVRP by dopamine was partially reversed by dopamine D1-like but not by D2-like receptor antagonists. SKF83959 and SKF81297, D1-like receptor agonists, and methamphetamine, an endogenous dopamine releaser, also caused the inhibition of sVRP. Methamphetamine also depressed MSR, which was inhibited by ketanserin, a 5-HT2A/2C receptor antagonist. Methamphetamine induced the release of dopamine and 5-HT from spinal cords, indicating that the release of endogenous dopamine and 5-HT depresses sVRP and MSR respectively. CONCLUSION AND IMPLICATIONS These results suggested that dopamine at lower concentrations preferentially inhibited sVRP, which is mediated via dopamine D1-like and other unidentified receptors. The dopamine-evoked depression is involved in modulating the spinal functions by the descending dopaminergic pathways. PMID:22168428

  19. Modulation of serotonergic transmission by eltoprazine in L-DOPA-induced dyskinesia: Behavioral, molecular, and synaptic mechanisms.

    PubMed

    Ghiglieri, Veronica; Mineo, Desiree; Vannelli, Anna; Cacace, Fabrizio; Mancini, Maria; Pendolino, Valentina; Napolitano, Francesco; di Maio, Anna; Mellone, Manuela; Stanic, Jennifer; Tronci, Elisabetta; Fidalgo, Camino; Stancampiano, Roberto; Carta, Manolo; Calabresi, Paolo; Gardoni, Fabrizio; Usiello, Alessandro; Picconi, Barbara

    2016-02-01

    L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LIDs) represent the main side effect of Parkinson's Disease (PD) therapy. Among the various pharmacological targets for novel therapeutic approaches, the serotonergic system represents a promising one. In experimental models of PD and in PD patients the development of abnormal involuntary movements (AIMs) and LIDs, respectively, is accompanied by the impairment of bidirectional synaptic plasticity in key structures such as striatum. Recently, it has been shown that the 5-HT1A/1B receptor agonist, eltoprazine, significantly decreased LIDs in experimental PD and human patients. Despite the fact that several papers have tested this and other serotonergic drugs, nothing is known about the electrophysiological consequences on this combined serotonin receptors modulation at striatal neurons. The present study demonstrates that activation of 5-HT1A/1B receptors reduces AIMs via the restoration of Long-Term Potentiation (LTP) and synaptic depotentiation in a sub-set of striatal spiny projection neurons (SPNs). This recovery is associated with the normalization of D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, and the recovery of NMDA receptor subunits balance, indicating these events as key elements in AIMs induction. Moreover, we analyzed whether the manipulation of the serotonergic system might affect motor behavior and cognitive performances. We found that a defect in locomotor activity in parkinsonian and L-DOPA-treated rats was reversed by eltoprazine treatment. Conversely, the impairment in the striatal-dependent learning was found exacerbated in L-DOPA-treated rats and eltoprazine failed to recover it.

  20. Impact of post-synaptic block of neuromuscular transmission, muscle unloading and mechanical ventilation on skeletal muscle protein and mRNA expression.

    PubMed

    Norman, H; Nordquist, J; Andersson, P; Ansved, T; Tang, X; Dworkin, B; Larsson, L

    2006-10-01

    To analyse mechanisms of muscle wasting in intensive care unit patients, we developed an experimental model where rats were pharmacologically paralysed by post-synaptic block of neuromuscular transmission (NMB) and mechanically ventilated for 9+/-2 days. Specific interest was focused on the effects on protein and mRNA expression of sarcomeric proteins, i.e., myosin heavy chain (MyHC), actin, myosin-binding protein C (MyBP-C) and myosin-binding protein H (MyBP-H) in fast- and slow-twitch limb, respiratory and masticatory muscles. Muscle-specific differences were observed in response to NMB at both the protein and mRNA levels. At the protein level, a decreased MyHC-to-actin ratio was observed in all muscles excluding the diaphragm, whereas at the mRNA level a decreased expression of the dominating MyHC isoform(s) was observed in the hind limb and intercostal muscles, but not in the diaphragm and masseter muscles. MyBP-C mRNA expression was decreased in the limb muscles, but it otherwise remained unaffected. MyBP-H conversely increased in all muscles. Furthermore, we found myofibrillar protein and mRNA expression to be affected differently when comparing NMB animals with peripherally denervated (DEN) ambulatory rats. We report that NMB has both a larger and different impact on muscle, at the protein and mRNA levels, than DEN has.

  1. Electrophysiological aspects of synaptic transmission at the electromotor junction of Torpedo marmorata.

    PubMed

    Erdelyi, L; Krenz, W D

    1984-01-01

    Miniature and stimulus-evoked electroplaque potentials were recorded in Torpedo electrocytes intracellularly and extracellularly and analysed quantitatively. Tetrodotoxin reversibly blocked stimulus evoked potentials but hardly affected spontaneous miniature potentials in amplitude and frequency. The quantum content of stimulus-evoked potentials varied between 150 and 400 in normal saline and decreased in low Ca2+ high Mg2+ solution. Quantal release conformed to binomial statistics and allowed determination of the release parameters p and n. Analysis of the time constant of decay of spontaneous miniature electroplaque currents showed variation around a mean of 0.75 +/- 0.16 msec (SD) which was greatly prolonged by application of neostigmine.

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

    PubMed

    Lei, Saobo; McBain, Chris J

    2003-01-15

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

  3. Inhibition of protein kinase C affects on mode of synaptic vesicle exocytosis due to cholesterol depletion

    SciTech Connect

    Petrov, Alexey M. Zakyrjanova, Guzalija F. Yakovleva, Anastasia A. Zefirov, Andrei L.

    2015-01-02

    Highlights: • We examine the involvement of PKC in MCD induced synaptic vesicle exocytosis. • PKC inhibitor does not decrease the effect MCD on MEPP frequency. • PKC inhibitor prevents MCD induced FM1-43 unloading. • PKC activation may switch MCD induced exocytosis from kiss-and-run to a full mode. • Inhibition of phospholipase C does not lead to similar change in exocytosis. - Abstract: Previous studies demonstrated that depletion of membrane cholesterol by 10 mM methyl-beta-cyclodextrin (MCD) results in increased spontaneous exocytosis at both peripheral and central synapses. Here, we investigated the role of protein kinase C in the enhancement of spontaneous exocytosis at frog motor nerve terminals after cholesterol depletion using electrophysiological and optical methods. Inhibition of the protein kinase C by myristoylated peptide and chelerythrine chloride prevented MCD-induced increases in FM1-43 unloading, whereas the frequency of spontaneous postsynaptic events remained enhanced. The increase in FM1-43 unloading still could be observed if sulforhodamine 101 (the water soluble FM1-43 quencher that can pass through the fusion pore) was added to the extracellular solution. This suggests a possibility that exocytosis of synaptic vesicles under these conditions could occur through the kiss-and-run mechanism with the formation of a transient fusion pore. Inhibition of phospholipase C did not lead to similar change in MCD-induced exocytosis.

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

    PubMed

    Spangler, Samantha A; Schmitz, Sabine K; Kevenaar, Josta T; de Graaff, Esther; de Wit, Heidi; Demmers, Jeroen; Toonen, Ruud F; Hoogenraad, Casper C

    2013-06-10

    The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-α2 as a key organizer in this process. We show that liprin-α2 levels were regulated by synaptic activity and the ubiquitin-proteasome system. Furthermore, liprin-α2 organized presynaptic ultrastructure and controlled synaptic output by regulating synaptic vesicle pool size. The presence of liprin-α2 at presynaptic sites did not depend on other active zone scaffolding proteins but was critical for recruitment of several components of the release machinery, including RIM1 and CASK. Fluorescence recovery after photobleaching showed that depletion of liprin-α2 resulted in reduced turnover of RIM1 and CASK at presynaptic terminals, suggesting that liprin-α2 promotes dynamic scaffolding for molecular complexes that facilitate synaptic vesicle release. Therefore, liprin-α2 plays an important role in maintaining active zone dynamics to modulate synaptic efficacy in response to changes in network activity.

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

    PubMed Central

    Spangler, Samantha A.; Schmitz, Sabine K.; Kevenaar, Josta T.; de Graaff, Esther; de Wit, Heidi; Demmers, Jeroen

    2013-01-01

    The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-α2 as a key organizer in this process. We show that liprin-α2 levels were regulated by synaptic activity and the ubiquitin–proteasome system. Furthermore, liprin-α2 organized presynaptic ultrastructure and controlled synaptic output by regulating synaptic vesicle pool size. The presence of liprin-α2 at presynaptic sites did not depend on other active zone scaffolding proteins but was critical for recruitment of several components of the release machinery, including RIM1 and CASK. Fluorescence recovery after photobleaching showed that depletion of liprin-α2 resulted in reduced turnover of RIM1 and CASK at presynaptic terminals, suggesting that liprin-α2 promotes dynamic scaffolding for molecular complexes that facilitate synaptic vesicle release. Therefore, liprin-α2 plays an important role in maintaining active zone dynamics to modulate synaptic efficacy in response to changes in network activity. PMID:23751498

  6. Brain-derived neurotrophic factor (BDNF)-induced mitochondrial motility arrest and presynaptic docking contribute to BDNF-enhanced synaptic transmission.

    PubMed

    Su, Bo; Ji, Yun-Song; Sun, Xu-lu; Liu, Xiang-Hua; Chen, Zhe-Yu

    2014-01-17

    Appropriate mitochondrial transport and distribution are essential for neurons because of the high energy and Ca(2+) buffering requirements at synapses. Brain-derived neurotrophic factor (BDNF) plays an essential role in regulating synaptic transmission and plasticity. However, whether and how BDNF can regulate mitochondrial transport and distribution are still unclear. Here, we find that in cultured hippocampal neurons, application of BDNF for 15 min decreased the percentage of moving mitochondria in axons, a process dependent on the activation of the TrkB receptor and its downstream PI3K and phospholipase-Cγ signaling pathways. Moreover, the BDNF-induced mitochondrial stopping requires the activation of transient receptor potential canonical 3 and 6 (TRPC3 and TRPC6) channels and elevated intracellular Ca(2+) levels. The Ca(2+) sensor Miro1 plays an important role in this process. Finally, the BDNF-induced mitochondrial stopping leads to the accumulation of more mitochondria at presynaptic sites. Mutant Miro1 lacking the ability to bind Ca(2+) prevents BDNF-induced mitochondrial presynaptic accumulation and synaptic transmission, suggesting that Miro1-mediated mitochondrial motility is involved in BDNF-induced mitochondrial presynaptic docking and neurotransmission. Together, these data suggest that mitochondrial transport and distribution play essential roles in BDNF-mediated synaptic transmission.

  7. The Ih Channel Gene Promotes Synaptic Transmission and Coordinated Movement in Drosophila melanogaster

    PubMed Central

    Hegle, Andrew P.; Frank, C. Andrew; Berndt, Anthony; Klose, Markus; Allan, Douglas W.; Accili, Eric A.

    2017-01-01

    Hyperpolarization-activated cyclic nucleotide-gated “HCN” channels, which underlie the hyperpolarization-activated current (Ih), have been proposed to play diverse roles in neurons. The presynaptic HCN channel is thought to both promote and inhibit neurotransmitter release from synapses, depending upon its interactions with other presynaptic ion channels. In larvae of Drosophila melanogaster, inhibition of the presynaptic HCN channel by the drug ZD7288 reduces the enhancement of neurotransmitter release at motor terminals by serotonin but this drug has no effect on basal neurotransmitter release, implying that the channel does not contribute to firing under basal conditions. Here, we show that genetic disruption of the sole HCN gene (Ih) reduces the amplitude of the evoked response at the neuromuscular junction (NMJ) of third instar larvae by decreasing the number of released vesicles. The anatomy of the (NMJ) is not notably affected by disruption of the Ih gene. We propose that the presynaptic HCN channel is active under basal conditions and promotes neurotransmission at larval motor terminals. Finally, we demonstrate that Ih partial loss-of-function mutant adult flies have impaired locomotion, and, thus, we hypothesize that the presynaptic HCN channel at the (NMJ) may contribute to coordinated movement. PMID:28286469

  8. Developmental nicotine exposure enhances inhibitory synaptic transmission in motor neurons and interneurons critical for normal breathing

    PubMed Central

    Jaiswal, Stuti J.; Wollman, Lila Buls; Harrison, Caitlyn M.; Pilarski, Jason Q.; Fregosi, Ralph F.

    2015-01-01

    Nicotine exposure in utero negatively affects neuronal growth, differentiation and synaptogenesis. We used rhythmic brainstems slices and immunohistochemistry to determine how developmental nicotine exposure (DNE) alters inhibitory neurotransmission in two regions essential to normal breathing, the hypoglossal motor nucleus (XIIn) and preBötzinger complex (preBötC). We microinjected glycine or muscimol (GABAA agonist) into the XIIn or preBötC of rhythmic brainstem slices from neonatal rats while recording from XII nerve roots to obtain XII motoneuron population activity. Injection of glycine or muscimol into the XIIn reduced XII nerve burst amplitude, while injection into the preBötC altered nerve burst frequency. These responses were exaggerated in preparations from DNE animals. Quantitative immunohistochemistry revealed a significantly higher GABAA receptor density on XII motoneurons from DNE pups. There were no differences in GABAA receptor density in the preBötC, and there were no differences in glycine receptor expression in either region. Nicotine, in the absence of other chemicals in tobacco smoke, alters normal development of brainstem circuits that are critical for normal breathing. PMID:26097160

  9. Chronic intermittent hypoxia affects endogenous serotonergic inputs and expression of synaptic proteins in rat hypoglossal nucleus

    PubMed Central

    Wu, Xu; Lu, Huan; Hu, Lijuan; Gong, Wankun; Wang, Juan; Fu, Cuiping; Liu, Zilong; Li, Shanqun

    2017-01-01

    Evidence has shown that hypoxic episodes elicit hypoglossal neuroplasticity which depends on elevated serotonin (5-HT), in contrast to the rationale of obstructive sleep apnea (OSA) that deficient serotonergic input to HMs fails to keep airway patency. Therefore, understanding of the 5-HT dynamic changes at hypoglossal nucleus (HN) during chronic intermittent hypoxia (CIH) will be essential to central pathogenic mechanism and pharmacological therapy of OSA. Moreover, the effect of CIH on BDNF-TrkB signaling proteins was quantified in an attempt to elucidate cellular cascades/synaptic mechanisms following 5-HT alteration. Male rats were randomly exposed to normal air (control), intermittent hypoxia of 3 weeks (IH3) and 5 weeks (IH5) groups. Through electrical stimulation of dorsal raphe nuclei (DRN), we conducted amperometric technique with carbon fiber electrode in vivo to measure the real time release of 5-HT at XII nucleus. 5-HT2A receptors immunostaining measured by intensity and c-Fos quantified visually were both determined by immunohistochemistry. CIH significantly reduced endogenous serotonergic inputs from DRN to XII nucleus, shown as decreased peak value of 5-HT signals both in IH3 and IH5groups, whereas time to peak and half-life period of 5-HT were unaffected. Neither 5-HT2A receptors nor c-Fos expression in HN were significantly altered by CIH. Except for marked increase in phosphorylation of ERK in IH5 rats, BDNF-TrkB signaling and synaptophys consistently demonstrated downregulated levels. These results suggest that the deficiency of 5-HT and BDNF-dependent synaptic proteins in our CIH protocol contribute to the decompensated mechanism of OSA. PMID:28337282

  10. Neonatal nicotine exposure increases excitatory synaptic transmission and attenuates nicotine-stimulated GABA release in the adult rat hippocampus.

    PubMed

    Damborsky, Joanne C; Griffith, William H; Winzer-Serhan, Ursula H

    2015-01-01

    Developmental exposure to nicotine has been linked to long-lasting changes in synaptic transmission which may contribute to behavioral abnormalities seen in offspring of women who smoke during pregnancy. Here, we examined the long-lasting effects of developmental nicotine exposure on glutamatergic and GABAergic neurotransmission, and on acute nicotine-induced glutamate and GABA release in the adult hippocampus, a structure important in cognitive and emotional behaviors. We utilized a chronic neonatal nicotine treatment model to administer nicotine (6 mg/kg/day) to rat pups from postnatal day (P) 1-7, a period that falls developmentally into the third human trimester. Using whole-cell voltage clamp recordings from CA1 pyramidal neurons in hippocampal slices, we measured excitatory and inhibitory postsynaptic currents in neonatally control- and nicotine-treated young adult males. Neonatal nicotine exposure significantly increased AMPA receptor-mediated spontaneous and evoked excitatory signaling, with no change in glutamate release probability in adults. Conversely, there was no increase in spontaneous GABAergic neurotransmission in nicotine-males. Chronic neonatal nicotine treatment had no effect on acute nicotine-stimulated glutamate release in adults, but acute nicotine-stimulated GABA release was significantly attenuated. Thus, neonatal nicotine exposure results in a persistent net increase in excitation and a concurrent loss of nicotinic acetylcholine receptor (nAChR)-mediated regulation of presynaptic GABA but not glutamate release, which would exacerbate excitation following endogenous or exogenous nAChR activation. Our data underscore an important role for nAChRs in hippocampal excitatory synapse development, and suggest selective long-term changes at specific presynaptic nAChRs which together could explain some of the behavioral abnormalities associated with maternal smoking.

  11. 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.

  12. Calcium binding by synaptotagmin's C2A domain is an essential element of the electrostatic switch that triggers synchronous synaptic transmission.

    PubMed

    Striegel, Amelia R; Biela, Laurie M; Evans, Chantell S; Wang, Zhao; Delehoy, Jillian B; Sutton, R Bryan; Chapman, Edwin R; Reist, Noreen E

    2012-01-25

    Synaptotagmin is the major calcium sensor for fast synaptic transmission that requires the synchronous fusion of synaptic vesicles. Synaptotagmin contains two calcium-binding domains: C2A and C2B. Mutation of a positively charged residue (R233Q in rat) showed that Ca2+-dependent interactions between the C2A domain and membranes play a role in the electrostatic switch that initiates fusion. Surprisingly, aspartate-to-asparagine mutations in C2A that inhibit Ca2+ binding support efficient synaptic transmission, suggesting that Ca2+ binding by C2A is not required for triggering synchronous fusion. Based on a structural analysis, we generated a novel mutation of a single Ca2+-binding residue in C2A (D229E in Drosophila) that inhibited Ca2+ binding but maintained the negative charge of the pocket. This C2A aspartate-to-glutamate mutation resulted in ∼80% decrease in synchronous transmitter release and a decrease in the apparent Ca2+ affinity of release. Previous aspartate-to-asparagine mutations in C2A partially mimicked Ca2+ binding by decreasing the negative charge of the pocket. We now show that the major function of Ca2+ binding to C2A is to neutralize the negative charge of the pocket, thereby unleashing the fusion-stimulating activity of synaptotagmin. Our results demonstrate that Ca2+ binding by C2A is a critical component of the electrostatic switch that triggers synchronous fusion. Thus, Ca2+ binding by C2B is necessary and sufficient to regulate the precise timing required for coupling vesicle fusion to Ca2+ influx, but Ca2+ binding by both C2 domains is required to flip the electrostatic switch that triggers efficient synchronous synaptic transmission.

  13. Positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators have different impact on synaptic transmission in the thalamus and hippocampus.

    PubMed

    Xia, Yan-Fang; Kessler, Markus; Arai, Amy C

    2005-04-01

    Earlier studies showed that positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors enhance synaptic responses and facilitate synaptic plasticity. Those studies focused mainly on hippocampal functions. However, AMPA receptors have regionally distinct subunit compositions and thus potencies and efficacies of modulators may vary across the brain. The present study compared the effects of CX546 [1-(1,4-benzodioxan-6-ylcarbonyl) piperidine], a benzamide-type modulator, on synaptic transmission in neurons of the reticular thalamic nucleus (RTN), which regulates the firing mode of relay cells in other thalamic nuclei, and on hippocampal CA1 pyramidal cells. CX546 greatly prolonged synaptic responses in CA1 pyramidal cells, but at the same concentration it had only weak modulatory effects in RTN neurons. Effects on miniature excitatory postsynaptic currents (EPSCs) were similar to those on EPSCs in both regions, suggesting that variations in neuronal morphology and transmitter release kinetics do not account for the differences. Relay cells in the ventrobasal thalamus also exhibited weak modulatory effects that were comparable with those in RTN neurons. Regionally different effects on response duration were also observed with CX516 [BDP-12, 1-(quinoxalin-6-ylcarbonyl)piperidine], a second benzamide drug. In contrast, 100 microM cyclothiazide produced comparable synaptic enhancements in hippocampus and RTN. The regional selectivity of benzamide drugs (ampakines) may be explained, at least in part, by a lower potency at thalamic AMPA receptors, perhaps due to the prevalence of the subunits GluR3 and 4. Although regional preferences of the ampakines were modest in their extent, they may be sufficient to be of relevance when considering future therapeutic applications of such compounds.

  14. Astrocytes optimize synaptic fidelity

    NASA Astrophysics Data System (ADS)

    Nadkarni, Suhita; Jung, Peter; Levine, Herbert

    2007-03-01

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

  15. Regulation of synaptic transmission at the photoreceptor terminal: a novel role for the cation–chloride co-transporter NKCC1

    PubMed Central

    Shen, Wen; Purpura, Lauren A; Li, Baoqin; Nan, Changlong; Chang, Irene J; Ripps, Harris

    2013-01-01

    The Na+–K+–2Cl− co-transporter type 1 (NKCC1) is localized primarily throughout the outer plexiform layer (OPL) of the distal retina, a synaptic lamina that is comprised of the axon terminals of photoreceptors and the dendrites of horizontal and bipolar cells. Although known to play a key role in development, signal transmission and the gating of sensory signals in other regions of the retina and in the CNS, the contribution of NKCC1 to synaptic transmission within the OPL is largely unknown. In the present study, we investigated the function of NKCC1 at the photoreceptor–horizontal cell synapse by recording the electrical responses of photoreceptors and horizontal cells before and after blocking the activity of the transporter with bumetanide (BMN). Because NKCC1 co-transports 1 Na+, 1 K+ and 2 Cl−, it is electroneutral and its activation had little effect on membrane conductance. However, recordings from postsynaptic horizontal cells revealed that inhibiting NKCC1 with BMN greatly increased glutamate release from both rod and cone terminals. In addition, we found that NKCC1 directly regulates Ca2+-dependent exocytosis at the photoreceptor synapse, raising the possibility that NKCC1 serves to suppress bulk release of glutamate vesicles from photoreceptor terminals in the dark and at light offset. Interestingly, NKCC1 gene and protein expressions were upregulated by light, which we attribute to the light-induced release of dopamine acting on D1-like receptors. In sum, our study reveals a new role for NKCC1 in the regulation of synaptic transmission in photoreceptors. PMID:23090945

  16. Synaptic connectivity in engineered neuronal networks.

    PubMed

    Molnar, Peter; Kang, Jung-Fong; Bhargava, Neelima; Das, Mainak; Hickman, James J

    2014-01-01

    We have developed a method to organize cells in dissociated cultures using engineered chemical clues on a culture surface and determined their connectivity patterns. Although almost all elements of the synaptic transmission machinery can be studied separately in single cell models in dissociated cultures, the complex physiological interactions between these elements are usually lost. Thus, factors affecting synaptic transmission are generally studied in organotypic cultures, brain slices, or in vivo where the cellular architecture generally remains intact. However, by utilizing engineered neuronal networks complex phenomenon such as synaptic transmission or synaptic plasticity can be studied in a simple, functional, cell culture-based system. We have utilized self-assembled monolayers and photolithography to create the surface templates. Embryonic hippocampal cells, plated on the resultant patterns in serum-free medium, followed the surface clues and formed the engineered neuronal networks. Basic whole-cell patch-clamp electrophysiology was applied to characterize the synaptic connectivity in these engineered two-cell networks. The same technology has been used to pattern other cell types such as cardiomyocytes or skeletal muscle fibers.

  17. The Kinase Function of MSK1 Regulates BDNF Signaling to CREB and Basal Synaptic Transmission, But Is Not Required for Hippocampal Long-Term Potentiation or Spatial Memory

    PubMed Central

    Daumas, Stephanie; Hunter, Christopher J.; Mistry, Rajen B.; Cooper, Daniel D.; Reyskens, Kathleen M.; Flynn, Harry T.

    2017-01-01

    Abstract The later stages of long-term potentiation (LTP) in vitro and spatial memory in vivo are believed to depend upon gene transcription. Accordingly, considerable attempts have been made to identify both the mechanisms by which transcription is regulated and indeed the gene products themselves. Previous studies have shown that deletion of one regulator of transcription, the mitogen- and stress-activated kinase 1 (MSK1), causes an impairment of spatial memory. Given the ability of MSK1 to regulate gene expression via the phosphorylation of cAMP response element binding protein (CREB) at serine 133 (S133), MSK1 is a plausible candidate as a prime regulator of transcription underpinning synaptic plasticity and learning and memory. Indeed, prior work has revealed the necessity for MSK1 in homeostatic and experience-dependent synaptic plasticity. However, using a knock-in kinase-dead mouse mutant of MSK1, the current study demonstrates that, while the kinase function of MSK1 is important in regulating the phosphorylation of CREB at S133 and basal synaptic transmission in hippocampal area CA1, it is not required for metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD), two forms of LTP or several forms of spatial learning in the watermaze. These data indicate that other functions of MSK1, such as a structural role for the whole enzyme, may explain previous observations of a role for MSK1 in learning and memory. PMID:28275711

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

    PubMed Central

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

    2016-01-01

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

  19. NMDA receptor dysfunction contributes to impaired brain-derived neurotrophic factor-induced facilitation of hippocampal synaptic transmission in a Tau transgenic model.

    PubMed

    Burnouf, Sylvie; Martire, Alberto; Derisbourg, Maxime; Laurent, Cyril; Belarbi, Karim; Leboucher, Antoine; Fernandez-Gomez, Francisco J; Troquier, Laetitia; Eddarkaoui, Sabiha; Grosjean, Marie-Eve; Demeyer, Dominique; Muhr-Tailleux, Anne; Buisson, Alain; Sergeant, Nicolas; Hamdane, Malika; Humez, Sandrine; Popoli, Patrizia; Buée, Luc; Blum, David

    2013-02-01

    While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies.

  20. Activation of Phosphatidylinositol-Linked Dopamine Receptors Induces a Facilitation of Glutamate-Mediated Synaptic Transmission in the Lateral Entorhinal Cortex

    PubMed Central

    Glovaci, Iulia; Chapman, C. Andrew

    2015-01-01

    The lateral entorhinal cortex receives strong inputs from midbrain dopamine neurons that can modulate its sensory and mnemonic function. We have previously demonstrated that 1 µM dopamine facilitates synaptic transmission in layer II entorhinal cortex cells via activation of D1-like receptors, increased cAMP-PKA activity, and a resulting enhancement of AMPA-receptor mediated currents. The present study assessed the contribution of phosphatidylinositol (PI)-linked D1 receptors to the dopaminergic facilitation of transmission in layer II of the rat entorhinal cortex, and the involvement of phospholipase C activity and release of calcium from internal stores. Whole-cell patch-clamp recordings of glutamate-mediated evoked excitatory postsynaptic currents were obtained from pyramidal and fan cells. Activation of D1-like receptors using SKF38393, SKF83959, or 1 µM dopamine induced a reversible facilitation of EPSCs which was abolished by loading cells with either the phospholipase C inhibitor U-73122 or the Ca2+ chelator BAPTA. Neither the L-type voltage-gated Ca2+ channel blocker nifedipine, nor the L/N-type channel blocker cilnidipine, blocked the facilitation of synaptic currents. However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3) receptors or ryanodine receptors. Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36) completely blocked the dopamine-induced facilitation. Overall, in addition to our previous report indicating a role for the cAMP-PKA pathway in dopamine-induced facilitation of synaptic transmission, we demonstrate here that the dopaminergic facilitation of synaptic responses in layer II entorhinal neurons also relies on a signaling cascade dependent on PI-linked D1 receptors, PLC, release of Ca2+ from internal stores, and PKC activation which is likely dependent

  1. 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.

  2. Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid 'Spice' compounds: comparison with Δ(9) -tetrahydrocannabinol.

    PubMed

    Hoffman, Alexander F; Lycas, Matthew D; Kaczmarzyk, Jakub R; Spivak, Charles E; Baumann, Michael H; Lupica, Carl R

    2017-03-01

    There has been a marked increase in the availability of synthetic drugs designed to mimic the effects of marijuana. These cannabimimetic drugs, sold illicitly as 'Spice' and related products, are associated with serious medical complications in some users. In vitro studies suggest that synthetic cannabinoids in these preparations are potent agonists at central cannabinoid CB1 receptors (CB1Rs), but few investigations have delineated their cellular effects, particularly in comparison with the psychoactive component of marijuana, Δ(9) -tetrahydrocannabinol (Δ(9) -THC). We compared the ability of three widely abused synthetic cannabinoids and Δ(9) -THC to alter glutamate release and long-term potentiation in the mouse hippocampus. JWH-018 was the most potent inhibitor of hippocampal synaptic transmission (EC50 ~15 nM), whereas its fluoropentyl derivative, AM2201, inhibited synaptic transmission with slightly lower potency (EC50 ~60 nM). The newer synthetic cannabinoid, XLR-11, displayed much lower potency (EC50 ~900 nM) that was similar to Δ(9) -THC (EC50 ~700 nM). The effects of all compounds occurred via activation of CB1Rs, as demonstrated by reversal with the selective antagonist/inverse agonist AM251 or the neutral CB1R antagonist PIMSR1. Moreover, AM2201 was without effect in the hippocampus of transgenic mice lacking the CB1R. Hippocampal slices exposed to either synthetic cannabinoids or Δ(9) -THC exhibited significantly impaired long-term potentiation (LTP). We find that, compared with Δ(9) -THC, the first-generation cannabinoids found in Spice preparations display higher potency, whereas a recent synthetic cannabinoid is roughly equipotent with Δ(9) -THC. The disruption of synaptic function by these synthetic cannabinoids is likely to lead to profound impairments in cognitive and behavioral function.

  3. Decreased anxiety, altered place learning, and increased CA1 basal excitatory synaptic transmission in mice with conditional ablation of the neural cell adhesion molecule L1.

    PubMed

    Law, Janice W S; Lee, Alan Y W; Sun, Mu; Nikonenko, Alexander G; Chung, Sookja K; Dityatev, Alexander; Schachner, Melitta; Morellini, Fabio

    2003-11-12

    L1, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation and axon outgrowth and guidance. Mutations in the human and mouse L1 gene result in similarly severe neurological abnormalities. To dissociate the functional roles of L1 in the adult brain from developmental abnormalities, we have generated a mutant in which the L1 gene is inactivated by cre-recombinase under the control of the calcium/calmodulin-dependent kinase II promoter. This mutant (L1fy+) did not show the overt morphological and behavioral abnormalities observed previously in constitutive L1-deficient (L1-/-) mice; however, there was an increase in basal excitatory synaptic transmission that was not apparent in L1-/- mice. Similar to L1-/- mice, no defects in short- and long-term potentiation in the CA1 region of the hippocampus were observed. Interestingly, L1fy+ mice showed decreased anxiety in the open field and elevated plus-maze, contrary to L1-/- mice, and altered place learning in the water maze, similar to L1-/- mice. Thus, mice conditionally deficient in L1 expression in the adult brain share some abnormalities, but also display different ones, as compared with L1-/- mice, highlighting the role of L1 in the regulation of synaptic transmission and behavior in adulthood.

  4. Cocaine differentially affects synaptic activity in memory and midbrain areas of female and male rats: an in vivo MEMRI study.

    PubMed

    Perez, Pablo D; Hall, Gabrielle; Zubcevic, Jasenka; Febo, Marcelo

    2017-02-24

    Manganese enhanced magnetic resonance imaging (MEMRI) has been previously used to determine the effect of acute cocaine on calcium-dependent synaptic activity in male rats. However, there have been no MEMRI studies examining sex differences in the functional neural circuits affected by repeated cocaine. In the present study, we used MEMRI to investigate the effects of repeated cocaine on brain activation in female and male rats. Adult female and male rats were scanned at 4.7 Tesla three days after final treatment with saline, a single cocaine injection (15 mg kg(-1), i.p. × 1 day) or repeated cocaine injections (15 mg kg(-1), i.p. × 10 days). A day before imaging rats were provided with an i.p. injection of manganese chloride (70 mg kg(-1)). Cocaine produced effects on MEMRI activity that were dependent on sex. In females, we observed that a single cocaine injection reduced MEMRI activity in hippocampal CA3, ventral tegmental area (VTA), and median Raphé, whereas repeated cocaine increased MEMRI activity in dentate gyrus and interpeduncular nucleus. In males, repeated cocaine reduced MEMRI activity in VTA. Overall, it appeared that female rats showed a general trend towards increase MEMRI activity with single cocaine and reduced activity with repeated exposure, while male rats showed a trend towards opposite effects. Our results provide evidence for sex differences in the in vivo neural response to cocaine, which involves primarily hippocampal, amygdala and midbrain areas.

  5. Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction

    PubMed Central

    Antonelli, Roberta; Pizzarelli, Rocco; Pedroni, Andrea; Fritschy, Jean-Marc; Del Sal, Giannino; Cherubini, Enrico; Zacchi, Paola

    2014-01-01

    The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis–trans isomerase Pin1. This signalling cascade negatively regulates NL2’s ability to interact with gephyrin at GABAergic post-synaptic sites. As a consequence, enhanced accumulation of NL2, gephyrin and GABAA receptors was detected at GABAergic synapses in the hippocampus of Pin1-knockout mice (Pin1−/−) associated with an increase in amplitude of spontaneous GABAA-mediated post-synaptic currents. Our results suggest that Pin1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NL2/gephyrin interaction. PMID:25297980

  6. Motor dysfunction and altered synaptic transmission at the parallel fiber-Purkinje cell synapse in mice lacking potassium channels Kv3.1 and Kv3.3.

    PubMed

    Matsukawa, Hiroshi; Wolf, Alexander M; Matsushita, Shinichi; Joho, Rolf H; Knöpfel, Thomas

    2003-08-20

    Micelacking both Kv3.1 and both Kv3.3 K+ channel alleles display severe motor deficits such as tremor, myoclonus, and ataxic gait. Micelacking one to three alleles at the Kv3.1 and Kv3.3 loci exhibit in an allele dose-dependent manner a modest degree of ataxia. Cerebellar granule cells coexpress Kv3.1 and Kv3.3 K+ channels and are therefore candidate neurons that might be involved in these behavioral deficits. Hence, we investigated the synaptic mechanisms of transmission in the parallel fiber-Purkinje cell system. Action potentials of parallel fibers were broader in mice lacking both Kv3.1 and both Kv3.3 alleles and in mice lacking both Kv3.1 and a single Kv3.3 allele compared with those of wild-type mice. The transmission of high-frequency trains of action potentials was only impaired at 200 Hz but not at 100 Hz in mice lacking both Kv3.1 and Kv3.3 genes. However, paired-pulse facilitation (PPF) at parallel fiber-Purkinje cell synapses was dramatically reduced in a gene dose-dependent manner in mice lacking Kv3.1 or Kv3.3 alleles. Normal PPF could be restored by reducing the extracellular Ca2+ concentration indicating that increased activity-dependent presynaptic Ca2+ influx, at least in part caused the altered PPF in mutant mice. Induction of metabotropic glutamate receptor-mediated EPSCs was facilitated, whereas longterm depression was not impaired but rather facilitated in Kv3.1/Kv3.3 double-knockout mice. These results demonstrate the importance of Kv3 potassium channels in regulating the dynamics of synaptic transmission at the parallel fiber-Purkinje cell synapse and suggest a correlation between short-term plasticity at the parallel fiber-Purkinje cell synapse and motor performance.

  7. Neuroligin-2 deletion selectively decreases inhibitory synaptic transmission originating from fast-spiking, but not from somatostatin-positive interneurons

    PubMed Central

    Gibson, Jay R.; Huber, Kimberly M.; Südhof, Thomas C.

    2009-01-01

    Neuroligins are cell-adhesion molecules involved in synapse formation and/or function. Neurons express four neuroligins (NL1–NL4), of which NL1 is specific to excitatory, and NL2 to inhibitory synapses. Excitatory and inhibitory synapses include numerous subtypes. However, it is unknown whether NL1 performs similar functions in all excitatory and NL2 in all inhibitory synapses, or whether they regulate the formation and/or function of specific subsets of synapses. To address this central question, we performed paired recordings in primary somatosensory cortex of mice lacking NL1 or NL2. Using this system, we examined neocortical microcircuits formed by reciprocal synapses between excitatory neurons and two subtypes of inhibitory interneurons, namely fast-spiking and somatostatin-positive interneurons. We find that the NL1 deletion had little effect on inhibitory synapses, whereas the NL2 deletion decreased (40–50%) the unitary (cell-to-cell) IPSC amplitude evoked from single fast-spiking interneurons. Strikingly, the NL2 deletion had no effect on IPSC amplitude evoked from single somatostatin-positive inhibitory interneurons. Moreover, the frequency of unitary synaptic connections between individual fast-spiking and somatostatin-positive interneurons and excitatory neurons was unchanged. The decrease in unitary IPSC amplitude originating from fast-spiking interneurons in NL2-deficient mice was due to a multiplicative and uniform down-scaling of the amplitude distribution, which in turn was mediated by a decrease in both synaptic quantal amplitude and quantal content – the latter inferred from an increase in the coefficient of variation. Thus, NL2 is not necessary for establishing unitary inhibitory synaptic connections, but is selectively required for “scaling up” unitary connections originating from a subset of interneurons. PMID:19889999

  8. Factors that affect the fatigue strength of power transmission shafting

    NASA Technical Reports Server (NTRS)

    Loewenthal, S. H.

    1984-01-01

    A long standing objective in the design of power transmission shafting is to eliminate excess shaft material without compromising operational reliability. A shaft design method is presented which accounts for variable amplitude loading histories and their influence on limited life designs. The effects of combined bending and torsional loading are considered along with a number of application factors known to influence the fatigue strength of shafting materials. Among the factors examined are surface condition, size, stress concentration, residual stress and corrosion fatigue.

  9. Changes in action potential duration alter reliance of excitatory synaptic transmission on multiple types of Ca2+ channels in rat hippocampus.

    PubMed

    Wheeler, D B; Randall, A; Tsien, R W

    1996-04-01

    It has been established that multiple types of Ca2+ channels participate in triggering neurotransmitter release at central synapses, but there is uncertainty about the nature of their combined actions. We investigated synaptic transmission at CA3-CA1 synapses of rat hippocampal slices and asked whether the dependence on omega-CTx-GVIA-sensitive N-type channels and omega-Aga-IVA-sensitive P/Q-type Ca2+ channels can be altered by physiological mechanisms. The reliance on multiple types of Ca2+ channels was not absolute but depended strongly on the amount of Ca2+ influx through individual channels, which was manipulated by prolonging the presynaptic action potential with the K+ channel blocker 4-aminopyridine (4-AP) and by varying the extracellular Ca2+ concentration ([Ca2+]o). We quantified the influence of spike broadening on Ca2+ influx through various Ca2+ channels by imposing mock action potentials on voltage-clamped cerebellar granule neurons. In field recordings of the EPSP in hippocampal slices, action potential prolongation increased the EPSP slope by 2-fold and decreased its reliance on either N-type or P/Q-type Ca2+ channels. The inhibition of synaptic transmission by N-type channel blockade was virtually eliminated in the presence of 4-AP, but it could be restored by lowering [Ca2+]o. These results rule out a scenario in which a significant fraction of presynaptic terminals rely solely on N-type channels to trigger transmission. The change in sensitivity to the neurotoxins with 4-AP could be explained in terms of a nonlinear relationship between Ca2+ entry and synaptic strength, which rises steeply at low [Ca2+]o, but approaches saturation at high [Ca2+]o. This relationship was evaluated experimentally by varying [CA2+]o in the absence and presence of 4-AP. One consequence of this relationship is that down-modulation of presynaptic Ca2+ channels by various modulators would increase the relative impact of spike broadening greatly.

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

    SciTech Connect

    Curnish, R.; Bencherif, M.; Rubio, R.; Berne, R.M.

    1986-03-05

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

  11. Dissociation of CA3 pyramidal cells with attached, functional, identified mossy fiber and interneuronal boutons for studying glutamatergic and GABAergic synaptic transmission.

    PubMed

    Beltrán, Jesús Q; Reyes, Sebastián; Pérez-Guzmán, José A; Elías-Viñas, David; Gutiérrez, Rafael

    2012-07-15

    Pyramidal cells of CA3 area receive glutamatergic signals from the mossy fibers (MFs), perforant path and collaterals of other pyramidal cells, as well as GABAergic inputs from interneurons. In hippocampal slices, an extracellular stimulation electrode is often used to activate the MFs, with the disadvantage of possibly activating fibers other than MFs. We set-up a preparation that allows the analysis of the glutamatergic input from identified, giant MF boutons as well as of GABAergic inputs from boutons of interneurons on single CA3 pyramidal cells. Mossy fiber boutons were labeled by exposing hippocampal slices to a zinc-reactive fluorescent dye, or by injecting a fluorescent dye in the granule cell layer and allowing its transport along the MFs to their terminals in CA3 area. After conducting an enzyme-free, mechanical dissociation of CA3 area, we obtained pyramidal cells containing fluorescent, giant MF boutons attached to their apical dendrites, as well as boutons of interneuronal origin. Whole cell recordings were then performed, whereby synaptic responses could be evoked by selective stimulation of the identified boutons. The synaptic currents evoked by stimulation of MF boutons, unlike those evoked by stimulation of interneuronal boutons, underwent strong frequency potentiation and were depressed by activation of metabotropic glutamate receptors, which are characteristics of transmission of MF origin. Combination of fluorophores can be used to label different tracts/boutons allowing the study of the different characteristics of neurotransmitter release from a variety of sources on single target cells.

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

    PubMed

    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.

  14. Ethanol potentiation of GABAergic synaptic transmission may be self-limiting: role of presynaptic GABA(B) receptors.

    PubMed

    Ariwodola, Olusegun J; Weiner, Jeffrey L

    2004-11-24

    Ethanol enhances GABAergic synaptic inhibition, and this interaction contributes to many of the behavioral and cognitive effects of this drug. Most studies suggest that ethanol enhances GABAergic neurotransmission via an allosteric potentiation of the postsynaptic GABA(A) receptors that mediate fast synaptic inhibition in the mammalian CNS. Despite widespread acceptance of this hypothesis, direct support for such a mechanism has been difficult to obtain. Ethanol does not enhance GABA(A) receptor function in all brain regions or under all experimental conditions, and factors responsible for this variability remain mostly unknown. Notably, blockade of GABA(B) receptors dramatically enhances ethanol potentiation of hippocampal GABA(A) IPSPs and IPSCs, suggesting that some unknown GABA(B) receptor mechanism limits the overall potentiating effect of ethanol on GABAergic synapses. In this study, we demonstrate that, at perisomatic synapses in the rat hippocampus, ethanol enhances presynaptic GABA(B) autoreceptor function and that this interaction reduces the overall potentiating effect of ethanol at these synapses. We further show that ethanol significantly elevates basal presynaptic GABA(B) receptor tone, possibly via an increase in spontaneous GABA release, and that pretreatment with a subthreshold concentration of the GABA(B) receptor agonist baclofen blocks ethanol but not flunitrazepam or pentobarbital potentiation of GABA(A) IPSCs. These data suggest that an interaction between ethanol and presynaptic GABA(B) autoreceptor activity regulates the ethanol sensitivity of GABAergic synapses. Given that the in vitro ethanol sensitivity of these synapses correlates with in vivo ethanol responsiveness in a number of rodent lines, our data further suggest that presynaptic GABA(B) receptor activity may play a role in regulating behavioral sensitivity to ethanol.

  15. Virtual leak channels modulate firing dynamics and synaptic integration in rat sympathetic neurons: implications for ganglionic transmission in vivo

    PubMed Central

    Springer, Mitchell G; Kullmann, Paul H M; Horn, John P

    2015-01-01

    Abstract The excitability of rat sympathetic neurons and integration of nicotinic EPSPs were compared in primary cell culture and in the acutely isolated intact superior cervical ganglion using whole cell patch electrode recordings. When repetitive firing was classified by Hodgkin's criteria in cultured cells, 18% displayed tonic class 1 excitability, 36% displayed adapting class 2 excitability and 46% displayed phasic class 3 excitability. In the intact ganglion, 71% of cells were class 1 and 29% were class 2. This diverges from microelectrode reports that nearly 100% of superior cervical ganglion neurons show phasic class 3 firing. The hypothesis that the disparity between patch and microelectrode data arises from a shunt conductance was tested using the dynamic clamp in cell culture. Non-depolarizing shunts of 3–10 nS converted cells from classes 1 and 2 to class 3 dynamics with current–voltage relations that replicated microelectrode data. Primary and secondary EPSPs recorded from the intact superior cervical ganglion were modelled as virtual synapses in cell culture using the dynamic clamp. Stimulating sympathetic neurons with virtual synaptic activity, designed to replicate in vivo recordings of EPSPs in muscle vasoconstrictor neurons, produced a 2.4-fold amplification of presynaptic activity. This gain in postsynaptic output did not differ between neurons displaying the three classes of excitability. Mimicry of microelectrode damage by virtual leak channels reduced and eventually obliterated synaptic gain by inhibiting summation of subthreshold EPSPs. These results provide a framework for interpreting sympathetic activity recorded from intact animals and support the hypothesis that paravertebral ganglia function as activity-dependent amplifiers of spinal output from preganglionic circuitry. PMID:25398531

  16. Berberine chloride improved synaptic plasticity in STZ induced diabetic rats.

    PubMed

    Moghaddam, Hamid Kalalian; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad; Goshadrou, Fatemeh; Ronaghi, Abdolaziz

    2013-09-01

    Previous studies indicated that diabetes affects synaptic transmission in the hippocampus, leading to impairments of synaptic plasticity and defects in learning and memory. Although berberine treatment ameliorates memory impairment and improves synaptic plasticity in streptozotocin (STZ) induced diabetic rats, it is not clear if the effects are pre- or post-synaptic or both. The aim of this study was to evaluate the effects of berberine chloride on short-term plasticity in inhibitory interneurons in the dentate gyrus of STZ-induced diabetic rats. Experimental groups included: The control, control berberine treated (100 mg/kg), diabetic and diabetic berberine treated (50,100 mg/kg/day for 12 weeks) groups. The paired pulse paradigm was used to stimulate the perforant pathway and field excitatory post-synaptic potentials (fEPSP) were recorded in dentate gyrus (DG). In comparison with control, paired pulse facilitation in the diabetic group was significantly increased (P < 0.01) and this effect prevented by chronic berberine treatment (50,100 mg/kg). However, there were no differences between responses of the control berberine 100 mg/kg treated and diabetes berberine treated (50 and 100 mg/kg) groups as compared to the control group. The present results suggest that the pre-synaptic component of synaptic plasticity in the dentate gyrus is affected under diabetic conditions and that berberine prevents this effect.

  17. Neuronal MHC Class I Molecules are Involved in Excitatory Synaptic Transmission at the Hippocampal Mossy Fiber Synapses of Marmoset Monkeys

    PubMed Central

    Zhang, Mingyue; Schlumbohm, Christina; Mätz-Rensing, Kerstin; Uchanska-Ziegler, Barbara; Flügge, Gabriele; Zhang, Weiqi; Walter, Lutz; Fuchs, Eberhard

    2010-01-01

    Several recent studies suggested a role for neuronal major histocompatibility complex class I (MHCI) molecules in certain forms of synaptic plasticity in the hippocampus of rodents. Here, we report for the first time on the expression pattern and functional properties of MHCI molecules in the hippocampus of a nonhuman primate, the common marmoset monkey (Callithrix jacchus). We detected a presynaptic, mossy fiber-specific localization of MHCI proteins within the marmoset hippocampus. MHCI molecules were present in the large, VGlut1-positive, mossy fiber terminals, which provide input to CA3 pyramidal neurons. Furthermore, whole-cell recordings of CA3 pyramidal neurons in acute hippocampal slices of the common marmoset demonstrated that application of antibodies which specifically block MHCI proteins caused a significant decrease in the frequency, and a transient increase in the amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in CA3 pyramidal neurons. These findings add to previous studies on neuronal MHCI molecules by describing their expression and localization in the primate hippocampus and by implicating them in plasticity-related processes at the mossy fiber–CA3 synapses. In addition, our results suggest significant interspecies differences in the localization of neuronal MHCI molecules in the hippocampus of mice and marmosets, as well as in their potential function in these species. Electronic supplementary material The online version of this article (doi:10.1007/s10571-010-9510-3) contains supplementary material, which is available to authorized users. PMID:20232136

  18. Different patterns of synaptic transmission revealed between hippocampal CA3 stratum oriens and stratum lucidum interneurons and their pyramidal cell targets.

    PubMed

    Aaron, G B; Wilcox, K S; Dichter, M A

    2003-01-01

    Stratum lucidum (SL) interneurons likely mediate feedforward inhibition between the dentate gyrus mossy fibers and CA3 pyramidal cells, while stratum oriens (SO) interneurons likely provide both feedforward and feedback inhibition within the CA3 commissural/associational network. Using dual whole-cell patch-clamp recordings between interneurons and CA3 pyramidal cells, we have examined SL and SO interneurons and their synapses within organotypic hippocampal slice cultures. Biocytin staining revealed different morphologies between these interneuron groups, both being very similar to those found previously in acute slices. The kinetics of IPSCs were similar between the two groups, but the reliability of synaptic transmission of SL interneuron (SL-INT) IPSCs was significantly lower than the virtually 100% reliability (non-existent failure rates) of SO-INT IPSCs. The SL-INT IPSCs also had a lower quantal content than the SO-INT IPSCs. In addition, SL-INTs were less likely than SO-INTs to innervate or to be innervated by nearby CA3 pyramidal cells. Paired-pulse stimulation at 100 ms interstimulus intervals produced similar paired-pulse depression in both interneuron synapses, despite the significantly higher failure rate of IPSCs produced by the SL-INTs compared with SO-INTs. CV analysis supported the hypothesis that paired-pulse depression was presynaptic. During repetitive, high frequency stimulation (>10 Hz for 500 ms) the two different synapses exhibited distinctly different forms of short-term plasticity: all SL interneurons displayed significant short-term facilitation (mean 113% facilitation, n=4), while, by contrast, SO interneuron synapses displayed either short-term depression (mean 42% depression, n=5 of 8) or no net facilitation or depression (n=3 of 8). These results indicate that the synaptic properties of interneurons can be quite different for interneurons in different hippocampal circuits.

  19. The involvement of P2Y12 receptors, NADPH oxidase, and lipid rafts in the action of extracellular ATP on synaptic transmission at the frog neuromuscular junction.

    PubMed

    Giniatullin, A; Petrov, A; Giniatullin, R

    2015-01-29

    Adenosine 5'-triphosphate (ATP) is the main co-transmitter accompanying the release of acetylcholine from motor nerve terminals. Previously, we revealed the direct inhibitory action of extracellular ATP on transmitter release via redox-dependent mechanism. However, the receptor mechanism of ATP action and ATP-induced sources of reactive oxygen sources (ROS) remained not fully understood. In the current study, using microelectrode recordings of synaptic currents from the frog neuromuscular junction, we analyzed the receptor subtype involved in synaptic action of ATP, receptor coupling to NADPH oxidase and potential location of ATP receptors within the lipid rafts. Using subtype-specific antagonists, we found that the P2Y13 blocker 2-[(2-chloro-5-nitrophenyl)azo]-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-4-pyridinecarboxaldehyde did not prevent the depressant action of ATP. In contrast, the P2Y12 antagonist 2-methylthioadenosine 5'-monophosphate abolished the inhibitory action of ATP, suggesting the key role of P2Y12 receptors in ATP action. As the action of ATP is redox-dependent, we also tested potential involvement of the NADPH oxidase, known as a common inducer of ROS. The depressant action of extracellular ATP was significantly reduced by diphenyleneiodonium chloride and 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, two structurally different inhibitors of NADPH oxidase, indicating that this enzyme indeed mediates the action of ATP. Since the location and activity of various receptors are often associated with lipid rafts, we next tested whether ATP-driven inhibition depends on lipid rafts. We found that the disruption of lipid rafts with methyl-beta-cyclodextrin reduced and largely delayed the action of ATP. Taken together, these data revealed key steps in the purinergic control of synaptic transmission via P2Y12 receptors associated with lipid rafts, and identified NADPH oxidase as the main source of ATP-induced inhibitory ROS at the neuromuscular

  20. 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

  1. Activation of Presynaptic GABAB(1a,2) Receptors Inhibits Synaptic Transmission at Mammalian Inhibitory Cholinergic Olivocochlear–Hair Cell Synapses

    PubMed Central

    Wedemeyer, Carolina; Zorrilla de San Martín, Javier; Ballestero, Jimena; Gómez-Casati, María Eugenia; Torbidoni, Ana Vanesa; Fuchs, Paul A.; Bettler, Bernhard; Elgoyhen, Ana Belén

    2013-01-01

    The synapse between olivocochlear (OC) neurons and cochlear mechanosensory hair cells is cholinergic, fast, and inhibitory. The inhibitory sign of this cholinergic synapse is accounted for by the activation of Ca2+-permeable postsynaptic α9α10 nicotinic receptors coupled to the opening of hyperpolarizing Ca2+-activated small-conductance type 2 (SK2)K+ channels. Acetylcholine (ACh) release at this synapse is supported by both P/Q- and N-type voltage-gated calcium channels (VGCCs). Although the OC synapse is cholinergic, an abundant OC GABA innervation is present along the mammalian cochlea. The role of this neurotransmitter at the OC efferent innervation, however, is for the most part unknown. We show that GABA fails to evoke fast postsynaptic inhibitory currents in apical developing inner and outer hair cells. However, electrical stimulation of OC efferent fibers activates presynaptic GABAB(1a,2) receptors [GABAB(1a,2)Rs] that downregulate the amount of ACh released at the OC–hair cell synapse, by inhibiting P/Q-type VGCCs. We confirmed the expression of GABABRs at OC terminals contacting the hair cells by coimmunostaining for GFP and synaptophysin in transgenic mice expressing GABAB1–GFP fusion proteins. Moreover, coimmunostaining with antibodies against the GABA synthetic enzyme glutamic acid decarboxylase and synaptophysin support the idea that GABA is directly synthesized at OC terminals contacting the hair cells during development. Thus, we demonstrate for the first time a physiological role for GABA in cochlear synaptic function. In addition, our data suggest that the GABAB1a isoform selectively inhibits release at efferent cholinergic synapses. PMID:24068816

  2. Role of extracellular signal-regulated kinase in synaptic transmission and plasticity of a nociceptive input on capsular central amygdaloid neurons in normal and acid-induced muscle pain mice.

    PubMed

    Cheng, Sin-Jhong; Chen, Chien-Chang; Yang, Hsiu-Wen; Chang, Ya-Ting; Bai, Shin-Wen; Chen, Chih-Cheng; Yen, Chen-Tung; Min, Ming-Yuan

    2011-02-09

    Application of phorbol 12,13-diacetate (PDA) caused marked enhancement of synaptic transmission of nociceptive parabrachio-amygdaloid (PBA) input onto neurons of the capsular central amygdaloid (CeAC) nucleus. The potentiation of PBA-CeAC EPSCs by PDA involved a presynaptic protein kinase C (PKC)-dependent component and a postsynaptic PKC-extracellular-regulated kinase (ERK)-dependent component. NMDA glutamatergic receptor (NMDAR)-dependent long-term potentiation (LTP) of PBA-CeAC EPSCs, which was also dependent on the PKC-ERK signaling pathway, was induced by tetanus stimulation at 100 Hz. In slices from mice subjected to acid-induced muscle pain (AIMP), phosphorylated ERK levels in the CeAC increased, and PBA-CeAC synaptic transmission was postsynaptically enhanced. The enhanced PBA-CeAC synaptic transmission in AIMP mice shared common mechanisms with the postsynaptic potentiation effect of PDA and induction of NMDAR-dependent LTP by high-frequency stimulation in normal slices, both of which required ERK activation. Since the CeAC plays an important role in the emotionality of pain, enhanced synaptic function of nociceptive (PBA) inputs onto CeAC neurons might partially account for the supraspinal mechanisms underlying central sensitization.

  3. μ-Opioid Receptor-Mediated Inhibition of Intercalated Neurons and Effect on Synaptic Transmission to the Central Amygdala.

    PubMed

    Blaesse, Peter; Goedecke, Lena; Bazelot, Michaël; Capogna, Marco; Pape, Hans-Christian; Jüngling, Kay

    2015-05-13

    The amygdala is a key region for the processing of information underlying fear, anxiety, and fear extinction. Within the local neuronal networks of the amygdala, a population of inhibitory, intercalated neurons (ITCs) modulates the flow of information among various nuclei of amygdala, including the basal nucleus (BA) and the centromedial nucleus (CeM) of the amygdala. These ITCs have been shown to be important during fear extinction and are target of a variety of neurotransmitters and neuropeptides. Here we provide evidence that the activation of μ-opioid receptors (MORs) by the specific agonist DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin) hyperpolarizes medially located ITCs (mITCs) in acute brain slices of mice. Moreover, we use whole-cell patch-clamp recordings in combination with local electrical stimulation or glutamate uncaging to analyze the effect of MOR activation on local microcircuits. We show that the GABAergic transmission between mITCs and CeM neurons is attenuated by DAMGO, whereas the glutamatergic transmission on CeM neurons and mITCs is unaffected. Furthermore, MOR activation induced by theta burst stimulation in BA suppresses plastic changes of feedforward inhibitory transmission onto CeM neurons as revealed by the MOR antagonist CTAP d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2. In summary, the mITCs constitute a target for the opioid system, and therefore, the activation of MOR in ITCs might play a central role in the modulation of the information processing between the basolateral complex of the amygdala and central nuclei of the amygdala.

  4. μ-Opioid Receptor-Mediated Inhibition of Intercalated Neurons and Effect on Synaptic Transmission to the Central Amygdala

    PubMed Central

    Blaesse, Peter; Goedecke, Lena; Bazelot, Michaël; Capogna, Marco; Pape, Hans-Christian

    2015-01-01

    The amygdala is a key region for the processing of information underlying fear, anxiety, and fear extinction. Within the local neuronal networks of the amygdala, a population of inhibitory, intercalated neurons (ITCs) modulates the flow of information among various nuclei of amygdala, including the basal nucleus (BA) and the centromedial nucleus (CeM) of the amygdala. These ITCs have been shown to be important during fear extinction and are target of a variety of neurotransmitters and neuropeptides. Here we provide evidence that the activation of μ-opioid receptors (MORs) by the specific agonist DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin) hyperpolarizes medially located ITCs (mITCs) in acute brain slices of mice. Moreover, we use whole-cell patch-clamp recordings in combination with local electrical stimulation or glutamate uncaging to analyze the effect of MOR activation on local microcircuits. We show that the GABAergic transmission between mITCs and CeM neurons is attenuated by DAMGO, whereas the glutamatergic transmission on CeM neurons and mITCs is unaffected. Furthermore, MOR activation induced by theta burst stimulation in BA suppresses plastic changes of feedforward inhibitory transmission onto CeM neurons as revealed by the MOR antagonist CTAP d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2. In summary, the mITCs constitute a target for the opioid system, and therefore, the activation of MOR in ITCs might play a central role in the modulation of the information processing between the basolateral complex of the amygdala and central nuclei of the amygdala. PMID:25972162

  5. Region-specific impairments in striatal synaptic transmission and impaired instrumental learning in a mouse model of Angelman syndrome.

    PubMed

    Hayrapetyan, Volodya; Castro, Stephen; Sukharnikova, Tatyana; Yu, Chunxiu; Cao, Xinyu; Jiang, Yong-Hui; Yin, Henry H

    2014-03-01

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation and impaired speech. Because patients with this disorder often exhibit motor tremor and stereotypical behaviors, which are associated with basal ganglia pathology, we hypothesized that AS is accompanied by abnormal functioning of the striatum, the input nucleus of the basal ganglia. Using mutant mice with maternal deficiency of AS E6-AP ubiquitin protein ligase Ube3a (Ube3a(m-/p+) ), we assessed the effects of Ube3a deficiency on instrumental conditioning, a striatum-dependent task. We used whole-cell patch-clamp recording to measure glutamatergic transmission in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). Ube3a(m-/p+) mice were severely impaired in initial acquisition of lever pressing. Whereas the lever pressing of wild-type controls was reduced by outcome devaluation and instrumental contingency reversal, the performance of Ube3a(m-/p+) mice were more habitual, impervious to changes in outcome value and action-outcome contingency. In the DMS, but not the DLS, Ube3a(m-/p+) mice showed reduced amplitude and frequency of miniature excitatory postsynaptic currents. These results show for the first time a selective deficit in instrumental conditioning in the Ube3a deficient mouse model, and suggest a specific impairment in glutmatergic transmission in the associative corticostriatal circuit in AS.

  6. The Excitatory Synaptic Transmission of the Nucleus of Solitary Tract Was Potentiated by Chronic Myocardial Infarction in Rats

    PubMed Central

    Feng, Ban; Zhang, Zi-Nan; Lei, Jie; Li, Yun-Qing; Du, Jian-Qing; Chen, Tao

    2015-01-01

    Angina pectoris is a common clinical symptom that often results from myocardial infarction. One typical characteristic of angina pectoris is that the pain does not match the severity of the myocardial ischemia. One possible explanation is that the intensity of cardiac nociceptive information could be dynamically regulated by certain brain areas. As an important nucleus for processing cardiac nociception, the nucleus of the solitary tract (NTS) has been studied to some extent. However, until now, the morphological and functional involvement of the NTS in chronic myocardial infarction (CMI) has remained unknown. In the present study, by exploring left anterior descending coronary artery ligation surgery, we found that the number of synaptophysin-immunoreactive puncta and Fos-immunoreactive neurons in the rat NTS two weeks after ligation surgery increased significantly. Excitatory pre- and postsynaptic transmission was potentiated. A bath application of a Ca2+ channel inhibitor GABApentin and Ca2+ permeable AMPA receptor antagonist NASPM could reverse the potentiated pre- and postsynaptic transmission, respectively. Meanwhile, rats with CMI showed significantly increased visceral pain behaviors. Microinjection of GABApentin or NASPM into the NTS decreased the CMI-induced visceral pain behaviors. In sum, our results suggest that the NTS is an important area for the process of cardiac afference in chronic myocardial infarction condition. PMID:25756354

  7. Synaptic Cell Adhesion Molecules in Alzheimer's Disease

    PubMed Central

    Leshchyns'ka, Iryna

    2016-01-01

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

  8. Larval nutritional stress affects vector life history traits and human malaria transmission

    PubMed Central

    Vantaux, Amélie; Lefèvre, Thierry; Cohuet, Anna; Dabiré, Kounbobr Roch; Roche, Benjamin; Roux, Olivier

    2016-01-01

    Exposure to stress during an insect’s larval development can have carry-over effects on adult life history traits and susceptibility to pathogens. We investigated the effects of larval nutritional stress for the first time using field mosquito vectors and malaria parasites. In contrast to previous studies, we show that larval nutritional stress may affect human to mosquito transmission antagonistically: nutritionally deprived larvae showed lower parasite prevalence for only one gametocyte carrier; they also had lower fecundity. However, they had greater survival rates that were even higher when infected. When combining these opposing effects into epidemiological models, we show that larval nutritional stress induced a decrease in malaria transmission at low mosquito densities and an increase in transmission at high mosquito densities, whereas transmission by mosquitoes from well-fed larvae was stable. Our work underscores the importance of including environmental stressors towards understanding host–parasite dynamics to improve disease transmission models and control. PMID:27827429

  9. Larval nutritional stress affects vector life history traits and human malaria transmission.

    PubMed

    Vantaux, Amélie; Lefèvre, Thierry; Cohuet, Anna; Dabiré, Kounbobr Roch; Roche, Benjamin; Roux, Olivier

    2016-11-09

    Exposure to stress during an insect's larval development can have carry-over effects on adult life history traits and susceptibility to pathogens. We investigated the effects of larval nutritional stress for the first time using field mosquito vectors and malaria parasites. In contrast to previous studies, we show that larval nutritional stress may affect human to mosquito transmission antagonistically: nutritionally deprived larvae showed lower parasite prevalence for only one gametocyte carrier; they also had lower fecundity. However, they had greater survival rates that were even higher when infected. When combining these opposing effects into epidemiological models, we show that larval nutritional stress induced a decrease in malaria transmission at low mosquito densities and an increase in transmission at high mosquito densities, whereas transmission by mosquitoes from well-fed larvae was stable. Our work underscores the importance of including environmental stressors towards understanding host-parasite dynamics to improve disease transmission models and control.

  10. Microbial Rhodopsin Optogenetic Tools: Application for Analyses of Synaptic Transmission and of Neuronal Network Activity in Behavior.

    PubMed

    Glock, Caspar; Nagpal, Jatin; Gottschalk, Alexander

    2015-01-01

    Optogenetics was introduced as a new technology in the neurosciences about a decade ago (Zemelman et al., Neuron 33:15-22, 2002; Boyden et al., Nat Neurosci 8:1263-1268, 2005; Nagel et al., Curr Biol 15:2279-2284, 2005; Zemelman et al., Proc Natl Acad Sci USA 100:1352-1357, 2003). It combines optics, genetics, and bioengineering to render neurons sensitive to light, in order to achieve a precise, exogenous, and noninvasive control of membrane potential, intracellular signaling, network activity, or behavior (Rein and Deussing, Mol Genet Genomics 287:95-109, 2012; Yizhar et al., Neuron 71:9-34, 2011). As C. elegans is transparent, genetically amenable, has a small nervous system mapped with synapse resolution, and exhibits a rich behavioral repertoire, it is especially open to optogenetic methods (White et al., Philos Trans R Soc Lond B Biol Sci 314:1-340, 1986; De Bono et al., Optogenetic actuation, inhibition, modulation and readout for neuronal networks generating behavior in the nematode Caenorhabditis elegans, In: Hegemann P, Sigrist SJ (eds) Optogenetics, De Gruyter, Berlin, 2013; Husson et al., Biol Cell 105:235-250, 2013; Xu and Kim, Nat Rev Genet 12:793-801, 2011). Optogenetics, by now an "exploding" field, comprises a repertoire of different tools ranging from transgenically expressed photo-sensor proteins (Boyden et al., Nat Neurosci 8:1263-1268, 2005; Nagel et al., Curr Biol 15:2279-2284, 2005) or cascades (Zemelman et al., Neuron 33:15-22, 2002) to chemical biology approaches, using photochromic ligands of endogenous channels (Szobota et al., Neuron 54:535-545, 2007). Here, we will focus only on optogenetics utilizing microbial rhodopsins, as these are most easily and most widely applied in C. elegans. For other optogenetic tools, for example the photoactivated adenylyl cyclases (PACs, that drive neuronal activity by increasing synaptic vesicle priming, thus exaggerating rather than overriding the intrinsic activity of a neuron, as occurs with

  11. Modulation of synaptic transmission from segmental afferents by spontaneous activity of dorsal horn spinal neurones in the cat.

    PubMed

    Manjarrez, E; Rojas-Piloni, J G; Jimenez, I; Rudomin, P

    2000-12-01

    We examined, in the anaesthetised cat, the influence of the neuronal ensembles producing spontaneous negative cord dorsum potentials (nCDPs) on segmental pathways mediating primary afferent depolarisation (PAD) of cutaneous and group I muscle afferents and on Ia monosynaptic activation of spinal motoneurones. The intraspinal distribution of the field potentials associated with the spontaneous nCDPs indicated that the neuronal ensembles involved in the generation of these potentials were located in the dorsal horn of lumbar segments, in the same region of termination of low-threshold cutaneous afferents. During the occurrence of spontaneous nCDPs, transmission from low-threshold cutaneous afferents to second order neurones in laminae III-VI, as well as transmission along pathways mediating PAD of cutaneous and Ib afferents, was facilitated. PAD of Ia afferents was instead inhibited. Monosynaptic reflexes of flexors and extensors were facilitated during the spontaneous nCDPs. The magnitude of the facilitation was proportional to the amplitude of the 'conditioning' spontaneous nCDPs. This led to a high positive correlation between amplitude fluctuations of spontaneous nCDPs and fluctuations of monosynaptic reflexes. Stimulation of low-threshold cutaneous afferents transiently reduced the probability of occurrence of spontaneous nCDPs as well as the fluctuations of monosynaptic reflexes. It is concluded that the spontaneous nCDPs were produced by the activation of a population of dorsal horn neurones that shared the same functional pathways and involved the same set of neurones as those responding monosynaptically to stimulation of large cutaneous afferents. The spontaneous activity of these neurones was probably the main cause of the fluctuations of the monosynaptic reflexes observed under anaesthesia and could provide a dynamic linkage between segmental sensory and motor pathways.

  12. Modulation of synaptic transmission from segmental afferents by spontaneous activity of dorsal horn spinal neurones in the cat

    PubMed Central

    Manjarrez, E; Rojas-Piloni, J G; Jiménez, I; Rudomin, P

    2000-01-01

    We examined, in the anaesthetised cat, the influence of the neuronal ensembles producing spontaneous negative cord dorsum potentials (nCDPs) on segmental pathways mediating primary afferent depolarisation (PAD) of cutaneous and group I muscle afferents and on Ia monosynaptic activation of spinal motoneurones. The intraspinal distribution of the field potentials associated with the spontaneous nCDPs indicated that the neuronal ensembles involved in the generation of these potentials were located in the dorsal horn of lumbar segments, in the same region of termination of low-threshold cutaneous afferents. During the occurrence of spontaneous nCDPs, transmission from low-threshold cutaneous afferents to second order neurones in laminae III-VI, as well as transmission along pathways mediating PAD of cutaneous and Ib afferents, was facilitated. PAD of Ia afferents was instead inhibited. Monosynaptic reflexes of flexors and extensors were facilitated during the spontaneous nCDPs. The magnitude of the facilitation was proportional to the amplitude of the ‘conditioning’ spontaneous nCDPs. This led to a high positive correlation between amplitude fluctuations of spontaneous nCDPs and fluctuations of monosynaptic reflexes. Stimulation of low-threshold cutaneous afferents transiently reduced the probability of occurrence of spontaneous nCDPs as well as the fluctuations of monosynaptic reflexes. It is concluded that the spontaneous nCDPs were produced by the activation of a population of dorsal horn neurones that shared the same functional pathways and involved the same set of neurones as those responding monosynaptically to stimulation of large cutaneous afferents. The spontaneous activity of these neurones was probably the main cause of the fluctuations of the monosynaptic reflexes observed under anaesthesia and could provide a dynamic linkage between segmental sensory and motor pathways. PMID:11101653

  13. Histamine H3 receptor-mediated suppression of inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine.

    PubMed

    Liu, S; Xia, Y; Hu, H z; Ren, J; Gao, C; Wood, J D

    2000-05-26

    Conventional intracellular microelectrodes and marker injection techniques were used to study the actions of histamine on inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine. Bath application of histamine (1-300 microM) reversibly suppressed both noradrenergic and non-adrenergic slow inhibitory postsynaptic potentials in a concentration-dependent manner. These effects of histamine were mimicked by the selective histamine H(3) receptor agonist R(-)-alpha-methylhistamine but not the selective histamine H(1) receptor agonist, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT dimaleate), or the selective histamine H(2) receptor agonist, dimaprit. The histamine H(3) receptor antagonist, thioperamide, blocked the effects of histamine. Histamine H(1) and H(2) receptor antagonists did not change the action of histamine. Hyperpolarizing responses to focal application of norepinephrine or somatostatin by pressure ejection from micropipettes were unaffected by histamine and R(-)-alpha-methylhistamine. The results suggest that histamine acts at presynaptic histamine H(3) receptors on the terminals of sympathetic postganglionic fibers and intrinsic somatostatinergic nerves in the small intestine to suppress the release of the inhibitory neurotransmitters, norepinephrine and somatostatin.

  14. 5-HT2 receptors mediate functional modulation of GABAa receptors and inhibitory synaptic transmissions in human iPS-derived neurons

    PubMed Central

    Wang, Haitao; Hu, Lingli; Liu, Chunhua; Su, Zhenghui; Wang, Lihui; Pan, Guangjin; Guo, Yiping; He, Jufang

    2016-01-01

    Neural progenitors differentiated from induced pluripotent stem cells (iPS) hold potentials for treating neurological diseases. Serotonin has potent effects on neuronal functions through multiple receptors, underlying a variety of neural disorders. Glutamate and GABA receptors have been proven functional in neurons differentiated from iPS, however, little is known about 5-HT receptor-mediated modulation in such neuronal networks. In the present study, human iPS were differentiated into cells possessing featured physiological properties of cortical neurons. Whole-cell patch-clamp recording was used to examine the involvement of 5-HT2 receptors in functional modulation of GABAergic synaptic transmission. We found that serotonin and DOI (a selective agonist of 5-HT2A/C receptor) reversibly reduced GABA-activated currents, and this 5-HT2A/C receptor mediated inhibition required G protein, PLC, PKC, and Ca2+ signaling. Serotonin increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), which could be mimicked by α-methylserotonin, a 5-HT2 receptor agonist. In contrast, DOI reduced both frequency and amplitude of mIPSCs. These findings suggested that in iPS-derived human neurons serotonin postsynaptically reduced GABAa receptor function through 5-HT2A/C receptors, but presynaptically other 5-HT2 receptors counteracted the action of 5-HT2A/C receptors. Functional expression of serotonin receptors in human iPS-derived neurons provides a pre-requisite for their normal behaviors after grafting. PMID:26837719

  15. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms.

    PubMed

    dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

    2015-10-05

    The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs.

  16. Role of P2 purinergic receptors in synaptic transmission under normoxic and ischaemic conditions in the CA1 region of rat hippocampal slices

    PubMed Central

    Coppi, Elisabetta; Pugliese, Anna Maria; Stephan, Holger; Müller, Christa E.

    2007-01-01

    The role of ATP and its stable analogue ATPγS [adenosine-5′-o-(3-thio)triphosphate] was studied in rat hippocampal neurotransmission under normoxic conditions and during oxygen and glucose deprivation (OGD). Field excitatory postsynaptic potentials (fEPSPs) from the dendritic layer or population spikes (PSs) from the soma were extracellularly recorded in the CA1 area of the rat hippocampus. Exogenous application of ATP or ATPγS reduced fEPSP and PS amplitudes. In both cases the inhibitory effect was blocked by the selective A1 adenosine receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) and was potentiated by different ecto-ATPase inhibitors: ARL 67156 (6-N,N-diethyl-D-β,γ-dibromomethylene), BGO 136 (1-hydroxynaphthalene-3,6-disulfonate) and PV4 [hexapotassium dihydrogen monotitanoundecatungstocobaltate(II) tridecahydrate, K6H2[TiW11CoO40]·13H2O]. ATPγS-mediated inhibition was reduced by the P2 antagonist suramin [8-(3-benzamido-4-methylbenzamido)naphthalene-1,3,5-trisulfonate] at the somatic level and by other P2 blockers, PPADS (pyridoxalphosphate-6-azophenyl-2′,4′-disulfonate) and MRS 2179 (2′-deoxy-N6-methyladenosine 3′,5′-bisphosphate), at the dendritic level. After removal of both P2 agonists, a persistent increase in evoked synaptic responses was recorded both at the dendritic and somatic levels. This effect was prevented in the presence of different P2 antagonists. A 7-min OGD induced tissue anoxic depolarization and was invariably followed by irreversible loss of fEPSP. PPADS, suramin, MRS2179 or BBG (brilliant blue G) significantly prevented the irreversible failure of neurotransmission induced by 7-min OGD. Furthermore, in the presence of these P2 antagonists, the development of anoxic depolarization was blocked or significantly delayed. Our results indicate that P2 receptors modulate CA1 synaptic transmission under normoxic conditions by eliciting both inhibitory and excitatory effects. In the same brain region, P2 receptor

  17. Properties of synaptic transmission from the reticular formation dorsal to the facial nucleus to trigeminal motoneurons during early postnatal development in rats.

    PubMed

    Gemba-Nishimura, A; Inoue, T; Nakamura, S; Nakayama, K; Mochizuki, A; Shintani, S; Yoshimura, S

    2010-03-31

    We previously reported that electrical stimulation of the reticular formation dorsal to the facial nucleus (RdVII) elicited excitatory masseter responses at short latencies and that RdVII neurons were antidromically activated by stimulation of the trigeminal motor nucleus (MoV), suggesting that excitatory premotor neurons targeting the MoV are likely located in the RdVII. We thus examined the properties of synaptic transmission from the RdVII to jaw-closing and jaw-opening motoneurons in horizontal brainstem preparations from developing rats using voltage-sensitive dye, patch-clamp recordings and laser photostimulation. Electrical stimulation of the RdVII evoked optical responses in the MoV. Combined bath application of the non-N-methyl-d-aspartate (non-NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (APV) reduced these optical responses, and addition of the glycine receptor antagonist strychnine and the GABA(A) receptor antagonist bicuculline further reduced the remaining responses. Electrical stimulation of the RdVII evoked postsynaptic currents (PSCs) in all 19 masseter motoneurons tested in postnatal day (P)1-4 rats, and application of CNQX and the NMDA receptor antagonist (+/-)-3(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) reduced the PSC amplitudes by more than 50%. In the presence of CNQX and CPP, the GABA(A) receptor antagonist SR95531 further reduced PSC amplitude, and addition of strychnine abolished the remaining PSCs. Photostimulation of the RdVII with caged glutamate also evoked PSCs in masseter motoneurons of P3-4 rats. In P8-11 rats, electrical stimulation of the RdVII also evoked PSCs in all 14 masseter motoneurons tested, and the effects of the antagonists on the PSCs were similar to those in P1-4 rats. On the other hand, RdVII stimulation evoked PSCs in only three of 16 digastric motoneurons tested. These results suggest that both neonatal and

  18. Role of glial and neuronal glycine transporters in the control of glycinergic and glutamatergic synaptic transmission in lamina X of the rat spinal cord

    PubMed Central

    Bradaïa, Amyaouch; Schlichter, Rémy; Trouslard, Jérôme

    2004-01-01

    Using whole cell voltage clamp recordings from lamina X neurones in rat spinal cord slices, we investigated the effect of glycine transporter (GlyT) antagonists on both glycinergic inhibitory postsynaptic current (IPSCs) and glutamatergic excitatory postsynaptic current (EPSCs). We used ORG 24598 and ORG 25543, selective antagonists of the glial GlyT (GlyT1) and neuronal GlyT (GlyT2), respectively. In rats (P12–P16) and in the presence of kynurenic acid, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and bicuculline, ORG 24598 and ORG 25543 applied individually at a concentration of 10 μm induced a mean inward current of −10/−50 pA at −60 mV and increased significantly the decay time constants of miniature (mIPSCs), spontaneous (sIPSCs) and electrically evoked glycinergic (eIPSCs) inhibitory postsynaptic currents. ORG 25543, but not ORG 24598, decreased the frequency of mIPSCs and sIPSCs. Replacing extracellular sodium with N-methyl-d-glucamine or superfusing the slice with micromolar concentrations of glycine also increased the decay time constant of glycinergic IPSCs. By contrast, the decay time constant, amplitude and frequency of miniature GABAergic IPSCs recorded in the presence of strychnine were not affected by ORG 24598 and ORG 25543. In the presence of strychnine, bicuculline and CNQX, we recorded electrically evoked NMDA receptor-mediated EPSCs (eEPSCs). eEPSCs were suppressed by 30 μmd-2-amino-5-phosphonovalerate (APV), an antagonist of the NMDA receptor, and by 30 μm dichlorokynurenic acid (DCKA), an antagonist of the glycine site of the NMDA receptor. Glycine (1–5 μm) and d-serine (10 μm) increased the amplitude of eEPSCs whereas l-serine had no effect. ORG 24598 and ORG 25543 increased significantly the amplitude of NMDA receptor-mediated eEPSCs without affecting the amplitude of non-NMDA receptor-mediated eEPSCs. We conclude that blocking glial and/or neuronal glycine transporters increased the level of glycine in spinal cord slices

  19. Neuromodulator-evoked synaptic metaplasticity within a central pattern generator network.

    PubMed

    Kvarta, Mark D; Harris-Warrick, Ronald M; Johnson, Bruce R

    2012-11-01

    Synapses show short-term activity-dependent dynamics that alter the strength of neuronal interactions. This synaptic plasticity can be tuned by neuromodulation as a form of metaplasticity. We examined neuromodulator-induced metaplasticity at a graded chemical synapse in a model central pattern generator (CPG), the pyloric network of the spiny lobster stomatogastric ganglion. Dopamine, serotonin, and octopamine each produce a unique motor pattern from the pyloric network, partially through their modulation of synaptic strength in the network. We characterized synaptic depression and its amine modulation at the graded synapse from the pyloric dilator neuron to the lateral pyloric neuron (PD→LP synapse), driving the PD neuron with both long square pulses and trains of realistic waveforms over a range of presynaptic voltages. We found that the three amines can differentially affect the amplitude of graded synaptic transmission independently of the synaptic dynamics. Low concentrations of dopamine had weak and variable effects on the strength of the graded inhibitory postsynaptic potentials (gIPSPs) but reliably accelerated the onset of synaptic depression and recovery from depression independently of gIPSP amplitude. Octopamine enhanced gIPSP amplitude but decreased the amount of synaptic depression; it slowed the onset of depression and accelerated its recovery during square pulse stimulation. Serotonin reduced gIPSP amplitude but increased the amount of synaptic depression and accelerated the onset of depression. These results suggest that amine-induced metaplasticity at graded chemical synapses can alter the parameters of synaptic dynamics in multiple and independent ways.

  20. Detecting differential transmissibilities that affect the size of self-limited outbreaks.

    PubMed

    Blumberg, Seth; Funk, Sebastian; Pulliam, Juliet R C

    2014-10-01

    studies lay the foundation for future investigations regarding how infection source, vaccination status or other putative transmissibility traits may affect self-limited transmission.

  1. Role of 5-HT1 receptor subtypes in the modulation of pain and synaptic transmission in rat spinal superficial dorsal horn

    PubMed Central

    Jeong, Hyo-Jin; Mitchell, Vanessa A; Vaughan, Christopher W

    2012-01-01

    BACKGROUND AND PURPOSE 5-HT receptor agonists have variable nociceptive effects within the spinal cord. While there is some evidence for 5-HT1A spinally-mediated analgesia, the role of other 5-HT1 receptor subtypes remains unclear. In the present study, we examined the spinal actions of a range of 5-HT1 agonists, including sumatriptan, on acute pain, plus their effect on afferent-evoked synaptic transmission onto superficial dorsal horn neurons. EXPERIMENTAL APPROACH For in vivo experiments, 5-HT agonists were injected via chronically implanted spinal catheters to examine their effects in acute mechanical and thermal pain assays using a paw pressure analgesymeter and a Hargreave's device. For in vitro experiments, whole-cell patch-clamp recordings of primary afferent-evoked glutamatergic EPSC were made from lamina II neurons in rat lumbar spinal slices. KEY RESULTS Intrathecal (i.t.) delivery of the 5-HT1A agonist R ± 8-OH-DPAT (30–300 nmol) produced a dose-dependent thermal, but not mechanical, analgesia. Sumatriptan and the 5-HT1B, 5-HT1D, 5-HT1F agonists CP93129, PNU109291 and LY344864 (100 nmol) had no effect on either acute pain assay. R ± 8-OH-DPAT (1 µM) and sumatriptan (3 µM) both reduced the amplitude of the evoked EPSC. In contrast, CP93129, PNU109291 and LY344864 (0.3–3 µM) had no effect on the evoked EPSC. The actions of both R ± 8-OH-DPAT and sumatriptan were abolished by the 5-HT1A antagonist WAY100635 (3 µM). CONCLUSIONS AND IMPLICATIONS These findings indicate that the 5-HT1A receptor subtype predominantly mediates the acute antinociceptive and cellular actions of 5-HT1 ligands within the rat superficial dorsal horn. PMID:21950560

  2. L-Arginyl-3,4-Spermidine is neuroprotective in several in vitro models of neurodegeneration and in vivo ischaemia without suppressing synaptic transmission

    PubMed Central

    Morrison, Barclay; Pringle, Ashley K; McManus, Terence; Ellard, John; Bradley, Mark; Signorelli, Francesco; Iannotti, Fausto; Sundstrom, Lars E

    2002-01-01

    Stroke is the third most common cause of death in the world, and there is a clear need to develop new therapeutics for the stroke victim. To address this need, we generated a combinatorial library of polyamine compounds based on sFTX-3.3 toxin from which L-Arginyl-3,4-Spermidine (L-Arg-3,4) emerged as a lead neuroprotective compound. In the present study, we have extended earlier results to examine the compound's neuroprotective actions in greater detail. In an in vitro ischaemia model, L-Arg-3,4 significantly reduced CA1 cell death when administered prior to induction of 60 min of ischaemia as well as when administered immediately after ischaemia. Surprisingly, L-Arg-3,4 continued to prevent cell death significantly when administration was delayed for as long as 60 min after ischaemia. L-Arg-3,4 significantly reduced cell death in excitotoxicity models mediated by glutamate, NMDA, AMPA, or kainate. Unlike glutamate receptor antagonists, 300 μM L-Arg-3,4 did not suppress synaptic transmission as measured by evoked responses in acute hippocampal slices. L-Arg-3,4 provided significant protection, in vitro, in a superoxide mediated injury model and prevented an increase of superoxide production after AMPA or NMDA stimulation. It also decreased nitric oxide production after in vitro ischaemia and NMDA stimulation, but did so without inhibiting nitric oxide synthase directly. Furthermore, L-Arg-3,4 was significantly neuroprotective in an in vivo model of global forebrain ischaemia, without any apparent neurological side-effects. Taken together, these results demonstrate that L-Arg-3,4 is protective in several models of neurodegeneration and may have potential as a new therapeutic compound for the treatment of stroke, trauma, and other neurodegenerative diseases. PMID:12466235

  3. The role of gamma-aminobutyric acid/glycinergic synaptic transmission in mediating bilirubin-induced hyperexcitation in developing auditory neurons.

    PubMed

    Yin, Xin-Lu; Liang, Min; Shi, Hai-Bo; Wang, Lu-Yang; Li, Chun-Yan; Yin, Shan-Kai

    2016-01-05

    Hyperbilirubinemia is a common clinical phenomenon observed in human newborns. A high level of bilirubin can result in severe jaundice and bilirubin encephalopathy. However, the cellular mechanisms underlying bilirubin excitotoxicity are unclear. Our previous studies showed the action of gamma-aminobutyric acid (GABA)/glycine switches from excitatory to inhibitory during development in the ventral cochlear nucleus (VCN), one of the most sensitive auditory nuclei to bilirubin toxicity. In the present study, we investigated the roles of GABAA/glycine receptors in the induction of bilirubin hyperexcitation in early developing neurons. Using the patch clamp technique, GABAA/glycine receptor-mediated spontaneous inhibitory synaptic currents (sIPSCs) were recorded from bushy and stellate cells in acute brainstem slices from young mice (postnatal day 2-6). Bilirubin significantly increased the frequency of sIPSCs, and this effect was prevented by pretreatments of slices with either fast or slow Ca(2+) chelators BAPTA-AM and EGTA-AM suggesting that bilirubin can increase the release of GABA/glycine via Ca(2+)-dependent mechanisms. Using cell-attached recording configuration, we found that antagonists of GABAA and glycine receptors strongly attenuated spontaneous spiking firings in P2-6 neurons but produced opposite effect in P15-19 neurons. Furthermore, these antagonists reversed bilirubin-evoked hyperexcitability in P2-6 neurons, indicating that excitatory action of GABA/glycinergic transmission specifically contribute to bilirubin-induced hyperexcitability in the early stage of development. Our results suggest that bilirubin-induced enhancement of presynaptic release GABA/Glycine via Ca(2+)-dependent mechanisms may play a critical role in mediating neuronal hyperexcitation associated with jaundice, implicating potential new strategies for predicting, preventing, and treating bilirubin neurotoxicity.

  4. Dystroglycan mediates homeostatic synaptic plasticity at GABAergic synapses.

    PubMed

    Pribiag, Horia; Peng, Huashan; Shah, Waris Ali; Stellwagen, David; Carbonetto, Salvatore

    2014-05-06

    Dystroglycan (DG), a cell adhesion molecule well known to be essential for skeletal muscle integrity and formation of neuromuscular synapses, is also present at inhibitory synapses in the central nervous system. Mutations that affect DG function not only result in muscular dystrophies, but also in severe cognitive deficits and epilepsy. Here we demonstrate a role of DG during activity-dependent homeostatic regulation of hippocampal inhibitory synapses. Prolonged elevation of neuronal activity up-regulates DG expression and glycosylation, and its localization to inhibitory synapses. Inhibition of protein synthesis prevents the activity-dependent increase in synaptic DG and GABAA receptors (GABAARs), as well as the homeostatic scaling up of GABAergic synaptic transmission. RNAi-mediated knockdown of DG blocks homeostatic scaling up of inhibitory synaptic strength, as does knockdown of like-acetylglucosaminyltransferase (LARGE)--a glycosyltransferase critical for DG function. In contrast, DG is not required for the bicuculline-induced scaling down of excitatory synaptic strength or the tetrodotoxin-induced scaling down of inhibitory synaptic strength. The DG ligand agrin increases GABAergic synaptic strength in a DG-dependent manner that mimics homeostatic scaling up induced by increased activity, indicating that activation of this pathway alone is sufficient to regulate GABAAR trafficking. These data demonstrate that DG is regulated in a physiologically relevant manner in neurons and that DG and its glycosylation are essential for homeostatic plasticity at inhibitory synapses.

  5. Plasticity-Related Gene 1 Affects Mouse Barrel Cortex Function via Strengthening of Glutamatergic Thalamocortical Transmission.

    PubMed

    Unichenko, Petr; Kirischuk, Sergei; Yang, Jenq-Wei; Baumgart, Jan; Roskoden, Thomas; Schneider, Patrick; Sommer, Angela; Horta, Guilherme; Radyushkin, Konstantin; Nitsch, Robert; Vogt, Johannes; Luhmann, Heiko J

    2016-07-01

    Plasticity-related gene-1 (PRG-1) is a brain-specific protein that modulates glutamatergic synaptic transmission. Here we investigated the functional role of PRG-1 in adolescent and adult mouse barrel cortex both in vitro and in vivo. Compared with wild-type (WT) animals, PRG-1-deficient (KO) mice showed specific behavioral deficits in tests assessing sensorimotor integration and whisker-based sensory discrimination as shown in the beam balance/walking test and sandpaper tactile discrimination test, respectively. At P25-31, spontaneous network activity in the barrel cortex in vivo was higher in KO mice compared with WT littermates, but not at P16-19. At P16-19, sensory evoked cortical responses in vivo elicited by single whisker stimulation were comparable in KO and WT mice. In contrast, at P25-31 evoked responses were smaller in amplitude and longer in duration in WT animals, whereas KO mice revealed no such developmental changes. In thalamocortical slices from KO mice, spontaneous activity was increased already at P16-19, and glutamatergic thalamocortical inputs to Layer 4 spiny stellate neurons were potentiated. We conclude that genetic ablation of PRG-1 modulates already at P16-19 spontaneous and evoked excitability of the barrel cortex, including enhancement of thalamocortical glutamatergic inputs to Layer 4, which distorts sensory processing in adulthood.

  6. Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology.

    PubMed

    Pröschel, Christoph; Hansen, Jeanne N; Ali, Adil; Tuttle, Emily; Lacagnina, Michelle; Buscaglia, Georgia; Halterman, Marc W; Paciorkowski, Alex R

    2017-02-01

    SIK1 syndrome is a newly described developmental epilepsy disorder caused by heterozygous mutations in the salt-inducible kinase SIK1. To better understand the pathophysiology of SIK1 syndrome, we studied the effects of SIK1 pathogenic sequence variations in human neurons. Primary human fetal cortical neurons were transfected with a lentiviral vector to overexpress wild-type and mutant SIK1 protein. We evaluated the transcriptional activity of known downstream gene targets in neurons expressing mutant SIK1 compared with wild type. We then assayed neuronal morphology by measuring neurite length, number and branching. Truncating SIK1 sequence variations were associated with abnormal MEF2C transcriptional activity and decreased MEF2C protein levels. Epilepsy-causing SIK1 sequence variations were associated with significantly decreased expression of ARC (activity-regulated cytoskeletal-associated) and other synaptic activity response element genes. Assay of mRNA levels for other MEF2C target genes NR4A1 (Nur77) and NRG1, found significantly, decreased the expression of these genes as well. The missense p.(Pro287Thr) SIK1 sequence variation was associated with abnormal neuronal morphology, with significant decreases in mean neurite length, mean number of neurites and a significant increase in proximal branches compared with wild type. Epilepsy-causing SIK1 sequence variations resulted in abnormalities in the MEF2C-ARC pathway of neuronal development and synapse activity response. This work provides the first insights into the mechanisms of pathogenesis in SIK1 syndrome, and extends the ARX-MEF2C pathway in the pathogenesis of developmental epilepsy.

  7. Familial Dysautonomia (FD) Human Embryonic Stem Cell Derived PNS Neurons Reveal that Synaptic Vesicular and Neuronal Transport Genes Are Directly or Indirectly Affected by IKBKAP Downregulation

    PubMed Central

    Kantor, Gal; Cheishvili, David; Even, Aviel; Birger, Anastasya; Turetsky, Tikva; Gil, Yaniv; Even-Ram, Sharona; Aizenman, Einat; Bashir, Nibal; Maayan, Channa; Razin, Aharon; Reubinoff, Benjamim E.; Weil, Miguel

    2015-01-01

    A splicing mutation in the IKBKAP gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we found new molecular insights for the IKAP role and the impact of the FD mutation in the human PNS lineage by using a novel and unique human embryonic stem cell (hESC) line homozygous to the FD mutation originated by pre implantation genetic diagnosis (PGD) analysis. We found that IKBKAP downregulation during PNS differentiation affects normal migration in FD-hESC derived neural crest cells (NCC) while at later stages the PNS neurons show reduced intracellular colocalization between vesicular proteins and IKAP. Comparative wide transcriptome analysis of FD and WT hESC-derived neurons together with the analysis of human brains from FD and WT 12 weeks old embryos and experimental validation of the results confirmed that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation in FD neurons. Moreover we show that kinetin (a drug that corrects IKBKAP alternative splicing) promotes the recovery of IKAP expression and these IKAP functional associated genes identified in the study. Altogether, these results support the view that IKAP might be a vesicular like protein that might be involved in neuronal transport in hESC derived PNS neurons. This function seems to be mostly affected in FD-hESC derived PNS neurons probably reflecting some PNS neuronal dysfunction observed in FD. PMID:26437462

  8. Familial Dysautonomia (FD) Human Embryonic Stem Cell Derived PNS Neurons Reveal that Synaptic Vesicular and Neuronal Transport Genes Are Directly or Indirectly Affected by IKBKAP Downregulation.

    PubMed

    Lefler, Sharon; Cohen, Malkiel A; Kantor, Gal; Cheishvili, David; Even, Aviel; Birger, Anastasya; Turetsky, Tikva; Gil, Yaniv; Even-Ram, Sharona; Aizenman, Einat; Bashir, Nibal; Maayan, Channa; Razin, Aharon; Reubinoff, Benjamim E; Weil, Miguel

    2015-01-01

    A splicing mutation in the IKBKAP gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we found new molecular insights for the IKAP role and the impact of the FD mutation in the human PNS lineage by using a novel and unique human embryonic stem cell (hESC) line homozygous to the FD mutation originated by pre implantation genetic diagnosis (PGD) analysis. We found that IKBKAP downregulation during PNS differentiation affects normal migration in FD-hESC derived neural crest cells (NCC) while at later stages the PNS neurons show reduced intracellular colocalization between vesicular proteins and IKAP. Comparative wide transcriptome analysis of FD and WT hESC-derived neurons together with the analysis of human brains from FD and WT 12 weeks old embryos and experimental validation of the results confirmed that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation in FD neurons. Moreover we show that kinetin (a drug that corrects IKBKAP alternative splicing) promotes the recovery of IKAP expression and these IKAP functional associated genes identified in the study. Altogether, these results support the view that IKAP might be a vesicular like protein that might be involved in neuronal transport in hESC derived PNS neurons. This function seems to be mostly affected in FD-hESC derived PNS neurons probably reflecting some PNS neuronal dysfunction observed in FD.

  9. Axonal Noise as a Source of Synaptic Variability

    PubMed Central

    Neishabouri, Ali; Faisal, A. Aldo

    2014-01-01

    Post-synaptic potential (PSP) variability is typically attributed to mechanisms inside synapses, yet recent advances in experimental methods and biophysical understanding have led us to reconsider the role of axons as highly reliable transmission channels. We show that in many thin axons of our brain, the action potential (AP) waveform and thus the Ca++ signal controlling vesicle release at synapses will be significantly affected by the inherent variability of ion channel gating. We investigate how and to what extent fluctuations in the AP waveform explain observed PSP variability. Using both biophysical theory and stochastic simulations of central and peripheral nervous system axons from vertebrates and invertebrates, we show that channel noise in thin axons (<1 µm diameter) causes random fluctuations in AP waveforms. AP height and width, both experimentally characterised parameters of post-synaptic response amplitude, vary e.g. by up to 20 mV and 0.5 ms while a single AP propagates in C-fibre axons. We show how AP height and width variabilities increase with a ¾ power-law as diameter decreases and translate these fluctuations into post-synaptic response variability using biophysical data and models of synaptic transmission. We find for example that for mammalian unmyelinated axons with 0.2 µm diameter (matching cerebellar parallel fibres) axonal noise alone can explain half of the PSP variability in cerebellar synapses. We conclude that axonal variability may have considerable impact on synaptic response variability. Thus, in many experimental frameworks investigating synaptic transmission through paired-cell recordings or extracellular stimulation of presynaptic neurons, causes of variability may have been confounded. We thereby show how bottom-up aggregation of molecular noise sources contributes to our understanding of variability observed at higher levels of biological organisation. PMID:24809823

  10. Summary of typical parameters that affect sound transmission through general aviation aircraft structures

    NASA Technical Reports Server (NTRS)

    Grosveld, F.; Navaneethan, R.; Roskam, J.

    1981-01-01

    This paper presents results of a systematic experimental investigation of parameters which affect sound transmission through general aviation structures. Parameters studied include angle of sound incidence, panel curvature, panel stresses, and edge conditions for bare panels; pane thickness, spacing, inclination of window panes, and depressurization for dual pane windows; densities of hard foam and sound absorption materials, air gaps, and trim panel thickness for multilayered panels. Based on the study, some promising methods for reducing interior noise in general aviation airplanes are discussed.

  11. Methamphetamine blunts Ca2+ currents and excitatory synaptic transmission through D1/5 receptor-mediated mechanisms in the mouse medial prefrontal cortex

    PubMed Central

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

    2015-01-01

    Psychostimulant addiction is associated with dysfunctions in frontal cortex. Previous data demonstrated that repeated exposure to methamphetamine (METH) can alter prefrontal cortex (PFC) dependent functions. Here, we show that withdrawal from repetitive non-contingent METH administration (7 days, 1mg/kg) depressed voltage-dependent calcium currents (ICa) and increased IH amplitude and the paired-pulse ratio of evoked EPSCs in deep-layer pyramidal mPFC neurons. Most of these effects were blocked by systemic co-administration of the D1/D5 receptor antagonist SCH23390 (0.5 and 0.05 mg/kg). In vitro METH (i.e bath-applied to slices from naïve-treated animals) was able to emulate its systemic effects on ICa and evoked EPSCs paired-pulse ratio. We also provide evidence of altered mRNA expression of i) voltage-gated calcium channels P/Q-type Cacna1a (Cav2.1), N-type Cacna1b (Cav2.2), T-type Cav3.1 Cacna1g, Cav3.2 Cacna1h, Cav3.3 Cacna1i and the auxiliary subunit Cacna2d1 (α2δ1), ii) hyperpolarization-activated cyclic nucleotide-gated channels Hcn1 and Hcn2 and iii) glutamate receptors subunits AMPA-type Gria1, NMDA-type Grin1 and metabotropic Grm1 in the mouse mPFC after repeated METH treatment. Moreover, we show that some of these changes in mRNA expression were sensitive D1/5 receptor blockade. Altogether these altered mechanisms affecting synaptic physiology and transcriptional regulation may underlie prefrontal cortex functional alterations that could lead to PFC impairments observed in METH-addicted individuals. PMID:25871318

  12. Changes in synaptic transmission of substantia gelatinosa neurons after spinal cord hemisection revealed by analysis using in vivo patch-clamp recording

    PubMed Central

    Kozuka, Yuji; Furue, Hidemasa; Ishida, Takashi; Tanaka, Satoshi; Namiki, Akiyoshi; Yamakage, Michiaki

    2016-01-01

    Background After spinal cord injury, central neuropathic pain develops in the majority of spinal cord injury patients. Spinal hemisection in rats, which has been developed as an animal model of spinal cord injury in humans, results in hyperexcitation of spinal dorsal horn neurons soon after the hemisection and thereafter. The hyperexcitation is likely caused by permanent elimination of the descending pain systems. We examined the change in synaptic transmission of substantia gelatinosa neurons following acute spinal hemisection by using an in vivo whole-cell patch-clamp technique. Results An increased spontaneous action potential firings of substantia gelatinosa neurons was detected in hemisected rats compared with that in control animals. The frequencies and amplitudes of spontaneous excitatory postsynaptic currents and of evoked excitatory postsynaptic currentss in response to non-noxious and noxious stimuli were not different between hemisected and control animals. On the contrary, the amplitude and frequency of spontaneous inhibitory postsynaptic currents of substantia gelatinosa neurons in hemisected animals were significantly smaller and lower, respectively, than those in control animals (P < 0.01). Large amplitude and high-frequency spontaneous inhibitory postsynaptic currents, which could not be elicited by mechanical stimuli, were seen in 44% of substantia gelatinosa neurons in control animals but only in 17% of substantia gelatinosa neurons in hemisected animals. In control animals, such large amplitude spontaneous inhibitory postsynaptic currents were suppressed by spinal application of tetrodotoxin (1 µM). Cervical application of lidocaine (2%, 10 µl) also inhibited such large amplitude of inhibitory postsynaptic currents. The proportion of multi-receptive substantia gelatinosa neurons, which exhibit action potential firing in response to non-noxious and noxious stimuli, was much larger in hemisected animals than in control animals

  13. Modulation of synaptic plasticity by stress and antidepressants.

    PubMed

    Popoli, Maurizio; Gennarelli, Massimo; Racagni, Giorgio

    2002-06-01

    Recent preclinical and clinical studies have shown that mechanisms underlying neuronal plasticity and survival are involved in both the outcome of stressful experiences and the action of antidepressants. Whereas most antidepressants predominantly affect the brain levels of monoamine neurotransmitters, it is increasingly appreciated that they also modulate neurotransmission at synapses using the neurotransmitter glutamate (the most abundant in the brain). In the hippocampus, a main area of the limbic system involved in cognitive functions as well as attention and affect, specific molecules enriched at glutamatergic synapses mediate major changes in synaptic plasticity induced by stress paradigms or antidepressant treatments. We analyze here the modifications induced by stress or antidepressants in the strength of synaptic transmission in hippocampus, and the molecular modifications induced by antidepressants in two main mediators of synaptic plasticity: the N-methyl-D-aspartate (NMDA) receptor complex for glutamate and the Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). Both stress and antidepressants induce alterations in long-term potentiation of hippocampal glutamatergic synapses, which may be partly accounted for by the influence of environmental or drug-induced stimulation of monoaminergic pathways projecting to the hippocampus. In the course of antidepressant treatments significant changes have been described in both the NMDA receptor and CaM kinase II, which may account for the physiological changes observed. A central role in these synaptic changes is exerted by brain-derived neurotrophic factor (BDNF), which modulates both synaptic plasticity and its molecular mediators, as well as inducing morphological synaptic changes. The role of these molecular effectors in synaptic plasticity is discussed in relation to the action of antidepressants and the search for new molecular targets of drug action in the therapy of mood disorders.

  14. Control by Preynaptic Correlation: a mechanism affecting information transmission from Ia fibers to motoneurons.

    PubMed

    Rudomin, P; Burke, R E; Núñez, R; Madrid, J; Dutton, H

    1975-03-01

    1. In the unanesthetized spinal cord of the cat, simultaneous intracellular recordings were made from two motoneurons belonging to the gastronemius motor nucleus. 2. Supramaximal iterative stimulation of small branches of the gastrocnemius nerve produced monosynaptic EPSPs (Ia EPSPs) of varying amplitude superimposed on a fluctuating base line. 3. In most cases the variance of the motoneuron membrane potential was increased above base-line levels with a time course approximately matching the Ia EPSP. This suggests that Ia EPSP fluctuations are greater than can be accounted for by the base-line fluctuations alone. 4. For a given series of Ia EPSPs, the smaller responses in the series had about the same decay phase as the larger EPSPs, suggesting that most of the Ia EPSP fluctuations were not due to systematic changes in postsynaptic conductances produced by ongoing activity, but rather to a presynaptic mechanism. 5. Simultaneous recording from two motoneurons showed that base-line fluctuations were positively correlated. In most cases, however, there was an additional increased correlation above base-line levels resembling the time course of the Ia EPSPs, indicating positive correlation between EPSP fluctuations which is attributed to a presynaptic mechanism. 6. Conditioning volleys to group I muscle afferents or to low-threshold cutaneous afferents reduced the variance of the Ia EPSPs and also their correlation in motoneuron pairs, often without changing the mean Ia EPSPs. 7. It is concluded that, in the unanesthetized spinal cord, in addition to the random process which governs transmitter release intrinsic to a given synaptic terminal, there is another stochastic process affecting, in a correlated manner, transmitter release in large sets of Ia synaptic terminals. Most likely, the correlation in transmitter release is achieved by membrane potential fluctuations imposed on the Ia terminal arborizations by ongoing activity of the segmental mechanism mediating

  15. Synaptic Plasticity, Dementia and Alzheimer Disease.

    PubMed

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

    2017-01-13

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

  16. Growth factors in synaptic function

    PubMed Central

    Poon, Vivian Y.; Choi, Sojoong; Park, Mikyoung

    2013-01-01

    Synapses are increasingly recognized as key structures that malfunction in disorders like schizophrenia, mental retardation, and neurodegenerative diseases. The importance and complexity of the synapse has fuelled research into the molecular mechanisms underlying synaptogenesis, synaptic transmission, and plasticity. In this regard, neurotrophic factors such as netrin, Wnt, transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and others have gained prominence for their ability to regulate synaptic function. Several of these factors were first implicated in neuroprotection, neuronal growth, and axon guidance. However, their roles in synaptic development and function have become increasingly clear, and the downstream signaling pathways employed by these factors have begun to be elucidated. In this review, we will address the role of these factors and their downstream effectors in synaptic function in vivo and in cultured neurons. PMID:24065916

  17. A new cytochemical method for in situ detection of cholinergic synaptic transmission by staining of Cu2+ incorporated in frog neuromuscular junction during nerve stimulation.

    PubMed

    Hirai, Keiji; Tanaka, Eiichiro; Motelica-heino, Ion; Katayama, Yoshifumi; Higashi, Hideo; Tsuji, Shigeru

    2006-06-01

    A new cytochemical method was devised in order to visualize Cu2+ ions in the synaptic area after their intracellular penetration during nerve stimulation of the frog neuromuscular junction (NMJ). The motor nerves were stimulated in presence of Cu2+. After total blockade of the neuromuscular junction, the tissue was treated by ferrocyanide, a precipitating agent of Cu2+, and fixed for optical and electron microscopic observation. The oxidoreductase-like catalytic activity of the copper ferrocyanide precipitate was used to amplify the cytochemical staining by a treatment with diaminobenzidine and H2O2, after permeabilization of cell membranes by Triton X-100. At optical level, an intense staining was observed in the synaptic area. Application of d-tubocurarine (d-TC), a selective inhibitor of nicotinic acetylcholine receptors (nAChRs), markedly reduced the staining. No reaction could be observed in absence of membrane permeabilization. These results suggest that Cu2+ was localized in the cytoplasm of muscle cells after its penetration through nAChRs. At electron microscopic level, cytochemical reaction was found in the cytoplasm of muscle cells near the postsynaptic membrane, and in a few synaptic vesicles in the vicinity of the active zone. This method may be used for the identification of cholinergic inputs in central and peripheral nerve systems and, generally speaking, for the detection of synaptic activity elicited by specific nerve stimulation.

  18. mGluR1 and mGluR5 Synergistically Control Cholinergic Synaptic Transmission in the Thalamic Reticular Nucleus

    PubMed Central

    Sun, Yan-Gang; Rupprecht, Vanessa; Zhou, Li; Dasgupta, Rajan; Seibt, Frederik

    2016-01-01

    Acetylcholine (ACh) signaling is involved in a wide range of processes, including arousal, attention, and learning. An increasing number of studies indicate that cholinergic control of these functions is highly deterministic, mediated by synaptic afferents that generate reliable and precise responses in postsynaptic neurons. However, mechanisms that govern plastic changes of cholinergic synaptic strength are poorly understood, even though they are likely critical in shaping the impact of cholinergic inputs on neuronal networks. We have recently shown that in the thalamic reticular nucleus (TRN), synaptic release of ACh generates excitatory–inhibitory biphasic postsynaptic responses, mediated by the activation of α4β2 nicotinic (nAChRs) and M2 muscarinic receptors (mAChRs), respectively. Here, using voltage-clamp recordings from TRN neurons in thalamocortical slices of mice, we demonstrate that the activation of Group I metabotropic glutamate receptors (mGluRs) by ambient or synaptically released glutamate evokes transient increases of nicotinic EPSCs. Additionally, we find that the selective Group I mGluR agonist DHPG [(S)-3,5-dihydroxyphenylglycine] evokes long-term potentiation of nicotinic EPSCs (mGluR-nLTP), dependent on increases in postsynaptic Ca2+ concentration and the activation of phospholipase C. Both the induction and the maintenance of mGluR-nLTP require synergistic activation of mGluR1 and mGluR5. Together, our results show that postsynaptic Group I mGluRs are critically involved in the regulation of cholinergic synaptic strength on different time scales, suggesting that cholinergic control of local thalamic circuits is highly context-dependent and regulated by the overall levels of glutamatergic afferent activity. SIGNIFICANCE STATEMENT Cholinergic signaling controls information processing and plasticity in neuronal circuits, but the mechanisms underlying the regulation of cholinergic synaptic strength on different time scales are unknown. Here

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

    SciTech Connect

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

    2007-10-01

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

  20. Energy Efficient Sparse Connectivity from Imbalanced Synaptic Plasticity Rules

    PubMed Central

    Sacramento, João; Wichert, Andreas; van Rossum, Mark C. W.

    2015-01-01

    It is believed that energy efficiency is an important constraint in brain evolution. As synaptic transmission dominates energy consumption, energy can be saved by ensuring that only a few synapses are active. It is therefore likely that the formation of sparse codes and sparse connectivity are fundamental objectives of synaptic plasticity. In this work we study how sparse connectivity can result from a synaptic learning rule of excitatory synapses. Information is maximised when potentiation and depression are balanced according to the mean presynaptic activity level and the resulting fraction of zero-weight synapses is around 50%. However, an imbalance towards depression increases the fraction of zero-weight synapses without significantly affecting performance. We show that imbalanced plasticity corresponds to imposing a regularising constraint on the L 1-norm of the synaptic weight vector, a procedure that is well-known to induce sparseness. Imbalanced plasticity is biophysically plausible and leads to more efficient synaptic configurations than a previously suggested approach that prunes synapses after learning. Our framework gives a novel interpretation to the high fraction of silent synapses found in brain regions like the cerebellum. PMID:26046817

  1. Long-Term Culture of Astrocytes Attenuates the Readily Releasable Pool of Synaptic Vesicles

    PubMed Central

    Kawano, Hiroyuki; Katsurabayashi, Shutaro; Kakazu, Yasuhiro; Yamashita, Yuta; Kubo, Natsuko; Kubo, Masafumi; Okuda, Hideto; Takasaki, Kotaro; Kubota, Kaori; Mishima, Kenichi; Fujiwara, Michihiro; Harata, N. Charles; Iwasaki, Katsunori

    2012-01-01

    The astrocyte is a major glial cell type of the brain, and plays key roles in the formation, maturation, stabilization and elimination of synapses. Thus, changes in astrocyte condition and age can influence information processing at synapses. However, whether and how aging astrocytes affect synaptic function and maturation have not yet been thoroughly investigated. Here, we show the effects of prolonged culture on the ability of astrocytes to induce synapse formation and to modify synaptic transmission, using cultured autaptic neurons. By 9 weeks in culture, astrocytes derived from the mouse cerebral cortex demonstrated increases in β-galactosidase activity and glial fibrillary acidic protein (GFAP) expression, both of which are characteristic of aging and glial activation in vitro. Autaptic hippocampal neurons plated on these aging astrocytes showed a smaller amount of evoked release of the excitatory neurotransmitter glutamate, and a lower frequency of miniature release of glutamate, both of which were attributable to a reduction in the pool of readily releasable synaptic vesicles. Other features of synaptogenesis and synaptic transmission were retained, for example the ability to induce structural synapses, the presynaptic release probability, the fraction of functional presynaptic nerve terminals, and the ability to recruit functional AMPA and NMDA glutamate receptors to synapses. Thus the presence of aging astrocytes affects the efficiency of synaptic transmission. Given that the pool of readily releasable vesicles is also small at immature synapses, our results are consistent with astrocytic aging leading to retarded synapse maturation. PMID:23110166

  2. Longitudinal Modeling of the Association Between Transmissible Risk, Affect During Drug Use and Development of Substance Use Disorder

    PubMed Central

    Tarter, Ralph E.; Kirisci, Levent; Reynolds, Maureen; Horner, Michelle; Zhai, ZuWei; Gathuru, Irene; Vanyukov, Michael

    2015-01-01

    Objective This longitudinal investigation examined the hypothesis that subjective experience during consumption of preferred drugs mediates the association of transmissible risk for substance use disorder (SUD) measured in childhood and adolescence and SUD diagnosis in adulthood. Transmissible risk denotes the psychological characteristics having intergenerational continuity between parents and their biological children. Methods The transmissible liability index (TLI) was administered to 483 10–12 year old boys (baseline). Follow-up evaluations were conducted when the boys attained 12–14, 16, 19 and 22 years of age using age-specific versions of the TLI. Frequency of consumption of the participant’s three most preferred drugs, affect on an ordinary day, affect while under influence of the preferred substances and presence/absence of current SUD were assessed at 22 years of age. Results Consumption frequency of preferred drugs among boys mediates the association of transmissible risk during childhood and adolescence and SUD diagnosis in adulthood. Severity of negative affect on a drug-free day predicts frequency of consumption of preferred drugs which, in turn, predicts severity of negative affect during the drug use event. Neither affect on a drug-free day nor affect during the drug use event mediates the association of transmissible risk and SUD. Conclusions Affect on drug-free days, and while under influence of preferred substances covary with consumption frequency; however, affect is not related to transmissible SUD risk or SUD outcome. PMID:26441401

  3. Antipredator behaviour of Myzus persicae affects transmission efficiency of Broad bean wilt virus 1.

    PubMed

    Belliure, Belén; Amorós-Jiménez, Rocco; Fereres, Alberto; Marcos-García, M Ángeles

    2011-08-01

    Biological control has the potential to limit the population growth of arthropod vectors and consequently may be expected to reduce plant virus spread in a crop. However, reduction of vector abundance is not the only effect of biological control. Natural enemies might induce antipredator behaviour that affects feeding and dispersal of vectors, and therefore virus spread. Here we test the effect of two natural enemies on dispersal of the aphid vector Myzus persicae and transmission of Broad bean wilt virus 1 (BBWV-1), genus Fabavirus, which is non-persistently transmitted by aphids. One of the predators tested, the syrphid Sphaerophoria rueppellii, is considered to induce low disturbance in aphid colonies, whereas the other, the coccinellid Adalia bipunctata, is assumed to induce high disturbance. Natural enemies enhanced aphid dispersal, but not virus transmission as compared to the control treatment without predators. However, transmission efficiency of BBWV-1 was higher in the presence of coccinellid adults than with syrphids. The behavioural observations of predators and the reactions of aphids to their presence indicate that a stronger antipredator behaviour is induced by coccinellid adults than by syrphids. The different antipredator behaviour displayed by aphids towards coccinellid adults and syrphids might explain the differences found in the rate of virus spread in their presence.

  4. Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity

    PubMed Central

    Latif-Hernandez, Amira; Shah, Disha; Ahmed, Tariq; Lo, Adrian C.; Callaerts-Vegh, Zsuzsanna; Van der Linden, Annemie; Balschun, Detlef; D’Hooge, Rudi

    2016-01-01

    Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connectivity (FC) and hippocampal neuroplasticity. FC between various cortical regions was assessed by resting-state fMRI (rsfMRI) methodology, and mice that had received QA injection into mPFC showed increased FC between various cortical regions. mPFC and hippocampus (HC) are anatomically as well as functionally linked as part of a cortical network that controls higher-order cognitive functions. Together, these observations demonstrate the central functional importance of rodent mPFC as well as the validity of QA-induced mPFC damage as a preclinical rodent model of the early stages of neurodegeneration. PMID:27819338

  5. Encephalitis and antibodies to synaptic and neuronal cell surface proteins

    PubMed Central

    Lancaster, Eric; Martinez-Hernandez, Eugenia

    2011-01-01

    The identification of encephalitis associated with antibodies against cell surface and synaptic proteins, although recent, has already had a substantial impact in clinical neurology and neuroscience. The target antigens are receptors and proteins that have critical roles in synaptic transmission and plasticity, including the NMDA receptor, the AMPA receptor, the GABAB receptor, and the glycine receptor. Other autoantigens, such as leucine-rich glioma-inactivated 1 and contactin-associated protein-like 2, form part of trans-synaptic complexes and neuronal cell adhesion molecules involved in fine-tuning synaptic transmission and nerve excitability. Syndromes resulting from these immune responses resemble those of pharmacologic or genetic models in which the antigens are disrupted. For some immune responses, there is evidence that the antibodies alter the structure and function of the antigen, suggesting a direct pathogenic effect. These disorders are important because they can affect children and young adults, are severe and protracted, occur with or without tumor association, and respond to treatment but may relapse. This review provides an update on these syndromes and autoantigens with special emphasis on clinical diagnosis and treatment. PMID:21747075

  6. Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid-β deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer's disease.

    PubMed

    Bae, Jae-sung; Jin, Hee Kyung; Lee, Jong Kil; Richardson, Jill C; Carter, Janet E

    2013-06-01

    The remarkable potentiality of bone marrow-derived mesenchymal stem cells (BM-MSCs) after transplantation to models of neurological disease and injury has been described. We have previously published data confirming the influence of BM-MSCs on β-amyloid (Aβ) deposition in an Alzheimer's disease (AD) mouse model. However, therapeutic approaches in neurological diseases such as AD, including those for BM-MSCs, are increasingly centered on the potential for prophylactic therapy in pro-dromal states where the underlying cause of the disease is apparent but functional deficits are not. In order to investigate whether BM-MSCs could have a beneficial effect in high-risk pre-dementia AD individuals, we treated young AD mice, at an age at which they display neuropathological, but not cognitive features of AD. Following a single intra-cerebral injection of BM-MSCs, interestingly, we found a significant decrease in the cerebral Aβ deposition compared with controls treated with PBS that was sustained up to 2 months post-injection. Expression of dynamin 1 and Synapsin 1, key pre-synaptic proteins associated with synaptic transmission, which are typically decreased in brains of AD patients, were considerably enhanced in the brains of AD mice treated with BM-MSCs and this response was sustained beyond 2 months. These data demonstrate that BM-MSCs produce an acute reduction in Aβ deposits and facilitate changes in key proteins required for synaptic transmission. These findings suggest that BM-MSC transplantation warrants further investigation as a potential therapy for early intervention in pro-dromal AD.

  7. GABAB receptor modulation of synaptic function

    PubMed Central

    Chalifoux, Jason R.; Carter, Adam G.

    2011-01-01

    Neuromodulators have complex effects on both the presynaptic release and postsynaptic detection of neurotransmitters. Here we describe recent advances in our understanding of synaptic modulation by metabotropic GABAB receptors. By inhibiting multivesicular release from the presynaptic terminal, these receptors decrease the synaptic glutamate signal. GABAB receptors also inhibit the Ca2+ permeability of NMDA receptors to decrease Ca2+ signals in postsynaptic spines. These new findings highlight the importance of GABAB receptors in regulating many aspects of synaptic transmission. They also point to novel questions about the spatiotemporal dynamics and sources of synaptic modulation in the brain. PMID:21376567

  8. Transmission distortion affecting human noncrossover but not crossover recombination: a hidden source of meiotic drive.

    PubMed

    Odenthal-Hesse, Linda; Berg, Ingrid L; Veselis, Amelia; Jeffreys, Alec J; May, Celia A

    2014-02-01

    Meiotic recombination ensures the correct segregation of homologous chromosomes during gamete formation and contributes to DNA diversity through both large-scale reciprocal crossovers and very localised gene conversion events, also known as noncrossovers. Considerable progress has been made in understanding factors such as PRDM9 and SNP variants that influence the initiation of recombination at human hotspots but very little is known about factors acting downstream. To address this, we simultaneously analysed both types of recombinant molecule in sperm DNA at six highly active hotspots, and looked for disparity in the transmission of allelic variants indicative of any cis-acting influences. At two of the hotspots we identified a novel form of biased transmission that was exclusive to the noncrossover class of recombinant, and which presumably arises through differences between crossovers and noncrossovers in heteroduplex formation and biased mismatch repair. This form of biased gene conversion is not predicted to influence hotspot activity as previously noted for SNPs that affect recombination initiation, but does constitute a powerful and previously undetected source of recombination-driven meiotic drive that by extrapolation may affect thousands of recombination hotspots throughout the human genome. Intriguingly, at both of the hotspots described here, this drive favours strong (G/C) over weak (A/T) base pairs as might be predicted from the well-established correlations between high GC content and recombination activity in mammalian genomes.

  9. Handling missing data in transmission disequilibrium test in nuclear families with one affected offspring.

    PubMed

    Bourget, Gulhan

    2012-01-01

    The Transmission Disequilibrium Test (TDT) compares frequencies of transmission of two alleles from heterozygote parents to an affected offspring. This test requires all genotypes to be known from all members of the nuclear families. However, obtaining all genotypes in a study might not be possible for some families, in which case, a data set results in missing genotypes. There are many techniques of handling missing genotypes in parents but only a few in offspring. The robust TDT (rTDT) is one of the methods that handles missing genotypes for all members of nuclear families [with one affected offspring]. Even though all family members can be imputed, the rTDT is a conservative test with low power. We propose a new method, Mendelian Inheritance TDT (MITDT-ONE), that controls type I error and has high power. The MITDT-ONE uses Mendelian Inheritance properties, and takes population frequencies of the disease allele and marker allele into account in the rTDT method. One of the advantages of using the MITDT-ONE is that the MITDT-ONE can identify additional significant genes that are not found by the rTDT. We demonstrate the performances of both tests along with Sib-TDT (S-TDT) in Monte Carlo simulation studies. Moreover, we apply our method to the type 1 diabetes data from the Warren families in the United Kingdom to identify significant genes that are related to type 1 diabetes.

  10. Morphophysiology of synaptic transmission between type I hair cells and vestibular primary afferents. An intracellular study employing horseradish peroxidase in the lizard, Calotes versicolor.

    PubMed

    Schessel, D A; Ginzberg, R; Highstein, S M

    1991-03-22

    Intracellular records with glass microelectrodes filled with horseradish peroxidase (HRP) were taken from primary afferents of the horizontal semicircular canal in the lizard, Calotes versicolor. A coefficient of variation (CV) of the interspike intervals of spontaneous action potentials (APs) was calculated and correlated with the terminal morphologies of afferents within the canal crista. Irregular fibers with CV greater than 0.4 always correlated with a nerve chalice or calyx afferent terminal expansion surrounding one or more type I hair cells; more regular fibers with CV less than 0.4 always correlated with a dimorphic or bouton only terminal expansion of afferents. Afferents with a CV greater than 0.4 demonstrated miniature excitatory postsynaptic potentials (mEPSPs) that summated to initiate APs. APs were blocked by tetrodotoxin and mEPSP frequency was modulated by caloric stimulation. Cobalt application reversibly blocked mEPSPs. Electron microscopic examination of physiologically studied afferents with CV greater than 0.4 revealed synaptic profiles consisting of typical synaptic bodies and synaptic vesicles in the type I hair cell presynaptic to the nerve chalice. Examples of the interspike baseline in regular and irregular afferents suggest differential modes of impulse initiation in these two fiber types.

  11. EDITORIAL: Synaptic electronics Synaptic electronics

    NASA Astrophysics Data System (ADS)

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

    2013-09-01

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

  12. TARP subtypes differentially and dose-dependently control synaptic AMPA receptor gating.

    PubMed

    Milstein, Aaron D; Zhou, Wei; Karimzadegan, Siavash; Bredt, David S; Nicoll, Roger A

    2007-09-20

    A family of transmembrane AMPA receptor regulatory proteins (TARPs) profoundly affects the trafficking and gating of AMPA receptors (AMPARs). Although TARP subtypes are differentially expressed throughout the CNS, it is unclear whether this imparts functional diversity to AMPARs in distinct neuronal populations. Here, we examine the effects of each TARP subtype on the kinetics of AMPAR gating in heterologous cells and in neurons. We report a striking heterogeneity in the effects of TARP subtypes on AMPAR deactivation and desensitization, which we demonstrate controls the time course of synaptic transmission. In addition, we find that some TARP subtypes dramatically slow AMPAR activation kinetics. Synaptic AMPAR kinetics also depend on TARP expression level, suggesting a variable TARP/AMPAR stoichiometry. Analysis of quantal synaptic transmission in a TARP gamma-4 knockout (KO) mouse corroborates our expression data and demonstrates that TARP subtype-specific gating of AMPARs contributes to the kinetics of native AMPARs at central synapses.

  13. 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. PMID:27630986

  14. The transmission of light affect the color reproduction of plastic print

    NASA Astrophysics Data System (ADS)

    Chen, Jie; Zhang, Yi-xin; Shi, Gongcheng

    2011-01-01

    By analyzing the different paths that the incident light traverses in the printing, the paper aims to study the effect the transmission of light produces on the color reproduction of the plastic printing. The article also analyzes object characteristics about the three color properties and the color density, so as to make an accurate prediction on the color reproduction of the printing where ink is printed on the end of the plastic base directly. In the research, the incident light on the plastic print are divided into two parts: the reflection of diffuse light in the ink and the optical multi-layer internal reflection of the light through ink layer onto the plastic substrate. In this paper, we use kubelka-munk theory to analyze the transmission of the incident light on the surface of the printing product and Clapper-Yule theory to analyze the incident light which through the ink to the plastic film surface. When the incident light through the ink to the film surface, we have a series of mutually parallel reflected beam and refracted beam, and then obtain the synthesis of the reflected light complex amplitude, using the similar methods to obtain the total reflected and refraction light intensity. Combining the total reflection light intensity through the plastic substrate and the overall reflectivity through a plastic print surface by the kubelka-munk theory, color density and light transmission factor of the plastic substrate can be drawn in the formula: D ∞ f (δ,d,i1 ). From the above equation, we can find that optical phase retardation δ, the thickness of plastic d and the angle of incidence on the plastic surface i1 affect the color reproduction of plastic print.

  15. Histone deacetylase 2 cell autonomously suppresses excitatory and enhances inhibitory synaptic function in CA1 pyramidal neurons.

    PubMed

    Hanson, Jesse E; Deng, Lunbin; Hackos, David H; Lo, Shih-Ching; Lauffer, Benjamin E; Steiner, Pascal; Zhou, Qiang

    2013-04-03

    Histone deacetylase 2 (HDAC2) negatively regulates excitatory synapse number and memory performance. However, whether HDAC2 regulation of excitatory synapses occurs in a cell-autonomous manner and whether HDAC2 regulates inhibitory synaptic functions are not well understood. To examine these aspects of HDAC2 function, we used sparse transfection of rat hippocampal slice cultures and whole-cell recordings in pyramidal neurons. HDAC2 knockdown (KD) in single postsynaptic pyramidal neurons enhanced, whereas HDAC2 overexpression (OE) reduced, excitatory synaptic transmission. Postsynaptic KD of HDAC2 also facilitated expression of long-term potentiation induced by subthreshold induction stimuli, without altering long-term depression. In contrast, HDAC2 KD reduced, whereas HDAC2 OE enhanced, inhibitory synaptic transmission. Alterations of postsynaptic GABA(A) receptors (GABA(A)Rs) likely underlie the impact of HDAC2 on inhibitory transmission. Consistent with this, we observed reduced transcript and protein levels of the GABA(A)R γ2 subunit and reduced surface expression of the α2 subunit after HDAC2 KD. Furthermore, we observed a reduction in synaptic but not tonic GABA(A)R currents by HDAC2 KD, suggesting that HDAC2 selectively affects synaptic abundance of functional GABA(A)Rs. Immunostaining for postsynaptic GABA(A)Rs confirmed that HDAC2 KD and OE can regulate the synaptic abundance of these receptors. Together, these results highlight a role for HDAC2 in suppressing synaptic excitation and enhancing synaptic inhibition of hippocampal neurons. Therefore, a shift in the balance of synaptic excitation versus inhibition favoring excitation could contribute to the beneficial effects of reducing HDAC2 function in wild-type mice or of inhibiting HDACs in models of cognitive impairment.

  16. Vertical transmission of Zika virus targeting the radial glial cells affects cortex development of offspring mice

    PubMed Central

    Wu, Kong-Yan; Zuo, Guo-Long; Li, Xiao-Feng; Ye, Qing; Deng, Yong-Qiang; Huang, Xing-Yao; Cao, Wu-Chun; Qin, Cheng-Feng; Luo, Zhen-Ge

    2016-01-01

    The recent Zika virus (ZIKV) epidemic in Latin America coincided with a marked increase in microcephaly in newborns. However, the causal link between maternal ZIKV infection and malformation of the fetal brain has not been firmly established. Here we show a vertical transmission of ZIKV in mice and a marked effect on fetal brain development. We found that intraperitoneal (i.p.) injection of a contemporary ZIKV strain in pregnant mice led to the infection of radial glia cells (RGs) of dorsal ventricular zone of the fetuses, the primary neural progenitors responsible for cortex development, and caused a marked reduction of these cortex founder cells in the fetuses. Interestingly, the infected fetal mice exhibited a reduced cavity of lateral ventricles and a discernable decrease in surface areas of the cortex. This study thus supports the conclusion that vertically transmitted ZIKV affects fetal brain development and provides a valuable animal model for the evaluation of potential therapeutic or preventative strategies. PMID:27174054

  17. Escitalopram affects cytoskeleton and synaptic plasticity pathways in a rat gene-environment interaction model of depression as revealed by proteomics. Part II: environmental challenge.

    PubMed

    Piubelli, Chiara; Vighini, Miriam; Mathé, Aleksander A; Domenici, Enrico; Carboni, Lucia

    2011-07-01

    Large-scale investigations aimed at elucidating the molecular mechanism of action of antidepressant treatment are achievable through the application of proteomic technologies. We performed a proteomic study on the Flinders Sensitive Line (FSL), a genetically selected rat model of depression, and the control Flinders Resistant Line (FRL). To evaluate gene-environment interactions, FSL and FRL animals were separated from their mothers for 3 h from postnatal days 2 to 14 (maternal separation; MS), since early-life trauma is considered an important antecedent of depression. All groups received either escitalopram (Esc) admixed to food pellets (25 mg/kg.d) or vehicle for 1 month. Protein extracts from prefrontal/frontal cortex and hippocampus were separated by 2D electrophoresis. Proteins differentially modulated were identified by mass spectrometry. Bioinformatics analyses were performed to discover gene ontology terms associated with the modulated proteins. This paper was focused on the modifications induced by the environmental challenge of MS, both on the predisposed genetic background and on the resistant phenotype. The combination between Esc treatment and MS was investigated by comparing the MS, Esc-treated rats with rats subjected to each single procedure. In MS rats, antidepressant treatment influenced mainly proteins involved in carbohydrate metabolism in FSL rats and in vesicle-mediated transport in FRL rats. When studying the interaction between Esc and MS vs. non-separated rats, proteins playing a role in cytoskeleton organization, neuronal development, vesicle-mediated transport and synaptic plasticity were identified. The results provide further support to the available reports that antidepressant treatment affects intracellular pathways and also suggest new potential targets for future therapeutic intervention.

  18. The role of synaptic ion channels in synaptic plasticity

    PubMed Central

    Voglis, Giannis; Tavernarakis, Nektarios

    2006-01-01

    The nervous system receives a large amount of information about the environment through elaborate sensory routes. Processing and integration of these wide-ranging inputs often results in long-term behavioural alterations as a result of past experiences. These relatively permanent changes in behaviour are manifestations of the capacity of the nervous system for learning and memory. At the cellular level, synaptic plasticity is one of the mechanisms underlying this process. Repeated neural activity generates physiological changes in the nervous system that ultimately modulate neuronal communication through synaptic transmission. Recent studies implicate both presynaptic and postsynaptic ion channels in the process of synapse strength modulation. Here, we review the role of synaptic ion channels in learning and memory, and discuss the implications and significance of these findings towards deciphering the molecular biology of learning and memory. PMID:17077866

  19. Synaptic plasticity along the sleep-wake cycle: implications for epilepsy.

    PubMed

    Romcy-Pereira, Rodrigo N; Leite, João P; Garcia-Cairasco, Norberto

    2009-01-01

    Activity-dependent changes in synaptic efficacy (i.e., synaptic plasticity) can alter the way neurons communicate and process information as a result of experience. Synaptic plasticity mechanisms involve both molecular and structural modifications that affect synaptic functioning, either enhancing or depressing neuronal transmission. They include redistribution of postsynaptic receptors, activation of intracellular signaling cascades, and formation/retraction of dendritic spines, among others. During the sleep-wake cycle, as the result of particular neurochemical and neuronal firing modes, distinct oscillatory patterns organize the activity of neuronal populations, modulating synaptic plasticity. Such modulation, for example, has been shown in the visual cortex following sleep deprivation and in the ability to induce hippocampal long-term potentiation during sleep. In epilepsy, synchronized behavioral states tend to contribute to the initiation of paroxystic discharges and are considered more epileptogenic than desynchronized states. Here, we review some of the current understandings of synaptic plasticity changes in wake and sleep states and how sleep may affect epileptic seizures.

  20. Mutations altering synaptic connectivity between identified neurons in Drosophila.

    PubMed

    Thomas, J B; Wyman, R J

    1984-02-01

    By studying the effects of mutations on a simple circuit of identified neurons in Drosophila, we have found genes whose proper functioning is necessary to produce normal synaptic connections between the neurons. These neurons comprise the giant fiber (GF) system; the GFs are command neurons activated by a light-off stimulus and evoke a stereotyped pattern of activity in the thoracic muscles producing an escape jump. Each GF monosynaptically drives a motor neuron innervating the tergotrochanteral muscle (jump muscle, TTM). Each GF also disynaptically drives the motor neurons innervating the dorsal longitudinal flight muscle (DLM) via the peripherally synapsing interneuron (PSI) (King, D. G., and R. J. Wyman (1980) J. Neurocytol. 9: 753-770; M. A. Tanouye and R. J. Wyman (1980) J. Neurophysiol. 44: 405-421). A search was made for mutations affecting these identified synapses. Fifty thousand mutagenized flies were screened for nonjumping behavior to the light-off stimulus. Fifty-seven nonjumping mutant lines were established from individuals selected in the screen. Members of the lines were then tested for abnormal GF motor output to the TTM and DLM. From these lines, four X-linked mutations (representing three complementation groups) were isolated which affect the circuit. The mutations differentially disrupt specific synapses within the GF system. One mutation, bendless, disrupts synaptic transmission between the GF and the TTM motor neuron. Another, gfA, disrupts the synaptic connections of the PSI, and a third mutation, passover, disrupts transmission in both pathways.

  1. A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission.

    PubMed

    Na, Elisa S; Nelson, Erika D; Adachi, Megumi; Autry, Anita E; Mahgoub, Melissa A; Kavalali, Ege T; Monteggia, Lisa M

    2012-02-29

    Rett syndrome and MECP2 duplication syndrome are neurodevelopmental disorders that arise from loss-of-function and gain-of-function alterations in methyl-CpG binding protein 2 (MeCP2) expression, respectively. Although there have been studies examining MeCP2 loss of function in animal models, there is limited information on MeCP2 overexpression in animal models. Here, we characterize a mouse line with MeCP2 overexpression restricted to neurons (Tau-Mecp2). This MeCP2 overexpression line shows motor coordination deficits, heightened anxiety, and impairments in learning and memory that are accompanied by deficits in long-term potentiation and short-term synaptic plasticity. Whole-cell voltage-clamp recordings of cultured hippocampal neurons from Tau-Mecp2 mice reveal augmented frequency of miniature EPSCs with no change in miniature IPSCs, indicating that overexpression of MeCP2 selectively impacts excitatory synapse function. Moreover, we show that alterations in transcriptional repression mechanisms underlie the synaptic phenotypes in hippocampal neurons from the Tau-Mecp2 mice. These results demonstrate that the Tau-Mecp2 mouse line recapitulates many key phenotypes of MECP2 duplication syndrome and support the use of these mice to further study this devastating disorder.

  2. Synaptic Effects of Electric Fields

    NASA Astrophysics Data System (ADS)

    Rahman, Asif

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

  3. 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…

  4. Membrane-Derived Phospholipids Control Synaptic Neurotransmission and Plasticity

    PubMed Central

    García-Morales, Victoria; Montero, Fernando; González-Forero, David; Rodríguez-Bey, Guillermo; Gómez-Pérez, Laura; Medialdea-Wandossell, María Jesús; Domínguez-Vías, Germán; García-Verdugo, José Manuel; Moreno-López, Bernardo

    2015-01-01

    Synaptic communication is a dynamic process that is key to the regulation of neuronal excitability and information processing in the brain. To date, however, the molecular signals controlling synaptic dynamics have been poorly understood. Membrane-derived bioactive phospholipids are potential candidates to control short-term tuning of synaptic signaling, a plastic event essential for information processing at both the cellular and neuronal network levels in the brain. Here, we showed that phospholipids affect excitatory and inhibitory neurotransmission by different degrees, loci, and mechanisms of action. Signaling triggered by lysophosphatidic acid (LPA) evoked rapid and reversible depression of excitatory and inhibitory postsynaptic currents. At excitatory synapses, LPA-induced depression depended on LPA1/Gαi/o-protein/phospholipase C/myosin light chain kinase cascade at the presynaptic site. LPA increased myosin light chain phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. At inhibitory synapses, postsynaptic LPA signaling led to dephosphorylation, and internalization of the GABAAγ2 subunit through the LPA1/Gα12/13-protein/RhoA/Rho kinase/calcineurin pathway. However, LPA-induced depression of GABAergic transmission was correlated with an endocytosis-independent reduction of GABAA receptors, possibly by GABAAγ2 dephosphorylation and subsequent increased lateral diffusion. Furthermore, endogenous LPA signaling, mainly via LPA1, mediated activity-dependent inhibitory depression in a model of experimental synaptic plasticity. Finally, LPA signaling, most likely restraining the excitatory drive incoming to motoneurons, regulated performance of motor output commands, a basic brain processing task. We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron. PMID:25996636

  5. Synaptic Vesicle Exocytosis

    PubMed Central

    Südhof, Thomas C.; Rizo, Josep

    2011-01-01

    Presynaptic nerve terminals release neurotransmitters by synaptic vesicle exocytosis. Membrane fusion mediating synaptic exocytosis and other intracellular membrane traffic is affected by a universal machinery that includes SNARE (for “soluble NSF-attachment protein receptor”) and SM (for “Sec1/Munc18-like”) proteins. During fusion, vesicular and target SNARE proteins assemble into an α-helical trans-SNARE complex that forces the two membranes tightly together, and SM proteins likely wrap around assembling trans-SNARE complexes to catalyze membrane fusion. After fusion, SNARE complexes are dissociated by the ATPase NSF (for “N-ethylmaleimide sensitive factor”). Fusion-competent conformations of SNARE proteins are maintained by chaperone complexes composed of CSPα, Hsc70, and SGT, and by nonenzymatically acting synuclein chaperones; dysfunction of these chaperones results in neurodegeneration. The synaptic membrane-fusion machinery is controlled by synaptotagmin, and additionally regulated by a presynaptic protein matrix (the “active zone”) that includes Munc13 and RIM proteins as central components. PMID:22026965

  6. Inhibition by efferent nerve fibres: action on hair cells and afferent synaptic transmission in the lateral line canal organ of the burbot Lota lota.

    PubMed Central

    Flock, A; Russell, I

    1976-01-01

    1. Intracellular recordings were made from morphologically identified hair cells in the lateral line canal organs of the burbot Lota lota. 2. I.p.s.p.s were recorded from hair cells when the efferent fibres were excited by electrical stimulation of the lateral line nerve. The i.p.s.p.s were abolished when the fish was injected with immobilizing concentration of Flaxedil which is known to block the efferent synapses. 3. The i.p.s.p.s are accompanied by a decrease in the resistance of the hair cell membrane and an increase in the intracellular receptor potential. 4. Spontaneous and mechanically evoked e.p.s.p.s which were recorded intracellularly from the post-synaptic afferent nerve terminals were reduced in amplitude for the duration of the i.p.s.p. Images A, B C PMID:948076

  7. Deep mRNA Sequencing of the Tritonia diomedea Brain Transcriptome Provides Access to Gene Homologues for Neuronal Excitability, Synaptic Transmission and Peptidergic Signalling

    PubMed Central

    Senatore, Adriano; Edirisinghe, Neranjan; Katz, Paul S.

    2015-01-01

    Background The sea slug Tritonia diomedea (Mollusca, Gastropoda, Nudibranchia), has a simple and highly accessible nervous system, making it useful for studying neuronal and synaptic mechanisms underlying behavior. Although many important contributions have been made using Tritonia, until now, a lack of genetic information has impeded exploration at the molecular level. Results We performed Illumina sequencing of central nervous system mRNAs from Tritonia, generating 133.1 million 100 base pair, paired-end reads. De novo reconstruction of the RNA-Seq data yielded a total of 185,546 contigs, which partitioned into 123,154 non-redundant gene clusters (unigenes). BLAST comparison with RefSeq and Swiss-Prot protein databases, as well as mRNA data from other invertebrates (gastropod molluscs: Aplysia californica, Lymnaea stagnalis and Biomphalaria glabrata; cnidarian: Nematostella vectensis) revealed that up to 76,292 unigenes in the Tritonia transcriptome have putative homologues in other databases, 18,246 of which are below a more stringent E-value cut-off of 1x10-6. In silico prediction of secreted proteins from the Tritonia transcriptome shotgun assembly (TSA) produced a database of 579 unique sequences of secreted proteins, which also exhibited markedly higher expression levels compared to other genes in the TSA. Conclusions Our efforts greatly expand the availability of gene sequences available for Tritonia diomedea. We were able to extract full length protein sequences for most queried genes, including those involved in electrical excitability, synaptic vesicle release and neurotransmission, thus confirming that the transcriptome will serve as a useful tool for probing the molecular correlates of behavior in this species. We also generated a neurosecretome database that will serve as a useful tool for probing peptidergic signalling systems in the Tritonia brain. PMID:25719197

  8. Synaptic Vesicle Proteins and Active Zone Plasticity

    PubMed Central

    Kittel, Robert J.; Heckmann, Manfred

    2016-01-01

    Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the AZ. The protein-rich cytomatrix at the active zone (CAZ) provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and AZ states, which has heretofore received little attention. PMID:27148040

  9. Transmission

    SciTech Connect

    Sugano, K.

    1988-12-27

    A transmission is described which consists of: an input shaft; an output shaft; a first planetary gear set including a first sun gear selectively connectable by a first clutch to the input shaft, a first carrier selectively connectable by a second clutch to the input shaft and a first ring gear connected to the output shaft. The first sun gear selectively held stationary by a first brake, the first carrier is allowed to rotate in the same forward direction as the input shaft when the second clutch is engaged, but prevented from rotating in a reverse direction opposite to the forward direction by a first one-way clutch, the first carrier being selectively held stationary by a second brake; a second planetary gear set including a second sun gear connected to the input shaft, a second carrier connected to the first ring gear and also the the output shaft, and a second ring gear.

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

    PubMed

    Schotten, Sebastiaan; Meijer, Marieke; Walter, Alexander Matthias; Huson, Vincent; Mamer, Lauren; Kalogreades, Lawrence; ter Veer, Mirelle; Ruiter, Marvin; Brose, Nils; Rosenmund, Christian; Sørensen, Jakob Balslev; Verhage, Matthijs; Cornelisse, Lennart Niels

    2015-04-14

    The energy required to fuse synaptic vesicles with the plasma membrane ('activation energy') is considered a major determinant in synaptic efficacy. From reaction rate theory, we predict that a class of modulations exists, which utilize linear modulation of the energy barrier for fusion to achieve supralinear effects on the fusion rate. To test this prediction experimentally, we developed a method to assess the number of releasable vesicles, rate constants for vesicle priming, unpriming, and fusion, and the activation energy for fusion by fitting a vesicle state model to synaptic responses induced by hypertonic solutions. We show that complexinI/II deficiency or phorbol ester stimulation indeed affects responses to hypertonic solution in a supralinear manner. An additive vs multiplicative relationship between activation energy and fusion rate provides a novel explanation for previously observed non-linear effects of genetic/pharmacological perturbations on synaptic transmission and a novel interpretation of the cooperative nature of Ca(2+)-dependent release.

  11. Evidence for loss of synaptic AMPA receptors in anterior piriform cortex of aged mice.

    PubMed

    Gocel, James; Larson, John

    2013-01-01

    It has been suggested that age-related impairments in learning and memory may be due to age-related deficits in long-term potentiation of glutamatergic synaptic transmission. For example, olfactory discrimination learning is significantly affected by aging in mice and this may be due, in part, to diminished synaptic plasticity in piriform cortex. In the present study, we tested for alterations in electrophysiological properties and synaptic transmission in this simple cortical network. Whole-cell recordings were made from principal neurons in slices of anterior piriform cortex from young (3-6 months old) and old (24-28 months) C57Bl/6 mice. Miniature excitatory postsynaptic currents (mEPSCs) mediated by AMPA receptors were collected from cells in presence of tetrodotoxin (TTX) and held at -80 mV in voltage-clamp. Amplitudes of mEPSCs were significantly reduced in aged mice, suggesting that synaptic AMPA receptor expression is decreased during aging. In a second set of experiments, spontaneous excitatory postsynaptic currents (s/mEPSCs) were recorded in slices from different cohorts of young and old mice, in the absence of TTX. These currents resembled mEPSCs and were similarly reduced in amplitude in old mice. The results represent the first electrophysiological evidence for age-related declines in glutamatergic synaptic function in the mammalian olfactory system.

  12. Homeostatic control of synaptic activity by endogenous adenosine is mediated by adenosine kinase.

    PubMed

    Diógenes, Maria José; Neves-Tomé, Raquel; Fucile, Sergio; Martinello, Katiuscia; Scianni, Maria; Theofilas, Panos; Lopatár, Jan; Ribeiro, Joaquim A; Maggi, Laura; Frenguelli, Bruno G; Limatola, Cristina; Boison, Detlev; Sebastião, Ana M

    2014-01-01

    Extracellular adenosine, a key regulator of neuronal excitability, is metabolized by astrocyte-based enzyme adenosine kinase (ADK). We hypothesized that ADK might be an upstream regulator of adenosine-based homeostatic brain functions by simultaneously affecting several downstream pathways. We therefore studied the relationship between ADK expression, levels of extracellular adenosine, synaptic transmission, intrinsic excitability, and brain-derived neurotrophic factor (BDNF)-dependent synaptic actions in transgenic mice underexpressing or overexpressing ADK. We demonstrate that ADK: 1) Critically influences the basal tone of adenosine, evaluated by microelectrode adenosine biosensors, and its release following stimulation; 2) determines the degree of tonic adenosine-dependent synaptic inhibition, which correlates with differential plasticity at hippocampal synapses with low release probability; 3) modulates the age-dependent effects of BDNF on hippocampal synaptic transmission, an action dependent upon co-activation of adenosine A2A receptors; and 4) influences GABAA receptor-mediated currents in CA3 pyramidal neurons. We conclude that ADK provides important upstream regulation of adenosine-based homeostatic function of the brain and that this mechanism is necessary and permissive to synaptic actions of adenosine acting on multiple pathways. These mechanistic studies support previous therapeutic studies and implicate ADK as a promising therapeutic target for upstream control of multiple neuronal signaling pathways crucial for a variety of neurological disorders.

  13. Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes

    PubMed Central

    Diaper, Danielle C.; Adachi, Yoshitsugu; Sutcliffe, Ben; Humphrey, Dickon M.; Elliott, Christopher J.H.; Stepto, Alan; Ludlow, Zoe N.; Vanden Broeck, Lies; Callaerts, Patrick; Dermaut, Bart; Al-Chalabi, Ammar; Shaw, Christopher E.; Robinson, Iain M.; Hirth, Frank

    2013-01-01

    Cytoplasmic accumulation and nuclear clearance of TDP-43 characterize familial and sporadic forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, suggesting that either loss or gain of TDP-43 function, or both, cause disease formation. Here we have systematically compared loss- and gain-of-function of Drosophila TDP-43, TAR DNA Binding Protein Homolog (TBPH), in synaptic function and morphology, motor control, and age-related neuronal survival. Both loss and gain of TBPH severely affect development and result in premature lethality. TBPH dysfunction caused impaired synaptic transmission at the larval neuromuscular junction (NMJ) and in the adult. Tissue-specific knockdown together with electrophysiological recordings at the larval NMJ also revealed that alterations of TBPH function predominantly affect pre-synaptic efficacy, suggesting that impaired pre-synaptic transmission is one of the earliest events in TDP-43-related pathogenesis. Prolonged loss and gain of TBPH in adults resulted in synaptic defects and age-related, progressive degeneration of neurons involved in motor control. Toxic gain of TBPH did not downregulate or mislocalize its own expression, indicating that a dominant-negative effect leads to progressive neurodegeneration also seen with mutational inactivation of TBPH. Together these data suggest that dysfunction of Drosophila TDP-43 triggers a cascade of events leading to loss-of-function phenotypes whereby impaired synaptic transmission results in defective motor behavior and progressive deconstruction of neuronal connections, ultimately causing age-related neurodegeneration. PMID:23307927

  14. Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes.

    PubMed

    Diaper, Danielle C; Adachi, Yoshitsugu; Sutcliffe, Ben; Humphrey, Dickon M; Elliott, Christopher J H; Stepto, Alan; Ludlow, Zoe N; Vanden Broeck, Lies; Callaerts, Patrick; Dermaut, Bart; Al-Chalabi, Ammar; Shaw, Christopher E; Robinson, Iain M; Hirth, Frank

    2013-04-15

    Cytoplasmic accumulation and nuclear clearance of TDP-43 characterize familial and sporadic forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, suggesting that either loss or gain of TDP-43 function, or both, cause disease formation. Here we have systematically compared loss- and gain-of-function of Drosophila TDP-43, TAR DNA Binding Protein Homolog (TBPH), in synaptic function and morphology, motor control, and age-related neuronal survival. Both loss and gain of TBPH severely affect development and result in premature lethality. TBPH dysfunction caused impaired synaptic transmission at the larval neuromuscular junction (NMJ) and in the adult. Tissue-specific knockdown together with electrophysiological recordings at the larval NMJ also revealed that alterations of TBPH function predominantly affect pre-synaptic efficacy, suggesting that impaired pre-synaptic transmission is one of the earliest events in TDP-43-related pathogenesis. Prolonged loss and gain of TBPH in adults resulted in synaptic defects and age-related, progressive degeneration of neurons involved in motor control. Toxic gain of TBPH did not downregulate or mislocalize its own expression, indicating that a dominant-negative effect leads to progressive neurodegeneration also seen with mutational inactivation of TBPH. Together these data suggest that dysfunction of Drosophila TDP-43 triggers a cascade of events leading to loss-of-function phenotypes whereby impaired synaptic transmission results in defective motor behavior and progressive deconstruction of neuronal connections, ultimately causing age-related neurodegeneration.

  15. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus.

    PubMed

    Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V

    2010-06-30

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

  16. Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex

    PubMed Central

    Komlósi, Gergely; Molnár, Gábor; Rózsa, Márton; Oláh, Szabolcs; Barzó, Pál

    2012-01-01

    Selective serotonin reuptake inhibitors are the most widely prescribed drugs targeting the CNS with acute and chronic effects in cognitive, emotional and behavioral processes. This suggests that microcircuits of the human cerebral cortex are powerfully modulated by selective serotonin reuptake inhibitors, however, direct measurements of serotonergic regulation on human synaptic interactions are missing. Using multiple whole-cell patch-clamp recordings from neurons in acute cortical slices derived from nonpathological human samples of the prefrontal cortex, we show that neuronal assemblies triggered by single action potentials of individual neurons in the human cortex are suppressed by therapeutic doses of fluoxetine (Prozac). This effect is boosted and can be mimicked by physiological concentrations of serotonin through 5HT-2A and 5HT-1A receptors. Monosynaptic excitatory connections from pyramidal cells to interneurons were suppressed by application of serotonin leaving the monosynaptic output of GABAergic cells unaffected. Changes in failure rate, in paired-pulse ratio, and in the coefficient of variation of the amplitude of EPSPs suggest a presynaptic action of serotonin. In conclusion, activation of neuronal assemblies, which were suggested as building blocks of high order cognitive processes, are effectively downregulated by the acute action of selective serotonin reuptake inhibitors or serotonin at the site of pyramidal output in human microcircuits. PMID:23152619

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

    PubMed

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

    2016-08-31

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-08-01

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

  19. Impact of Synaptic Neurotransmitter Concentration Time Course on the Kinetics and Pharmacological Modulation of Inhibitory Synaptic Currents

    PubMed Central

    Barberis, Andrea; Petrini, Enrica Maria; Mozrzymas, Jerzy W.

    2011-01-01

    The time course of synaptic currents is a crucial determinant of rapid signaling between neurons. Traditionally, the mechanisms underlying the shape of synaptic signals are classified as pre- and post-synaptic. Over the last two decades, an extensive body of evidence indicated that synaptic signals are critically shaped by the neurotransmitter time course which encompasses several phenomena including pre- and post-synaptic ones. The agonist transient depends on neurotransmitter release mechanisms, diffusion within the synaptic cleft, spill-over to the extra-synaptic space, uptake, and binding to post-synaptic receptors. Most estimates indicate that the neurotransmitter transient is very brief, lasting between one hundred up to several hundreds of microseconds, implying that post-synaptic activation is characterized by a high degree of non-equilibrium. Moreover, pharmacological studies provide evidence that the kinetics of agonist transient plays a crucial role in setting the susceptibility of synaptic currents to modulation by a variety of compounds of physiological or clinical relevance. More recently, the role of the neurotransmitter time course has been emphasized by studies carried out on brain slice models that revealed a striking, cell-dependent variability of synaptic agonist waveforms ranging from rapid pulses to slow volume transmission. In the present paper we review the advances on studies addressing the impact of synaptic neurotransmitter transient on kinetics and pharmacological modulation of synaptic currents at inhibitory synapses. PMID:21734864

  20. Intrinsic modulators of auditory thalamocortical transmission.

    PubMed

    Lee, Charles C; Sherman, S Murray

    2012-05-01

    Neurons in layer 4 of the primary auditory cortex receive convergent glutamatergic inputs from thalamic and cortical projections that activate different groups of postsynaptic glutamate receptors. Of particular interest in layer 4 neurons are the Group II metabotropic glutamate receptors (mGluRs), which hyperpolarize neurons postsynaptically via the downstream opening of GIRK channels. This pronounced effect on membrane conductance could influence the neuronal processing of synaptic inputs, such as those from the thalamus, essentially modulating information flow through the thalamocortical pathway. To examine how Group II mGluRs affect thalamocortical transmission, we used an in vitro slice preparation of the auditory thalamocortical pathways in the mouse to examine synaptic transmission under conditions where Group II mGluRs were activated. We found that both pre- and post-synaptic Group II mGluRs are involved in the attenuation of thalamocortical EPSP/Cs. Thus, thalamocortical synaptic transmission is suppressed via the presynaptic reduction of thalamocortical neurotransmitter release and the postsynaptic inhibition of the layer 4 thalamorecipient neurons. This could enable the thalamocortical pathway to autoregulate transmission, via either a gating or gain control mechanism, or both.

  1. BMP signaling and microtubule organization regulate synaptic strength

    PubMed Central

    Ball, Robin W.; Peled, Einat; Guerrero, Giovanna; Isacoff, Ehud Y.

    2015-01-01

    The strength of synaptic transmission between a neuron and multiple postsynaptic partners can vary considerably. We have studied synaptic heterogeneity using the glutamatergic Drosophila neuromuscular junction (NMJ), which contains multiple synaptic connections of varying strength between a motor axon and muscle fiber. In larval NMJs, there is a gradient of synaptic transmission from weak proximal to strong distal boutons. We imaged synaptic transmission with the postsynaptically targeted fluorescent calcium sensor SynapCam, to investigate the molecular pathways that determine synaptic strength and set up this gradient. We discovered that mutations in the Bone Morphogenetic Protein (BMP) signaling pathway disrupt production of strong distal boutons. We find that strong connections contain unbundled microtubules in the boutons, suggesting a role for microtubule organization in transmission strength. The spastin mutation, which disorganizes microtubules, disrupted the transmission gradient, supporting this interpretation. We propose that the BMP pathway, shown previously to function in the homeostatic regulation of synaptic growth, also boosts synaptic transmission in a spatially selective manner that depends on the microtubule system. PMID:25681521

  2. Postnatal Loss of P/Q-type Channels Confined to Rhombic Lip Derived Neurons Alters Synaptic Transmission at the Parallel Fiber to Purkinje Cell Synapse and Replicates Genomic Cacna1a Mutation Phenotype of Ataxia and Seizures in Mice

    PubMed Central

    Maejima, Takashi; Wollenweber, Patric; Teusner, Lena U. C.; Noebels, Jeffrey L.; Herlitze, Stefan; Mark, Melanie D.

    2013-01-01

    Ataxia, episodic dyskinesia and thalamocortical seizures are associated with an inherited loss of P/Q-type voltage-gated Ca2+ channel function. P/Q-type channels are widely expressed throughout the neuraxis, obscuring identification of the critical networks underlying these complex neurological disorders. We recently showed that the conditional postnatal loss of P/Q-type channels in cerebellar Purkinje cells (PCs) in mice (purky) leads to these aberrant phenotypes, suggesting that intrinsic alteration in PC output is a sufficient pathogenic factor for disease initiation. The question arises whether P/Q-type channel deletion confined to a single upstream cerebellar synapse might induce the pathophysiological abnormality of genomically inherited P/Q-type channel disorders. PCs integrate two excitatory inputs, climbing fibers from inferior olive and parallel fibers (PFs) from granule cells (GCs) that receive mossy fiber (MF) input derived from precerebellar nuclei. In this paper, we introduce a new mouse model with a selective knock-out of P/Q-type channels in rhombic lip derived neurons including PF- and MF-pathways (quirky). We found that in quirky mice, PF-PC synaptic transmission is reduced during low-frequency stimulation. Using focal light stimulation of GCs that express optogenetic light-sensitive channels, channelrhodopsin-2, we found that modulation of PC firing via GC input is reduced in quirky mice. Phenotypic analysis revealed that quirky mice display ataxia, dyskinesia and absence epilepsy. These results suggest that developmental alteration of patterned input confined to only one of the main afferent cerebellar excitatory synaptic pathways has a significant role in generating the neurological phenotype associated with the global genomic loss of P/Q-type channel function. PMID:23516282

  3. GABBR1 and SLC6A1, two genes involved in modulation of GABA synaptic transmission influence risk for alcoholism; results from three ethnically diverse populations

    PubMed Central

    Enoch, Mary-Anne; Hodgkinson, Colin A.; Shen, Pei-Hong; Gorodetsky, Elena; Marietta, Cheryl A.; Roy, Alex; Goldman, David

    2015-01-01

    Background Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1, encoding the neuronal GABA transporter GAT1, play a role in addiction by modulating synaptic GABA. Therefore variants in these genes might predict risk/resilience for alcoholism. Methods This study included three populations that differed by ethnicity and alcoholism phenotype: African American (AA) men: 401 treatment-seeking inpatients with single/comorbid diagnoses of alcohol and drug dependence, 193 controls; Finnish Caucasian men: 159 incarcerated alcoholics, half with comorbid ASPD, 181 controls; a community sample of Plains Indian (PI) men and women: 239 alcoholics, 178 controls. Seven GABBR1 tag SNPs were genotyped in the AA and Finnish samples; rs29220 was genotyped in the PI for replication. Also, a uniquely African, functional SLC6A1 insertion promoter polymorphism (IND) was genotyped in the AAs. Results We found a significant and congruent association between GABBR1 rs29220 and alcoholism in all three populations. The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. Moreover, SLC6A1 IND was more abundant in controls, i.e. the major genotype predicted alcoholism. An analysis of combined GABBR1 rs29220 and SLC6A1 IND genotypes showed that rs29220 heterozygotes, irrespective of their IND status, had an increased risk for alcoholism whereas carriers of the IND allele and either rs29220 homozygote were more resilient. Conclusions Our results show that with both GABBR1 and SLC6A1, the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR1 rs29220 might predict treatment response/adverse effects for baclofen, a GABAB receptor agonist. PMID:26727527

  4. HDAC4 governs a transcriptional program essential for synaptic plasticity and memory.

    PubMed

    Sando, Richard; Gounko, Natalia; Pieraut, Simon; Liao, Lujian; Yates, John; Maximov, Anton

    2012-11-09

    Neuronal activity influences genes involved in circuit development and information processing. However, the molecular basis of this process remains poorly understood. We found that HDAC4, a histone deacetylase that shuttles between the nucleus and cytoplasm, controls a transcriptional program essential for synaptic plasticity and memory. The nuclear import of HDAC4 and its association with chromatin is negatively regulated by NMDA receptors. In the nucleus, HDAC4 represses genes encoding constituents of central synapses, thereby affecting synaptic architecture and strength. Furthermore, we show that a truncated form of HDAC4 encoded by an allele associated with mental retardation is a gain-of-function nuclear repressor that abolishes transcription and synaptic transmission despite the loss of the deacetylase domain. Accordingly, mice carrying a mutant that mimics this allele exhibit deficits in neurotransmission, spatial learning, and memory. These studies elucidate a mechanism of experience-dependent plasticity and define the biological role of HDAC4 in the brain.

  5. Environmental Conditions Affect Exhalation of H3N2 Seasonal and Variant Influenza Viruses and Respiratory Droplet Transmission in Ferrets

    PubMed Central

    Gustin, Kortney M.; Belser, Jessica A.; Veguilla, Vic; Zeng, Hui; Katz, Jacqueline M.; Tumpey, Terrence M.; Maines, Taronna R.

    2015-01-01

    The seasonality of influenza virus infections in temperate climates and the role of environmental conditions like temperature and humidity in the transmission of influenza virus through the air are not well understood. Using ferrets housed at four different environmental conditions, we evaluated the respiratory droplet transmission of two influenza viruses (a seasonal H3N2 virus and an H3N2 variant virus, the etiologic virus of a swine to human summertime infection) and concurrently characterized the aerosol shedding profiles of infected animals. Comparisons were made among the different temperature and humidity conditions and between the two viruses to determine if the H3N2 variant virus exhibited enhanced capabilities that may have contributed to the infections occurring in the summer. We report here that although increased levels of H3N2 variant virus were found in ferret nasal wash and exhaled aerosol samples compared to the seasonal H3N2 virus, enhanced respiratory droplet transmission was not observed under any of the environmental settings. However, overall environmental conditions were shown to modulate the frequency of influenza virus transmission through the air. Transmission occurred most frequently at 23°C/30%RH, while the levels of infectious virus in aerosols exhaled by infected ferrets agree with these results. Improving our understanding of how environmental conditions affect influenza virus infectivity and transmission may reveal ways to better protect the public against influenza virus infections. PMID:25969995

  6. Quantitative proteomics of synaptic and nonsynaptic mitochondria: insights for synaptic mitochondrial vulnerability.

    PubMed

    Stauch, Kelly L; Purnell, Phillip R; Fox, Howard S

    2014-05-02

    Synaptic mitochondria are essential for maintaining calcium homeostasis and producing ATP, processes vital for neuronal integrity and synaptic transmission. Synaptic mitochondria exhibit increased oxidative damage during aging and are more vulnerable to calcium insult than nonsynaptic mitochondria. Why synaptic mitochondria are specifically more susceptible to cumulative damage remains to be determined. In this study, the generation of a super-SILAC mix that served as an appropriate internal standard for mouse brain mitochondria mass spectrometry based analysis allowed for the quantification of the proteomic differences between synaptic and nonsynaptic mitochondria isolated from 10-month-old mice. We identified a total of 2260 common proteins between synaptic and nonsynaptic mitochondria of which 1629 were annotated as mitochondrial. Quantitative proteomic analysis of the proteins common between synaptic and nonsynaptic mitochondria revealed significant differential expression of 522 proteins involved in several pathways including oxidative phosphorylation, mitochondrial fission/fusion, calcium transport, and mitochondrial DNA replication and maintenance. In comparison to nonsynaptic mitochondria, synaptic mitochondria exhibited increased age-associated mitochondrial DNA deletions and decreased bioenergetic function. These findings provide insights into synaptic mitochondrial susceptibility to damage.

  7. Natural patterns of activity and long-term synaptic plasticity

    PubMed Central

    Paulsen, Ole; Sejnowski, Terrence J

    2010-01-01

    Long-term potentiation (LTP) of synaptic transmission is traditionally elicited by massively synchronous, high-frequency inputs, which rarely occur naturally. Recent in vitro experiments have revealed that both LTP and long-term depression (LTD) can arise by appropriately pairing weak synaptic inputs with action potentials in the postsynaptic cell. This discovery has generated new insights into the conditions under which synaptic modification may occur in pyramidal neurons in vivo. First, it has been shown that the temporal order of the synaptic input and the postsynaptic spike within a narrow temporal window determines whether LTP or LTD is elicited, according to a temporally asymmetric Hebbian learning rule. Second, backpropagating action potentials are able to serve as a global signal for synaptic plasticity in a neuron compared with local associative interactions between synaptic inputs on dendrites. Third, a specific temporal pattern of activity — postsynaptic bursting — accompanies synaptic potentiation in adults. PMID:10753798

  8. Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

    PubMed Central

    Arendt, Kristin L.; Zhang, Zhenjie; Ganesan, Subhashree; Hintze, Maik; Shin, Maggie M.; Tang, Yitai; Cho, Ahryon; Graef, Isabella A.; Chen, Lu

    2015-01-01

    Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca2+-levels to RA synthesis remains unknown. Here we identify the Ca2+-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca2+-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity. PMID:26443861

  9. How Ambient Humidity May Affect the Transmission of Viral Infectious Diseases

    NASA Astrophysics Data System (ADS)

    Yang, Wan; Marr, Linsey; Elankumaran, Subbiah

    2013-04-01

    Viral infectious diseases such as influenza have been a great burden to public health. The airborne transmission route is an important venue for the spread of many respiratory viral diseases. Many airborne viruses have been shown to be sensitive to ambient humidity, yet the mechanisms responsible for this phenomenon remain elusive. A thorough understanding of this phenomenon may provide insight into the temporal and spatial distribution of diseases. For instance, studies have repeatedly suggested ambient humidity as an important environmental determinant in the transmission of influenza in temperate regions. Further, knowing how to optimize humidity so as to minimize virus survival may have practical implications for disease prevention. In this talk, we will discuss multiple mechanisms that may account for the association between humidity and viability of viruses in aerosols, including water activity, surface inactivation, salt toxicity, and conformational changes to the virus in response to varying pH. As a case study, we will discuss our work on the effect of relative humidity (RH) on survival of influenza A virus (IAV) and how it may contribute to the transmission patterns of seasonal flu around the world. We measured the change in viability of IAV in droplets at various RHs. Results suggest three potential regimes defined by humidity: physiological (~100% RH) with high viability, concentrated (~50% to near 100% RH) with lower viability, and dry (<~50% RH) with high viability. Based on these results, we propose a mechanistic basis for the dependence of IAV's transmission on humidity. In temperate regions, the increase in influenza activity in winter may be due to enhanced transmission via the aerosol route thanks to IAV's higher viability in droplets at low RH. In tropical regions, transmission could be enhanced due to high viability of IAV at extremely high RH (rainy season), as observed in our study, possibly through both the aerosol route and the contact

  10. Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization.

    PubMed

    Lange, Maren D; Jüngling, Kay; Paulukat, Linda; Vieler, Marc; Gaburro, Stefano; Sosulina, Ludmila; Blaesse, Peter; Sreepathi, Hari K; Ferraguti, Francesco; Pape, Hans-Christian

    2014-08-01

    An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders.

  11. AMPA receptor inhibition by synaptically released zinc

    PubMed Central

    Kalappa, Bopanna I.; Anderson, Charles T.; Lippard, Stephen J.; Tzounopoulos, Thanos

    2015-01-01

    The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses. PMID:26647187

  12. Transcriptional coupling of synaptic transmission and energy metabolism: role of nuclear respiratory factor 1 in co-regulating neuronal nitric oxide synthase and cytochrome c oxidase genes in neurons.

    PubMed

    Dhar, Shilpa S; Liang, Huan Ling; Wong-Riley, Margaret T T

    2009-10-01

    Neuronal activity is highly dependent on energy metabolism; yet, the two processes have traditionally been regarded as independently regulated at the transcriptional level. Recently, we found that the same transcription factor, nuclear respiratory factor 1 (NRF-1) co-regulates an important energy-generating enzyme, cytochrome c oxidase, as well as critical subunits of glutamatergic receptors. The present study tests our hypothesis that the co-regulation extends to the next level of glutamatergic synapses, namely, neuronal nitric oxide synthase, which generates nitric oxide as a downstream signaling molecule. Using in silico analysis, electrophoretic mobility shift assay, chromatin immunoprecipitation, promoter mutations, and NRF-1 silencing, we documented that NRF-1 functionally bound to Nos1, but not Nos2 (inducible) and Nos3 (endothelial) gene promoters. Both COX and Nos1 transcripts were up-regulated by depolarizing KCl treatment and down-regulated by TTX-mediated impulse blockade in neurons. However, NRF-1 silencing blocked the up-regulation of both Nos1 and COX induced by KCl depolarization, and over-expression of NRF-1 rescued both Nos1 and COX transcripts down-regulated by TTX. These findings are consistent with our hypothesis that synaptic neuronal transmission and energy metabolism are tightly coupled at the molecular level.

  13. Consideration of some factors affecting low-frequency fuselage noise transmission for propeller aircraft

    NASA Technical Reports Server (NTRS)

    Mixson, J. S.; Roussos, L. A.

    1986-01-01

    Possible reasons for disagreement between measured and predicted trends of sidewall noise transmission at low frequency are investigated using simplified analysis methods. An analytical model combining incident plane acoustic waves with an infinite flat panel is used to study the effects of sound incidence angle, plate structural properties, frequency, absorption, and the difference between noise reduction and transmission loss. Analysis shows that these factors have significant effects on noise transmission but they do not account for the differences between measured and predicted trends at low frequencies. An analytical model combining an infinite flat plate with a normally incident acoustic wave having exponentially decaying magnitude along one coordinate is used to study the effect of a localized source distribution such as is associated with propeller noise. Results show that the localization brings the predicted low-frequency trend of noise transmission into better agreement with measured propeller results. This effect is independent of low-frequency stiffness effects that have been previously reported to be associated with boundary conditions.

  14. Involvement of Synaptic Genes in the Pathogenesis of Autism Spectrum Disorders: The Case of Synapsins

    PubMed Central

    Giovedí, Silvia; Corradi, Anna; Fassio, Anna; Benfenati, Fabio

    2014-01-01

    Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders characterized by deficits in social interaction and social communication, restricted interests, and repetitive behaviors. Many synaptic protein genes are linked to the pathogenesis of ASDs, making them prototypical synaptopathies. An array of mutations in the synapsin (Syn) genes in humans has been recently associated with ASD and epilepsy, diseases that display a frequent comorbidity. Syns are pre-synaptic proteins regulating synaptic vesicle traffic, neurotransmitter release, and short-term synaptic plasticity. In doing so, Syn isoforms control the tone of activity of neural circuits and the balance between excitation and inhibition. As ASD pathogenesis is believed to result from dysfunctions in the balance between excitatory and inhibitory transmissions in neocortical areas, Syns are novel ASD candidate genes. Accordingly, deletion of single Syn genes in mice, in addition to epilepsy, causes core symptoms of ASD by affecting social behavior, social communication, and repetitive behaviors. Thus, Syn knockout mice represent a good experimental model to define synaptic alterations involved in the pathogenesis of ASD and epilepsy. PMID:25237665

  15. Intracerebroventricular administration of ouabain alters synaptic plasticity and dopamine release in rat medial prefrontal cortex.

    PubMed

    Sui, Li; Song, Xiao-Jin; Ren, Jie; Ju, Li-Hua; Wang, Yan

    2013-08-01

    Intracerebroventricular (ICV) administration of ouabain, a specific Na-K-ATPase inhibitor, in rats mimics the manic phenotypes of bipolar disorder and thus has been proposed as one of the best animal models of mania. Bipolar mania has been known to be associated with dysfunctions of medial prefrontal cortex (mPFC), a brain area critically involved in mental functions; however, the exact mechanism underlying these dysfunctions is not yet clear. The present study investigated synaptic transmission, synaptic plasticity, and dopamine release in Sprague-Dawley rat mPFC following ICV administration of ouabain (5 μl of 1 mM ouabain). The electrophysiological results demonstrated that ouabain depressed the short- and the long-term synaptic plasticity, represented by paired-pulse facilitation and long-term potentiation, respectively, in the mPFC. These ouabain-induced alterations in synaptic plasticity can be prevented by pre-treatment with lithium (intraperitoneal injection of 47.5 mg/kg lithium, twice a day, 7 days), which acts as an effective mood stabilizer in preventing mania. The electrochemical results demonstrated that ICV administration of ouabain enhanced dopamine release in the mPFC, which did not be affected by pre-treatment with lithium. These findings suggested that alterations in synaptic plasticity and dopamine release in the mPFC might underlie the dysfunctions of mPFC accompanied with ouabain administration-induced bipolar mania.

  16. Presynaptic calcium stores contribute to nicotine-elicited potentiation of evoked synaptic transmission at CA3-CA1 connections in the neonatal rat hippocampus.

    PubMed

    Le Magueresse, Corentin; Cherubini, Enrico

    2007-01-01

    Nicotine acetylcholine (ACh) receptors (nAChRs) are ligand-gated ion channels that are widely expressed throughout the central nervous system. It is well established that presynaptic, alpha7-containing nAChRs modulate glutamate release in several brain areas, and that this modulation requires extracellular calcium. However, the intracellular mechanisms consecutive to nAChR opening are unclear. Recent studies have suggested a role for presynaptic calcium stores in the increase of neurotransmitter release following nAChR activation. Using the minimal stimulation protocol at low-probability Schaffer collateral synapses in acute hippocampal slices from neonatal rats, we show that nicotine acting on presynaptic alpha7 nAChRs persistently upregulates glutamate release. We tested the role of calcium stores in this potentiation. First, we examined the relationship between calcium stores and glutamate release. We found that bath application of SERCA pump inhibitors (cyclopiazonic acid and thapsigargin), as well as an agonist of ryanodine receptors (ryanodine 2 microM) increases the probability of glutamate release at CA3-CA1 synapses, decreases the coefficient of variation and the paired-pulse ratio, indicating that presynaptic activation of calcium-induced calcium release can modulate glutamatergic transmission. Next, we investigated whether blocking calcium release from internal stores could alter the effect of nicotine. Preincubation with thapsigargin (10 microM), cyclopiazonic acid (30 microM), or with a high (blocking) concentration of ryanodine (100 microM) for 30 min to 5 h failed to block the effect of nicotine. However, after preincubation in ryanodine, nicotine-elicited potentiation was significantly shortened. These results indicate that at immature Schaffer collateral-CA1 synapses, activation of presynaptic calcium stores is not necessary for but contributes to nicotine-elicited increase of neurotransmitter release.

  17. Factors that affect the fatigue strength of power transmission shafting and their impact on design

    NASA Technical Reports Server (NTRS)

    Leowenthal, S. H.

    1986-01-01

    A long standing objective in the design of power transmission shafting is to eliminate excess shaft material without compromising operational reliability. A shaft design method is presented which accounts for variable amplitude loading histories and their influence on limited life designs. The effects of combined bending and torsional loading are considered along with a number of application factors known to influence the fatigue strength of shafting materials. Among the factors examined are surface condition, size, stress concentration, residual stress and corrosion fatigue.

  18. Genetic risk transmission in a family affected by familial breast cancer.

    PubMed

    Pilato, Brunella; De Summa, Simona; Danza, Katia; Lacalamita, Rosanna; Lambo, Rossana; Sambiasi, Domenico; Paradiso, Angelo; Tommasi, Stefania

    2014-01-01

    Breast Cancer is the most common malignancy among women. Family history is the strongest single predictor of breast cancer risk, and thus great attention has been focused on BRCA1 and BRCA2 genes whose mutations lead to a high risk of developing this disease. Today, only 25% of high- and moderate-risk genes are known, suggesting the importance of the discovery of new risk modifiers. Therefore, the investigation of new polygenic alterations is of great importance, especially if considered high- and moderate-risk variants. In this study, the transmission of BRCA1-2 polymorphisms in association with the transmission of polymorphisms in the genes NUMA1, CCND1, COX11, FGFR2, TNRC9 and SLC4A7 were examined in all members of a family with the BRCA2 c.6447_6448dup mutation. This is the first study about the transmission of high-risk polygenic variants in all members of a family with a strong history of breast cancer. The results about the possible polygenic variant associations that could increase and modify the risk suggested the importance to search new variants to better manage patients and their family members.

  19. Synaptic Function of Rab11Fip5: Selective Requirement for Hippocampal Long-Term Depression

    PubMed Central

    Ahmad, Mohiuddin; Jurado, Sandra; Malenka, Robert C.

    2015-01-01

    Postsynaptic AMPA-type glutamate receptors (AMPARs) are among the major determinants of synaptic strength and can be trafficked into and out of synapses. Neuronal activity regulates AMPAR trafficking during synaptic plasticity to induce long-term changes in synaptic strength, including long-term potentiation (LTP) and long-term depression (LTD). Rab family GTPases regulate most membrane trafficking in eukaryotic cells; particularly, Rab11 and its effectors are implicated in mediating postsynaptic AMPAR insertion during LTP. To explore the synaptic function of Rab11Fip5, a neuronal Rab11 effector and a candidate autism-spectrum disorder gene, we performed shRNA-mediated knock-down and genetic knock-out (KO) studies. Surprisingly, we observed robust shRNA-induced synaptic phenotypes that were rescued by a Rab11Fip5 cDNA but that were nevertheless not observed in conditional KO neurons. Both in cultured neurons and acute slices, KO of Rab11Fip5 had no significant effect on basic parameters of synaptic transmission, indicating that Rab11Fip5 is not required for fundamental synaptic operations, such as neurotransmitter release or postsynaptic AMPAR insertion. KO of Rab11Fip5 did, however, abolish hippocampal LTD as measured both in acute slices or using a chemical LTD protocol in cultured neurons but did not affect hippocampal LTP. The Rab11Fip5 KO mice performed normally in several behavioral tasks, including fear conditioning, but showed enhanced contextual fear extinction. These are the first findings to suggest a requirement for Rab11Fip5, and presumably Rab11, during LTD. PMID:25972173

  20. Phosphorylation of Synaptojanin Differentially Regulates Endocytosis of Functionally Distinct Synaptic Vesicle Pools

    PubMed Central

    Geng, Junhua; Wang, Liping; Lee, Joo Yeun; Chen, Chun-Kan

    2016-01-01

    The rapid replenishment of synaptic vesicles through endocytosis is crucial for sustaining synaptic transmission during intense neuronal activity. Synaptojanin (Synj), a phosphoinositide phosphatase, is known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake. Synj has been shown to be a substrate of the minibrain (Mnb) kinase, a fly homolog of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); however, the functional impacts of Synj phosphorylation by Mnb are not well understood. Here we identify that Mnb phosphorylates Synj at S1029 in Drosophila. We find that phosphorylation of Synj at S1029 enhances Synj phosphatase activity, alters interaction between Synj and endophilin, and promotes efficient endocytosis of the active cycling vesicle pool (also referred to as exo-endo cycling pool) at the expense of reserve pool vesicle endocytosis. Dephosphorylated Synj, on the other hand, is deficient in the endocytosis of the active recycling pool vesicles but maintains reserve pool vesicle endocytosis to restore total vesicle pool size and sustain synaptic transmission. Together, our findings reveal a novel role for Synj in modulating reserve pool vesicle endocytosis and further indicate that dynamic phosphorylation and dephosphorylation of Synj differentially maintain endocytosis of distinct functional synaptic vesicle pools. SIGNIFICANCE STATEMENT Synaptic vesicle endocytosis sustains communication between neurons during a wide range of neuronal activities by recycling used vesicle membrane and protein components. Here we identify that Synaptojanin, a protein with a known role in synaptic vesicle endocytosis, is phosphorylated at S1029 in vivo by the Minibrain kinase. We further demonstrate that the phosphorylation status of Synaptojanin at S1029 differentially regulates its participation in the recycling of distinct synaptic vesicle pools. Our results reveal a new role for

  1. Receiver operating characteristic (ROC) analysis for characterizing synaptic efficacy.

    PubMed

    Chance, Frances S

    2007-02-01

    The role of background synaptic activity in cortical processing has recently received much attention. How do individual neurons extract information when embedded in a noisy background? When examining the impact of a synaptic input on postsynaptic firing, it is important to distinguish a change in overall firing probability from a true change in neuronal sensitivity to a particular input (synaptic efficacy) that corresponds to a change in detection performance. Here we study the impact of background synaptic input on neuronal sensitivity to individual synaptic inputs using receiver operating characteristic (ROC) analysis. We use the area under the ROC curve as a measure of synaptic efficacy, here defined as the ability of a postsynaptic action potential to identify a particular synaptic input event. An advantage of using ROC analysis to measure synaptic efficacy is that it provides a measure that is independent of postsynaptic firing rate. Furthermore, changes in mean excitation or inhibition, although affecting overall firing probability, do not modulate synaptic efficacy when measured in this way. Changes in overall conductance also affect firing probability but not this form of synaptic efficacy. Input noise, here defined as the variance of the input current, does modulate synaptic efficacy, however. This effect persists when the change in input variance is coupled with a change in conductance (as would result from changing background activity).

  2. Low temperature affects cattle tick reproduction but does not lead to transovarial transmission of Anaplasma marginale.

    PubMed

    Esteves, E; Pohl, P C; Klafke, G M; Reck, J; Fogaça, A C; Martins, J R; Daffre, S

    2015-12-15

    Anaplasma marginale is an obligate intracellular pathogen that infects the erythrocytes of calves, causing bovine anaplasmosis. This rickettsia is biologically transmitted by several species of ticks. In tropical and subtropical regions of the world, Rhipicephalus microplus is the main vector. Due to their mobility and longevity, the adult males play an important role in the transmission of A. marginale to calves. Some studies have demonstrated that A. marginale can be intrastadially and interstadially transmitted in R. microplus, but the transovarial transmission has not been demonstrated so far. In the present study, we investigated the effects of