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Sample records for itinerant synaptic receptors

  1. 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

  2. Synaptic NMDA Receptors Mediate Hypoxic Excitotoxic Death

    PubMed Central

    Wroge, Christine M.; Hogins, Joshua; Eisenman, Larry; Mennerick, Steven

    2012-01-01

    Excessive NMDA receptor activation and excitotoxicity underlies pathology in many neuropsychiatric and neurological disorders, including hypoxia/ischemia. Thus, the development of effective therapeutics for these disorders demands a complete understanding of NMDA receptor (NMDAR) activation during excitotoxic insults. The extrasynaptic NMDAR hypothesis posits that synaptic NMDARs are neurotrophic/neuroprotective and extrasynaptic NMDARs are neurotoxic. In part, the extrasynaptic hypothesis is built on observed selectivity for extrasynaptic receptors of a neuroprotective use-dependent NMDAR channel blocker, memantine. In rat hippocampal neurons we found that a neuroprotective concentration of memantine shows little selectivity for extrasynaptic NMDARs when all receptors are tonically activated by exogenous glutamate. This led us to test the extrasynaptic NMDAR hypothesis using metabolic challenge, where the source of excitotoxic glutamate buildup may be largely synaptic. Three independent approaches suggest strongly that synaptic receptors participate prominently in hypoxic excitotoxicity. First, block of glutamate transporters with a non-substrate antagonist exacerbated rather than prevented damage, consistent with a primarily synaptic source of glutamate. Second, selective, preblock of synaptic NMDARs with a slowly reversible, use-dependent antagonist protected nearly fully against prolonged hypoxic insult. Third, glutamate pyruvate transaminase (GPT), which degrades ambient but not synaptic glutamate, did not protect against hypoxia but protected against exogenous glutamate damage. Together, these results suggest that synaptic NMDARs can mediate excitotoxicity, particularly when the glutamate source is synaptic and when synaptic receptor contributions are rigorously defined. Moreover, the results suggest that in some situations therapeutically targeting extrasynaptic receptors may be inappropriate. PMID:22573696

  3. Recruiting extrasynaptic NMDA receptors augments synaptic signaling.

    PubMed

    Harris, Alexander Z; Pettit, Diana L

    2008-02-01

    N-Methyl-d-aspartate receptor (NMDAR) activation may promote cell survival or initiate cell death, with the outcome dependent on whether synaptic or extrasynaptic receptors are activated. Similarly, this differential activation has been proposed to govern the direction of plasticity. However, the physiological parameters necessary to activate extrasynaptic NMDARs in brain slices remain unknown. Using the irreversible use-dependent NMDAR antagonist MK-801 to isolate extrasynaptic NMDARs, we have tested the ability of short-stimulation trains from 5 to 400 Hz to activate these receptors on CA1 hippocampal slice pyramidal neurons. Frequencies as low as 25 Hz engage extrasynaptic NMDARs, with maximal activation at frequencies between 100 and 200 Hz. Since similar bursts of synaptic input occur during exploratory behavior in rats, our results demonstrate that "extrasynaptic" NMDARs regularly participate in synaptic transmission. Further, 175-Hz-stimulation trains activate all available synaptic and extrasynaptic dendritic NMDARs, suggesting these NMDARs act as synaptic receptors as needed, transiently increasing synaptic strength. Thus extrasynaptic NMDARs play a vital role in synaptic physiology, calling into question their status as "extrasynaptic."

  4. NMDA Receptors Mediate Synaptic Competition in Culture

    PubMed Central

    She, Kevin; Craig, Ann Marie

    2011-01-01

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

  5. 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

  6. Synaptic Neurotransmitter-Gated Receptors

    PubMed Central

    Smart, Trevor G.; Paoletti, Pierre

    2012-01-01

    Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families. PMID:22233560

  7. Caffeine, adenosine receptors, and synaptic plasticity.

    PubMed

    Costenla, Ana Rita; Cunha, Rodrigo A; de Mendonça, Alexandre

    2010-01-01

    Few studies to date have looked at the effects of caffeine on synaptic plasticity, and those that did used very high concentrations of caffeine, whereas the brain concentrations attained by regular coffee consumption in humans should be in the low micromolar range, where caffeine exerts pharmacological actions mainly by antagonizing adenosine receptors. Accordingly, rats drinking caffeine (1 g/L) for 3 weeks, displayed a concentration of caffeine of circa 22 microM in the hippocampus. It is known that selective adenosine A1 receptor antagonists facilitate, whereas selective adenosine A2A receptor antagonists attenuate, long term potentiation (LTP) in the hippocampus. Although caffeine is a non-selective antagonist of adenosine receptors, it attenuates frequency-induced LTP in hippocampal slices in a manner similar to selective adenosine A2A receptor antagonists. These effects of low micromolar concentration of caffeine (30 microM) are maintained in aged animals, which is important when a possible beneficial effect for caffeine in age-related cognitive decline is proposed. Future studies will still be required to confirm and detail the involvement of A1 and A2A receptors in the effects of caffeine on hippocampal synaptic plasticity, using both pharmacological and genetic approaches.

  8. Transferrin Receptor Controls AMPA Receptor Trafficking Efficiency and Synaptic Plasticity

    PubMed Central

    Liu, Ke; Lei, Run; Li, Qiong; Wang, Xin-Xin; Wu, Qian; An, Peng; Zhang, Jianchao; Zhu, Minyan; Xu, Zhiheng; Hong, Yang; Wang, Fudi; Shen, Ying; Li, Hongchang; Li, Huashun

    2016-01-01

    Transferrin receptor (TFR) is an important iron transporter regulating iron homeostasis and has long been used as a marker for clathrin mediated endocytosis. However, little is known about its additional function other than iron transport in the development of central nervous system (CNS). Here we demonstrate that TFR functions as a regulator to control AMPA receptor trafficking efficiency and synaptic plasticity. The conditional knockout (KO) of TFR in neural progenitor cells causes mice to develop progressive epileptic seizure, and dramatically reduces basal synaptic transmission and long-term potentiation (LTP). We further demonstrate that TFR KO remarkably reduces the binding efficiency of GluR2 to AP2 and subsequently decreases AMPA receptor endocytosis and recycling. Thus, our study reveals that TFR functions as a novel regulator to control AMPA trafficking efficiency and synaptic plasticity. PMID:26880306

  9. ECM receptors in neuronal structure, synaptic plasticity, and behavior

    PubMed Central

    Kerrisk, Meghan E.; Cingolani, Lorenzo A.; Koleske, Anthony J.

    2015-01-01

    During central nervous system development, extracellular matrix (ECM) receptors and their ligands play key roles as guidance molecules, informing neurons where and when to send axonal and dendritic projections, establish connections, and form synapses between pre- and postsynaptic cells. Once stable synapses are formed, many ECM receptors transition in function to control the maintenance of stable connections between neurons and regulate synaptic plasticity. These receptors bind to and are activated by ECM ligands. In turn, ECM receptor activation modulates downstream signaling cascades that control cytoskeletal dynamics and synaptic activity to regulate neuronal structure and function and thereby impact animal behavior. The activities of cell adhesion receptors that mediate interactions between pre- and post-synaptic partners are also strongly influenced by ECM composition. This chapter highlights a number of ECM receptors, their roles in the control of synapse structure and function, and the impact of these receptors on synaptic plasticity and animal behavior. PMID:25410355

  10. Dynamic DNA methylation controls glutamate receptor trafficking and synaptic scaling.

    PubMed

    Sweatt, J David

    2016-05-01

    Hebbian plasticity, including long-term potentiation and long-term depression, has long been regarded as important for local circuit refinement in the context of memory formation and stabilization. However, circuit development and stabilization additionally relies on non-Hebbian, homeostatic, forms of plasticity such as synaptic scaling. Synaptic scaling is induced by chronic increases or decreases in neuronal activity. Synaptic scaling is associated with cell-wide adjustments in postsynaptic receptor density, and can occur in a multiplicative manner resulting in preservation of relative synaptic strengths across the entire neuron's population of synapses. Both active DNA methylation and demethylation have been validated as crucial regulators of gene transcription during learning, and synaptic scaling is known to be transcriptionally dependent. However, it has been unclear whether homeostatic forms of plasticity such as synaptic scaling are regulated via epigenetic mechanisms. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously largely considered separately: DNA methylation, homeostatic plasticity, and glutamate receptor trafficking. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously considered separately: glutamate receptor trafficking, DNA methylation, and homeostatic plasticity.

  11. ECM receptors in neuronal structure, synaptic plasticity, and behavior.

    PubMed

    Kerrisk, Meghan E; Cingolani, Lorenzo A; Koleske, Anthony J

    2014-01-01

    During central nervous system development, extracellular matrix (ECM) receptors and their ligands play key roles as guidance molecules, informing neurons where and when to send axonal and dendritic projections, establish connections, and form synapses between pre- and postsynaptic cells. Once stable synapses are formed, many ECM receptors transition in function to control the maintenance of stable connections between neurons and regulate synaptic plasticity. These receptors bind to and are activated by ECM ligands. In turn, ECM receptor activation modulates downstream signaling cascades that control cytoskeletal dynamics and synaptic activity to regulate neuronal structure and function and thereby impact animal behavior. The activities of cell adhesion receptors that mediate interactions between pre- and postsynaptic partners are also strongly influenced by ECM composition. This chapter highlights a number of ECM receptors, their roles in the control of synapse structure and function, and the impact of these receptors on synaptic plasticity and animal behavior.

  12. TARP phosphorylation regulates synaptic AMPA receptors through lipid bilayers

    PubMed Central

    Sumioka, Akio; Yan, Dan; Tomita, Susumu

    2010-01-01

    Summary Neurons use neurotransmitters to communicate across synapses, constructing neural circuits in the brain. AMPA-type glutamate receptors are the predominant excitatory neurotransmitter receptors mediating fast synaptic transmission. AMPA receptors localize at synapses by forming protein complexes with transmembrane AMPA receptor regulatory proteins (TARPs) and PSD-95-like MAGUKs. Among the three classes of ionotropic glutamate receptors (AMPA-, NMDA, kainate-type), AMPA receptor activity is most regulatable by neuronal activity to adjust synaptic strength. Here, we mutated the prototypical TARP, stargazin, and found that TARP phosphorylation regulates synaptic AMPA receptor activity in vivo. We also found that stargazin interacts with negatively-charged lipid bilayers in its phosphorylation dependent manner, and that the lipid interaction inhibited stargazin binding to PSD-95. Cationic lipids dissociated stargazin from lipid bilayers and enhanced synaptic AMPA receptor activity in a stargazin phosphorylation-dependent manner. Thus, TARP phosphorylation plays a critical role in regulating AMPA receptor-mediated synaptic transmission via a lipid bilayer interaction. PMID:20547132

  13. TARP phosphorylation regulates synaptic AMPA receptors through lipid bilayers.

    PubMed

    Sumioka, Akio; Yan, Dan; Tomita, Susumu

    2010-06-10

    Neurons use neurotransmitters to communicate across synapses, constructing neural circuits in the brain. AMPA-type glutamate receptors are the predominant excitatory neurotransmitter receptors mediating fast synaptic transmission. AMPA receptors localize at synapses by forming protein complexes with transmembrane AMPA receptor regulatory proteins (TARPs) and PSD-95-like membrane-associated guanylate kinases. Among the three classes of ionotropic glutamate receptors (AMPA, NMDA, and kainate type), AMPA receptor activity is most regulatable by neuronal activity to adjust synaptic strength. Here, we mutated the prototypical TARP, stargazin, and found that TARP phosphorylation regulates synaptic AMPA receptor activity in vivo. We also found that stargazin interacts with negatively charged lipid bilayers in a phosphorylation-dependent manner and that the lipid interaction inhibited stargazin binding to PSD-95. Cationic lipids dissociated stargazin from lipid bilayers and enhanced synaptic AMPA receptor activity in a stargazin phosphorylation-dependent manner. Thus, TARP phosphorylation plays a critical role in regulating AMPA receptor-mediated synaptic transmission via a lipid bilayer interaction.

  14. Dynamic DNA Methylation Controls Glutamate Receptor Trafficking and Synaptic Scaling

    PubMed Central

    Sweatt, J. David

    2016-01-01

    Hebbian plasticity, including LTP and LTD, has long been regarded as important for local circuit refinement in the context of memory formation and stabilization. However, circuit development and stabilization additionally relies on non-Hebbian, homoeostatic, forms of plasticity such as synaptic scaling. Synaptic scaling is induced by chronic increases or decreases in neuronal activity. Synaptic scaling is associated with cell-wide adjustments in postsynaptic receptor density, and can occur in a multiplicative manner resulting in preservation of relative synaptic strengths across the entire neuron's population of synapses. Both active DNA methylation and de-methylation have been validated as crucial regulators of gene transcription during learning, and synaptic scaling is known to be transcriptionally dependent. However, it has been unclear whether homeostatic forms of plasticity such as synaptic scaling are regulated via epigenetic mechanisms. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously largely considered separately: DNA methylation, homeostatic plasticity, and glutamate receptor trafficking. PMID:26849493

  15. D1/5 modulation of synaptic NMDA receptor currents

    PubMed Central

    Varela, Juan A.; Hirsch, Silke J.; Chapman, David; Leverich, Leah S.; Greene, Robert W.

    2009-01-01

    Converging evidence suggests that salience-associated modulation of behavior is mediated by the release of monoamines and that monoaminergic activation of D1/5 receptors is required for normal hippocampal-dependent learning and memory. However, it is not understood how D1/5 modulation of hippocampal circuits can affect salience-associated learning and memory. We have observed in CA1 pyramidal neurons that D1/5 receptor activation elicits a bi-directional long-term plasticity of NMDA receptor-mediated synaptic currents with the polarity of plasticity determined by NMDA receptor, NR2A/B subunit composition. This plasticity results in a decrease in the NR2A/NR2B ratio of subunit composition. Synaptic responses mediated by NMDA receptors that include NR2B subunits are potentiated by D1/5 receptor activation, while responses mediated by NMDA receptors that include NR2A subunits are depressed. Furthermore, these bidirectional, subunit-specific effects are mediated by distinctive intracellular signaling mechanisms. As there is a predominance of NMDA receptors composed of NR2A subunits observed in entorhinal-CA1 inputs and a predominance of NMDA receptors composed of NR2B subunits in CA3-CA1 synapses, potentiation of synaptic NMDA currents predominates in the proximal CA3-CA1 synapses, while depression of synaptic NMDA currents predominates in the distal entorhinal-CA1 synapses. Finally, all of these effects are reproduced by the release of endogenous monoamines through activation of D1/5 receptors. Thus, endogenous D1/5 activation can, 1) decrease the NR2A/B ratio of NMDAR subunit composition at glutamatergic synapses, a rejuvenation to a composition similar to developmentally immature synapses, and, 2) in CA1, bias NMDA receptor responsiveness towards the more highly processed tri-synaptic CA3-CA1 circuit and away from the direct entorhinal-CA1 input. PMID:19279248

  16. Synaptic plasticity of NMDA receptors: mechanisms and functional implications

    PubMed Central

    Hunt, David L.; Castillo, Pablo E.

    2012-01-01

    Beyond their well-established role as triggers for LTP and LTD of fast synaptic transmission mediated by AMPA receptors, an expanding body of evidence indicates that NMDA receptors (NMDARs) themselves are also dynamically regulated and subject to activity-dependent long-term plasticity. NMDARs can significantly contribute to information transfer at synapses particularly during periods of repetitive activity. It is also increasingly recognized that NMDARs participate in dendritic synaptic integration and are critical for generating persistent activity of neural assemblies. Here we review recent advances on the mechanisms and functional consequences of NMDAR plasticity. Given the unique biophysical properties of NMDARs, synaptic plasticity of NMDAR-mediated transmission emerges as a particularly powerful mechanism for the fine tuning of information encoding and storage throughout the brain. PMID:22325859

  17. Contextual learning requires synaptic AMPA receptor delivery in the hippocampus

    PubMed Central

    Mitsushima, Dai; Ishihara, Kouji; Sano, Akane; Kessels, Helmut W.; Takahashi, Takuya

    2011-01-01

    The hippocampus plays a central role in learning and memory. Although synaptic delivery of AMPA-type glutamate receptors (AMPARs) contributes to experience-dependent synaptic strengthening, its role in hippocampus-dependent learning remains elusive. By combining viral-mediated in vivo gene delivery with in vitro patch-clamp recordings, we found that the inhibitory avoidance task, a hippocampus-dependent contextual fear-learning paradigm, delivered GluR1-containing AMPARs into CA3-CA1 synapses of the dorsal hippocampus. To block the synaptic delivery of endogenous AMPARs, we expressed a fragment of the GluR1-cytoplasmic tail (the 14-aa GluR1 membrane-proximal region with two serines mutated to phospho-mimicking aspartates: MPR-DD). MPR-DD prevented learning-driven synaptic AMPAR delivery in CA1 neurons. Bilateral expression of MPR-DD in the CA1 region of the rat impaired inhibitory avoidance learning, indicating that synaptic GluR1 trafficking in the CA1 region of the hippocampus is required for encoding contextual fear memories. The fraction of CA1 neurons that underwent synaptic strengthening positively correlated with the performance in the inhibitory avoidance fear memory task. These data suggest that the robustness of a contextual memory depends on the number of hippocampal neurons that participate in the encoding of a memory trace. PMID:21746893

  18. Contextual learning requires synaptic AMPA receptor delivery in the hippocampus.

    PubMed

    Mitsushima, Dai; Ishihara, Kouji; Sano, Akane; Kessels, Helmut W; Takahashi, Takuya

    2011-07-26

    The hippocampus plays a central role in learning and memory. Although synaptic delivery of AMPA-type glutamate receptors (AMPARs) contributes to experience-dependent synaptic strengthening, its role in hippocampus-dependent learning remains elusive. By combining viral-mediated in vivo gene delivery with in vitro patch-clamp recordings, we found that the inhibitory avoidance task, a hippocampus-dependent contextual fear-learning paradigm, delivered GluR1-containing AMPARs into CA3-CA1 synapses of the dorsal hippocampus. To block the synaptic delivery of endogenous AMPARs, we expressed a fragment of the GluR1-cytoplasmic tail (the 14-aa GluR1 membrane-proximal region with two serines mutated to phospho-mimicking aspartates: MPR-DD). MPR-DD prevented learning-driven synaptic AMPAR delivery in CA1 neurons. Bilateral expression of MPR-DD in the CA1 region of the rat impaired inhibitory avoidance learning, indicating that synaptic GluR1 trafficking in the CA1 region of the hippocampus is required for encoding contextual fear memories. The fraction of CA1 neurons that underwent synaptic strengthening positively correlated with the performance in the inhibitory avoidance fear memory task. These data suggest that the robustness of a contextual memory depends on the number of hippocampal neurons that participate in the encoding of a memory trace.

  19. Synaptic activity regulates AMPA receptor trafficking through different recycling pathways

    PubMed Central

    Zheng, Ning; Jeyifous, Okunola; Munro, Charlotte; Montgomery, Johanna M; Green, William N

    2015-01-01

    Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. In this study, we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites. DOI: http://dx.doi.org/10.7554/eLife.06878.001 PMID:25970033

  20. Glycinergic inhibition in thalamus revealed by synaptic receptor blockade.

    PubMed

    Ghavanini, Ahmad A; Mathers, David A; Puil, Ernest

    2005-09-01

    Using juvenile rat brain slices, we examined the possibility that strychnine-sensitive receptors for glycine-like amino acids contributed to synaptic inhibition in ventrobasal thalamus, where gamma-aminobutyrate (GABA) is the prevalent inhibitory transmitter. Ventrobasal nuclei showed staining for antibodies against alpha1 and alpha2 subunits of the glycine receptor. Exogenously applied glycine, taurine and beta-alanine increased membrane conductance, effects antagonized by strychnine, indicative of functional glycine receptors. Using glutamate receptor antagonists, we isolated inhibitory postsynaptic potentials and currents (IPSPs and IPSCs) evoked by high-threshold stimulation of medial lemniscus. Like the responses to glycine agonists, these synaptic responses reversed near E(Cl). In comparative tests with GABA receptor antagonists, strychnine attenuated inhibition in a majority of neurons, but did not alter slow, GABA(B) inhibition. For complete blockade, the majority of fast IPSPs required co-application of strychnine with bicuculline or gabazine, GABA(A) receptor antagonists. Strychnine acting with an IC50 approximately = 33 nM, eliminated residual fast inhibition during selective GABA(A) receptor blockade with gabazine. The latency of onset for IPSPs was compatible with polysynaptic pathways or prolonged axonal propagation time. Strychnine lacked effects on monosynaptic, GABAergic IPSPs from zona incerta. The specific actions of strychnine implicated a glycine receptor contribution to fast inhibition in somatosensory thalamus.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Tse, Yiu Chung; Bagot, Rosemary C; Hutter, Juliana A; Wong, Alice S; Wong, Tak Pan

    2011-01-01

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

  3. Cornichon proteins determine the subunit composition of synaptic AMPA receptors.

    PubMed

    Herring, Bruce E; Shi, Yun; Suh, Young Ho; Zheng, Chan-Ying; Blankenship, Sabine M; Roche, Katherine W; Nicoll, Roger A

    2013-03-20

    Cornichon-2 and cornichon-3 (CNIH-2/-3) are AMPA receptor (AMPAR) binding proteins that promote receptor trafficking and markedly slow AMPAR deactivation in heterologous cells, but their role in neurons is unclear. Using CNIH-2 and CNIH-3 conditional knockout mice, we find a profound reduction of AMPAR synaptic transmission in the hippocampus. This deficit is due to the selective loss of surface GluA1-containing AMPARs (GluA1A2 heteromers), leaving a small residual pool of synaptic GluA2A3 heteromers. The kinetics of AMPARs in neurons lacking CNIH-2/-3 are faster than those in WT neurons due to the fast kinetics of GluA2A3 heteromers. The remarkably selective effect of CNIHs on the GluA1 subunit is probably mediated by TARP γ-8, which prevents a functional association of CNIHs with non-GluA1 subunits. These results point to a sophisticated interplay between CNIHs and γ-8 that dictates subunit-specific AMPAR trafficking and the strength and kinetics of synaptic AMPAR-mediated transmission.

  4. Interneuron- and GABAA receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells

    PubMed Central

    He, Qionger; Duguid, Ian; Clark, Beverley; Panzanelli, Patrizia; Patel, Bijal; Thomas, Philip; Fritschy, Jean-Marc; Smart, Trevor G.

    2015-01-01

    Inhibitory synaptic plasticity is important for shaping both neuronal excitability and network activity. Here we investigate the input and GABAA receptor subunit specificity of inhibitory synaptic plasticity by studying cerebellar interneuron–Purkinje cell (PC) synapses. Depolarizing PCs initiated a long-lasting increase in GABA-mediated synaptic currents. By stimulating individual interneurons, this plasticity was observed at somatodendritic basket cell synapses, but not at distal dendritic stellate cell synapses. Basket cell synapses predominantly express β2-subunit-containing GABAA receptors; deletion of the β2-subunit ablates this plasticity, demonstrating its reliance on GABAA receptor subunit composition. The increase in synaptic currents is dependent upon an increase in newly synthesized cell surface synaptic GABAA receptors and is abolished by preventing CaMKII phosphorylation of GABAA receptors. Our results reveal a novel GABAA receptor subunit- and input-specific form of inhibitory synaptic plasticity that regulates the temporal firing pattern of the principal output cells of the cerebellum. PMID:26179122

  5. Interneuron- and GABAA receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells

    NASA Astrophysics Data System (ADS)

    He, Qionger; Duguid, Ian; Clark, Beverley; Panzanelli, Patrizia; Patel, Bijal; Thomas, Philip; Fritschy, Jean-Marc; Smart, Trevor G.

    2015-07-01

    Inhibitory synaptic plasticity is important for shaping both neuronal excitability and network activity. Here we investigate the input and GABAA receptor subunit specificity of inhibitory synaptic plasticity by studying cerebellar interneuron-Purkinje cell (PC) synapses. Depolarizing PCs initiated a long-lasting increase in GABA-mediated synaptic currents. By stimulating individual interneurons, this plasticity was observed at somatodendritic basket cell synapses, but not at distal dendritic stellate cell synapses. Basket cell synapses predominantly express β2-subunit-containing GABAA receptors; deletion of the β2-subunit ablates this plasticity, demonstrating its reliance on GABAA receptor subunit composition. The increase in synaptic currents is dependent upon an increase in newly synthesized cell surface synaptic GABAA receptors and is abolished by preventing CaMKII phosphorylation of GABAA receptors. Our results reveal a novel GABAA receptor subunit- and input-specific form of inhibitory synaptic plasticity that regulates the temporal firing pattern of the principal output cells of the cerebellum.

  6. Bridging the synaptic cleft: lessons from orphan glutamate receptors.

    PubMed

    Schmid, Sabine M; Hollmann, Michael

    2010-08-24

    For neurons to communicate, signals must cross the cell-to-cell distance at their points of contact. At the predominant cell-cell contact in the central nervous system, the chemical synapse, the synaptic cleft spans roughly 20 nanometers. To signal across this distance, the presynaptic neuron secretes a diffusible neurotransmitter, which is detected by receptors on the postsynaptic neuron. Although this signaling mechanism has become common knowledge, it remains unclear how synapses are maintained when they are not in immediate use. New evidence reveals how Nature solved this problem at a particular type of synapse in the cerebellum: Three old acquaintances bridge the cleft. The ionotropic glutamate receptor GluD2 constitutes the postsynaptic anchor that indirectly interacts with the presynaptic anchor neurexin through a presynaptically secreted soluble factor, a member of the C1q protein family named Cbln1. This trio collaborates to align pre- and postsynaptic sides.

  7. GluN2B-Containing NMDA Receptors Regulate AMPA Receptor Traffic through Anchoring of the Synaptic Proteasome.

    PubMed

    Ferreira, Joana S; Schmidt, Jeannette; Rio, Pedro; Águas, Rodolfo; Rooyakkers, Amanda; Li, Ka Wan; Smit, August B; Craig, Ann Marie; Carvalho, Ana Luisa

    2015-06-03

    NMDA receptors play a central role in shaping the strength of synaptic connections throughout development and in mediating synaptic plasticity mechanisms that underlie some forms of learning and memory formation in the CNS. In the hippocampus and the neocortex, GluN1 is combined primarily with GluN2A and GluN2B, which are differentially expressed during development and confer distinct molecular and physiological properties to NMDA receptors. The contribution of each subunit to the synaptic traffic of NMDA receptors and therefore to their role during development and in synaptic plasticity is still controversial. We report a critical role for the GluN2B subunit in regulating NMDA receptor synaptic targeting. In the absence of GluN2B, the synaptic levels of AMPA receptors are increased and accompanied by decreased constitutive endocytosis of GluA1-AMPA receptor. We used quantitative proteomic analysis to identify changes in the composition of postsynaptic densities from GluN2B(-/-) mouse primary neuronal cultures and found altered levels of several ubiquitin proteasome system components, in particular decreased levels of proteasome subunits. Enhancing the proteasome activity with a novel proteasome activator restored the synaptic levels of AMPA receptors in GluN2B(-/-) neurons and their endocytosis, revealing that GluN2B-mediated anchoring of the synaptic proteasome is responsible for fine tuning AMPA receptor synaptic levels under basal conditions.

  8. A network of autism linked genes stabilizes two pools of synaptic GABAA receptors

    PubMed Central

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

    2015-01-01

    Changing receptor abundance at synapses is an important mechanism for regulating synaptic strength. Synapses contain two pools of receptors, immobilized and diffusing receptors, both of which are confined to post-synaptic elements. Here we show that immobile and diffusing GABAA receptors are stabilized by distinct synaptic scaffolds at C. elegans neuromuscular junctions. Immobilized GABAA receptors are stabilized by binding to FRM-3/EPB4.1 and LIN-2A/CASK. Diffusing GABAA receptors are stabilized by the synaptic adhesion molecules Neurexin and Neuroligin. Inhibitory post-synaptic currents are eliminated in double mutants lacking both scaffolds. Neurexin, Neuroligin, and CASK mutations are all linked to Autism Spectrum Disorders (ASD). Our results suggest that these mutations may directly alter inhibitory transmission, which could contribute to the developmental and cognitive deficits observed in ASD. DOI: http://dx.doi.org/10.7554/eLife.09648.001 PMID:26575289

  9. ATP from synaptic terminals and astrocytes regulates NMDA receptors and synaptic plasticity through PSD-95 multi-protein complex

    PubMed Central

    Lalo, U.; Palygin, O.; Verkhratsky, A.; Grant, S. G. N.; Pankratov, Y.

    2016-01-01

    Recent studies highlighted the importance of astrocyte-secreted molecules, such as ATP, for the slow modulation of synaptic transmission in central neurones. Biophysical mechanisms underlying the impact of gliotransmitters on the strength of individual synapse remain, however, unclear. Here we show that purinergic P2X receptors can bring significant contribution to the signalling in the individual synaptic boutons. ATP released from astrocytes facilitates a recruitment of P2X receptors into excitatory synapses by Ca2+-dependent mechanism. P2X receptors, co-localized with NMDA receptors in the excitatory synapses, can be activated by ATP co-released with glutamate from pre-synaptic terminals and by glia-derived ATP. An activation of P2X receptors in turn leads to down-regulation of postsynaptic NMDA receptors via Ca2+-dependent de-phosphorylation and interaction with PSD-95 multi-protein complex. Genetic deletion of the PSD-95 or P2X4 receptors obliterated ATP-mediated down-regulation of NMDA receptors. Impairment of purinergic modulation of NMDA receptors in the PSD-95 mutants dramatically decreased the threshold of LTP induction and increased the net magnitude of LTP. Our findings show that synergistic action of glia- and neurone-derived ATP can pre-modulate efficacy of excitatory synapses and thereby can have an important role in the glia-neuron communications and brain meta-plasticity. PMID:27640997

  10. 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.

  11. A putative lysophosphatidylinositol receptor GPR55 modulates hippocampal synaptic plasticity.

    PubMed

    Hurst, Katrina; Badgley, Corinne; Ellsworth, Tanner; Bell, Spencer; Friend, Lindsey; Prince, Brad; Welch, Jacob; Cowan, Zack; Williamson, Ryan; Lyon, Chris; Anderson, Brandon; Poole, Brian; Christensen, Michael; McNeil, Michael; Call, Jarrod; Edwards, Jeffrey G

    2017-09-01

    GPR55, an orphan G-protein coupled receptor, is activated by lysophosphatidylinositol (LPI) and the endocannabinoid anandamide, as well as by other compounds including THC. LPI is a potent endogenous ligand of GPR55 and neither GPR55 nor LPIs' functions in the brain are well understood. While endocannabinoids are well known to modulate brain synaptic plasticity, the potential role LPI could have on brain plasticity has never been demonstrated. Therefore, we examined not only GPR55 expression, but also the role its endogenous ligand could play in long-term potentiation, a common form of synaptic plasticity. Using quantitative RT-PCR, electrophysiology, and behavioral assays, we examined hippocampal GPR55 expression and function. qRT-PCR results indicate that GPR55 is expressed in hippocampi of both rats and mice. Immunohistochemistry and single cell PCR demonstrates GPR55 protein in pyramidal cells of CA1 and CA3 layers in the hippocampus. Application of the GPR55 endogenous agonist LPI to hippocampal slices of GPR55(+/+) mice significantly enhanced CA1 LTP. This effect was absent in GPR55(-/-) mice, and blocked by the GPR55 antagonist CID 16020046. We also examined paired-pulse ratios of GPR55(-/-) and GPR55(+/+) mice with or without LPI and noted significant enhancement in paired-pulse ratios by LPI in GPR55(+/+) mice. Behaviorally, GPR55(-/-) and GPR55(+/+) mice did not differ in memory tasks including novel object recognition, radial arm maze, or Morris water maze. However, performance on radial arm maze and elevated plus maze task suggests GPR55(-/-) mice have a higher frequency of immobile behavior. This is the first demonstration of LPI involvement in hippocampal synaptic plasticity. © 2017 Wiley Periodicals, Inc.

  12. Synaptic Efficacy as a Function of Ionotropic Receptor Distribution: A Computational Study

    PubMed Central

    Allam, Sushmita L.; Bouteiller, Jean-Marie C.; Hu, Eric Y.; Ambert, Nicolas; Greget, Renaud; Bischoff, Serge; Baudry, Michel; Berger, Theodore W.

    2015-01-01

    Glutamatergic synapses are the most prevalent functional elements of information processing in the brain. Changes in pre-synaptic activity and in the function of various post-synaptic elements contribute to generate a large variety of synaptic responses. Previous studies have explored postsynaptic factors responsible for regulating synaptic strength variations, but have given far less importance to synaptic geometry, and more specifically to the subcellular distribution of ionotropic receptors. We analyzed the functional effects resulting from changing the subsynaptic localization of ionotropic receptors by using a hippocampal synaptic computational framework. The present study was performed using the EONS (Elementary Objects of the Nervous System) synaptic modeling platform, which was specifically developed to explore the roles of subsynaptic elements as well as their interactions, and that of synaptic geometry. More specifically, we determined the effects of changing the localization of ionotropic receptors relative to the presynaptic glutamate release site, on synaptic efficacy and its variations following single pulse and paired-pulse stimulation protocols. The results indicate that changes in synaptic geometry do have consequences on synaptic efficacy and its dynamics. PMID:26480028

  13. Synaptic Efficacy as a Function of Ionotropic Receptor Distribution: A Computational Study.

    PubMed

    Allam, Sushmita L; Bouteiller, Jean-Marie C; Hu, Eric Y; Ambert, Nicolas; Greget, Renaud; Bischoff, Serge; Baudry, Michel; Berger, Theodore W

    2015-01-01

    Glutamatergic synapses are the most prevalent functional elements of information processing in the brain. Changes in pre-synaptic activity and in the function of various post-synaptic elements contribute to generate a large variety of synaptic responses. Previous studies have explored postsynaptic factors responsible for regulating synaptic strength variations, but have given far less importance to synaptic geometry, and more specifically to the subcellular distribution of ionotropic receptors. We analyzed the functional effects resulting from changing the subsynaptic localization of ionotropic receptors by using a hippocampal synaptic computational framework. The present study was performed using the EONS (Elementary Objects of the Nervous System) synaptic modeling platform, which was specifically developed to explore the roles of subsynaptic elements as well as their interactions, and that of synaptic geometry. More specifically, we determined the effects of changing the localization of ionotropic receptors relative to the presynaptic glutamate release site, on synaptic efficacy and its variations following single pulse and paired-pulse stimulation protocols. The results indicate that changes in synaptic geometry do have consequences on synaptic efficacy and its dynamics.

  14. Structurally dissimilar antimanic agents modulate synaptic plasticity by regulating AMPA glutamate receptor subunit GluR1 synaptic expression.

    PubMed

    Du, Jing; Gray, Neil A; Falke, Cynthia; Yuan, Peixiong; Szabo, Steven; Manji, Husseini K

    2003-11-01

    A growing body of data from clinical and preclinical studies suggests that the glutamatergic system may represent a novel therapeutic target for severe recurrent mood disorders. Since synapse-specific glutamate receptor expression/localization is known to play critical roles in synaptic plasticity, we investigated the effects of mood stabilizers on AMPA receptor expression. Rats were treated chronically with lithium or valproate, hippocampal synaptosomes were isolated, and GluR1 levels were determined. Additionally, hippocampal neurons were prepared from E18 rat embryos and treated with lithium or valproate. Surface expression of GluR1 was determined using a biotinylation assay, and double-immunostaining with anti-GluR1 and anti-synaptotagmin antibodies was used to determine synaptic GluR1 levels. The AMPA receptor subunit GluR1 expression in hippocampal synaptosomes was significantly reduced by both chronic lithium and valproate. Overall, these studies show that AMPA receptor subunit GluR1 is a common target for two structurally highly dissimilar, but highly efficacious, mood stabilizers, lithium and valproate. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.

  15. The Influence of Synaptic Size on AMPA Receptor Activation: A Monte Carlo Model

    PubMed Central

    Montes, Jesus; Peña, Jose M.; DeFelipe, Javier; Herreras, Oscar; Merchan-Perez, Angel

    2015-01-01

    Physiological and electron microscope studies have shown that synapses are functionally and morphologically heterogeneous and that variations in size of synaptic junctions are related to characteristics such as release probability and density of postsynaptic AMPA receptors. The present article focuses on how these morphological variations impact synaptic transmission. We based our study on Monte Carlo computational simulations of simplified model synapses whose morphological features have been extracted from hundreds of actual synaptic junctions reconstructed by three-dimensional electron microscopy. We have examined the effects that parameters such as synaptic size or density of AMPA receptors have on the number of receptors that open after release of a single synaptic vesicle. Our results indicate that the maximum number of receptors that will open after the release of a single synaptic vesicle may show a ten-fold variation in the whole population of synapses. When individual synapses are considered, there is also a stochastical variability that is maximal in small synapses with low numbers of receptors. The number of postsynaptic receptors and the size of the synaptic junction are the most influential parameters, while the packing density of receptors or the concentration of extrasynaptic transporters have little or no influence on the opening of AMPA receptors. PMID:26107874

  16. The influence of synaptic size on AMPA receptor activation: a Monte Carlo model.

    PubMed

    Montes, Jesus; Peña, Jose M; DeFelipe, Javier; Herreras, Oscar; Merchan-Perez, Angel

    2015-01-01

    Physiological and electron microscope studies have shown that synapses are functionally and morphologically heterogeneous and that variations in size of synaptic junctions are related to characteristics such as release probability and density of postsynaptic AMPA receptors. The present article focuses on how these morphological variations impact synaptic transmission. We based our study on Monte Carlo computational simulations of simplified model synapses whose morphological features have been extracted from hundreds of actual synaptic junctions reconstructed by three-dimensional electron microscopy. We have examined the effects that parameters such as synaptic size or density of AMPA receptors have on the number of receptors that open after release of a single synaptic vesicle. Our results indicate that the maximum number of receptors that will open after the release of a single synaptic vesicle may show a ten-fold variation in the whole population of synapses. When individual synapses are considered, there is also a stochastical variability that is maximal in small synapses with low numbers of receptors. The number of postsynaptic receptors and the size of the synaptic junction are the most influential parameters, while the packing density of receptors or the concentration of extrasynaptic transporters have little or no influence on the opening of AMPA receptors.

  17. Synaptic localization of kappa opioid receptors in guinea pig neostriatum.

    PubMed Central

    Jomary, C; Gairin, J E; Beaudet, A

    1992-01-01

    Distribution of kappa opioid receptors was examined by EM radioautography in sections of guinea pig neostriatum with the selective 125I-labeled dynorphin analog [D-Pro10]dynorphin-(1-11). Most specifically labeled binding sites were found by probability circle analysis to be associated with neuronal membrane appositions. Because of limitations in resolution of the method, the radioactive sources could not be ascribed directly to either one of the apposed plasma membranes. Nevertheless, three lines of evidence favored a predominant association of ligand with dendrites of intrinsic striatal neurons: (i) the high frequency with which labeled interfaces implicated a dendrite, (ii) the enrichment of dendro-dendritic interfaces, and (iii) the occurrence of dendritic profiles labeled at several contact points along their plasma membranes. A small proportion of labeled sites was associated with axo-axonic interfaces, which may subserve the kappa opioid-induced regulation of presynaptic dopamine and acetylcholine release documented in guinea pig neostriatum. Although most membrane-associated kappa sites were found at extrasynaptic locations, approximately 23% were associated with synaptic specializations. This proportion is markedly higher than that previously reported for either mu or delta sites in rat neostriatum. Whether labeled synapses represent preferential sites of action for kappa ligands remains to be established. In any event, these results support the hypothesis that in mammalian brain kappa opioid receptors are conformationally and functionally distinct from mu and delta types. Images PMID:1346233

  18. Synaptic localization of kappa opioid receptors in guinea pig neostriatum.

    PubMed

    Jomary, C; Gairin, J E; Beaudet, A

    1992-01-15

    Distribution of kappa opioid receptors was examined by EM radioautography in sections of guinea pig neostriatum with the selective 125I-labeled dynorphin analog [D-Pro10]dynorphin-(1-11). Most specifically labeled binding sites were found by probability circle analysis to be associated with neuronal membrane appositions. Because of limitations in resolution of the method, the radioactive sources could not be ascribed directly to either one of the apposed plasma membranes. Nevertheless, three lines of evidence favored a predominant association of ligand with dendrites of intrinsic striatal neurons: (i) the high frequency with which labeled interfaces implicated a dendrite, (ii) the enrichment of dendro-dendritic interfaces, and (iii) the occurrence of dendritic profiles labeled at several contact points along their plasma membranes. A small proportion of labeled sites was associated with axo-axonic interfaces, which may subserve the kappa opioid-induced regulation of presynaptic dopamine and acetylcholine release documented in guinea pig neostriatum. Although most membrane-associated kappa sites were found at extrasynaptic locations, approximately 23% were associated with synaptic specializations. This proportion is markedly higher than that previously reported for either mu or delta sites in rat neostriatum. Whether labeled synapses represent preferential sites of action for kappa ligands remains to be established. In any event, these results support the hypothesis that in mammalian brain kappa opioid receptors are conformationally and functionally distinct from mu and delta types.

  19. 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

  20. 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.

  1. Regulation of synaptic signalling by postsynaptic, non-glutamate receptor ion channels

    PubMed Central

    Bloodgood, Brenda L; Sabatini, Bernardo L

    2008-01-01

    Activation of glutamatergic synapses onto pyramidal neurons produces a synaptic depolarization as well as a buildup of intracellular calcium (Ca2+). The synaptic depolarization propagates through the dendritic arbor and can be detected at the soma with a recording electrode. Current influx through AMPA-type glutamate receptors (AMPARs) provides the depolarizing drive, and the amplitudes of synaptic potentials are generally thought to reflect the number and properties of these receptors at each synapse. In contrast, synaptically evoked Ca2+ transients are limited to the spine containing the active synapse and result primarily from Ca2+ influx through NMDA-type glutamate receptors (NMDARs). Here we review recent studies that reveal that both synaptic depolarizations and spine head Ca2+ transients are strongly regulated by the activity of postsynaptic, non-glutamate receptor ion channels. In hippocampal pyramidal neurons, voltage- and Ca2+-gated ion channels located in dendritic spines open as downstream consequences of glutamate receptor activation and act within a complex signalling loop that feeds back to regulate synaptic signals. Dynamic regulation of these ion channels offers a powerful mechanism of synaptic plasticity that is independent of direct modulation of glutamate receptors. PMID:18096597

  2. 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

  3. Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signalling and BDNF gene regulation.

    PubMed

    Vanhoutte, Peter; Bading, Hilmar

    2003-06-01

    Neuronal responses to electrical activity-induced calcium signals are specified by the localization of the calcium entry site and the spatial properties of the calcium transient. Calcium flux through NMDA receptors located in the synapse initiates changes in synaptic efficacy and promotes pro-survival events, whereas calcium flux through extrasynaptic NMDA receptors is coupled to cell death pathways. The dialogue between the synaptic NMDA receptors and the nucleus is also modulated by extrasynaptic NMDA receptors, which shut down activity of CRE-binding protein (CREB) and antagonize the increase in brain-derived neurotrophic factor (BDNF) expression induced by synaptic NMDA receptors. The specification of the biological response by the localization of the receptor activated is a new concept in neuronal calcium signalling that can explain many of the opposing roles of NMDA receptors.

  4. Itinerant magnetic metals

    NASA Astrophysics Data System (ADS)

    Santiago, J. M.; Huang, C.-L.; Morosan, E.

    2017-09-01

    In this review, an overview of itinerant magnets without magnetic elements is presented, beginning with a comparison of the local and itinerant moment pictures, the two extremes of magnetism. Then, the theoretical developments leading up to the self-consistent renormalization theory of spin fluctuations will be discussed, followed by an introduction to quantum criticality and the experimental signatures associated with systems near a quantum critical point. Three itinerant magnets without magnetic elements, ZrZn2, Sc3.1In, and TiAu are the focus of this review, as their empty d shells set them apart in their purely itinerant character, while several enhanced Pauli paramagnets and intermediate moment magnets are also discussed to put the overall comparison into perspective.

  5. Endocytic Trafficking and Recycling Maintain a Pool of Mobile Surface AMPA Receptors Required for Synaptic Potentiation

    PubMed Central

    Petrini, Enrica Maria; Lu, Jiuyi; Cognet, Laurent; Lounis, Brahim; Ehlers, Michael D.; Choquet, Daniel

    2010-01-01

    SUMMARY At excitatory glutamatergic synapses, postsynaptic endocytic zones (EZs), which are adjacent to the postsynaptic density (PSD), mediate clathrin-dependent endocytosis of surface AMPA Receptors (AMPAR) as a first step to receptor recycling or degradation. However, it remains unknown if receptor recycling influences AMPARs lateral diffusion, and if EZs are important for the expression of synaptic potentiation. Here we demonstrate that the presence of both EZs and AMPAR recycling maintain a large pool of mobile AMPARs at synapses. In addition, we find that synaptic potentiation is accompanied by an accumulation and immobilization of AMPARs at synapses resulting from both their exocytosis and stabilization at the PSD. Displacement of EZs from the postsynaptic region impairs the expression of synaptic potentiation by blocking AMPAR recycling. Thus receptor recycling is crucial for maintaining a mobile population of surface AMPARs which can be delivered to synapses for increases in synaptic strength. PMID:19607795

  6. Metabotropic Glutamate Receptor 7: From Synaptic Function to Therapeutic Implications

    PubMed Central

    Palazzo, Enza; Marabese, Ida; de Novellis, Vito; Rossi, Francesco; Maione, Sabatino

    2016-01-01

    Metabotropic glutamate receptor 7 (mGluR7) is localized presynaptically at the active zone of neurotransmitter release. Unlike mGluR4 and mGluR8, which share mGluR7’s presynaptic location, mGluR7 shows low affinity for glutamate and is activated only by high glutamate concentrations. Its wide distribution in the central nervous system (CNS) and evolutionary conservation across species suggest that mGluR7 plays a primary role in controlling excitatory synapse function. High mGluR7 expression has been observed in several brain regions that are critical for CNS functioning and are involved in neurological and psychiatric disorder development. Until the recent discovery of selective ligands for mGluR7, techniques to elucidate its role in neural function were limited to the use of knockout mice and gene silencing. Studies using these two techniques have revealed that mGluR7 modulates emotionality, stress and fear responses. N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) was reported as the first selective mGluR7 allosteric agonist. Pharmacological effects of AMN082 have not completely confirmed the mGluR7-knockout mouse phenotype; this has been attributed to rapid receptor internalization after drug treatment and to the drug’s apparent lack of in vivo selectivity. Therefore, the more recently developed mGluR7 negative allosteric modulators (NAMs) are crucial for understanding mGluR7 function and for exploiting its potential as a target for therapeutic interventions. This review presents the main findings regarding mGluR7’s effect on modulation of synaptic function and its role in normal CNS function and in models of neurologic and psychiatric disorders. PMID:27306064

  7. The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABAA receptors

    PubMed Central

    Alexeev, Mikhail; Grosenbaugh, Denise K.; Mott, David D.; Fisher, Janet L.

    2012-01-01

    The National Center for Complementary and Alternative Medicine (NCCAM) estimates that nearly 40% of adults in the United States use alternative medicines, often in the form of an herbal supplement. Extracts from the tree bark of magnolia species have been used for centuries in traditional Chinese and Japanese medicines to treat a variety of neurological diseases, including anxiety, depression, and seizures. The active ingredients in the extracts have been identified as the bi-phenolic isomers magnolol and honokiol. These compounds were shown to enhance the activity of GABAA receptors, consistent with their biological effects. The GABAA receptors exhibit substantial subunit heterogeneity, which influences both their functional and pharmacological properties. We examined the activity of magnolol and honokiol at different populations of both neuronal and recombinant GABAA receptors to characterize their mechanism of action and to determine whether sensitivity to modulation was dependent upon the receptor’s subunit composition. We found that magnolol and honokiol enhanced both phasic and tonic GABAergic neurotransmission in hippocampal dentate granule neurons. In addition, all recombinant receptors examined were sensitive to modulation, regardless of the identity of the α, β, or γ subunit subtype, although the compounds showed particularly high efficacy at δ-containing receptors. This direct positive modulation of both synaptic and extra-synaptic populations of GABAA receptors suggests that supplements containing magnolol and/or honokiol would be effective anxiolytics, sedatives, and anti-convulsants. However, significant side-effects and risk of drug interactions would also be expected. PMID:22445602

  8. Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices

    PubMed Central

    Harris, Alexander Z; Pettit, Diana L

    2007-01-01

    N-methyl-d-aspartate receptor (NMDAR) activation can trigger both long- and short-term plasticity, promote cell survival, and initiate cell death. A number of studies suggest that the consequences of NMDAR activation can vary widely depending on whether synaptic or extrasynaptic receptors are activated. Here we have examined the spatial distribution of NMDARs of CA1 pyramidal neurons in acutely dissected hippocampal slices. Using a physiological definition of extrasynaptic receptors as those not accessible to single release events, we find that extrasynaptic NMDARs comprise a substantial proportion of the dendritic NMDAR pool (36%). This pool of extrasynaptic NMDARs is stable and does not shuttle into the synaptic receptor pool, as we observe no recovery of synaptic current after MK-801 synaptic blockade and washout. The subunit composition of synaptic and extrasynaptic NMDA receptor pools is similar at 3 weeks of age, with NR2B subunits present in both compartments. NR2B receptors are not enriched in the extrasynaptic compartment. Our data suggest that any role played by extrasynaptic NMDARs in synaptic transmission is dictated by their subcellular location rather than their subunit composition or mobility. PMID:17717018

  9. Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices.

    PubMed

    Harris, Alexander Z; Pettit, Diana L

    2007-10-15

    N-methyl-d-aspartate receptor (NMDAR) activation can trigger both long- and short-term plasticity, promote cell survival, and initiate cell death. A number of studies suggest that the consequences of NMDAR activation can vary widely depending on whether synaptic or extrasynaptic receptors are activated. Here we have examined the spatial distribution of NMDARs of CA1 pyramidal neurons in acutely dissected hippocampal slices. Using a physiological definition of extrasynaptic receptors as those not accessible to single release events, we find that extrasynaptic NMDARs comprise a substantial proportion of the dendritic NMDAR pool (36%). This pool of extrasynaptic NMDARs is stable and does not shuttle into the synaptic receptor pool, as we observe no recovery of synaptic current after MK-801 synaptic blockade and washout. The subunit composition of synaptic and extrasynaptic NMDA receptor pools is similar at 3 weeks of age, with NR2B subunits present in both compartments. NR2B receptors are not enriched in the extrasynaptic compartment. Our data suggest that any role played by extrasynaptic NMDARs in synaptic transmission is dictated by their subcellular location rather than their subunit composition or mobility.

  10. Visualization of NMDA receptor-dependent AMPA receptor synaptic plasticity in vivo

    PubMed Central

    Zhang, Yong; Cudmore, Robert H.; Lin, Da-Ting; Linden, David J.; Huganir, Richard L.

    2015-01-01

    Regulation of AMPA receptor (AMPAR) membrane trafficking plays a critical role in synaptic plasticity and learning and memory. However, how AMPAR trafficking occurs in vivo remains elusive. Using in vivo two-photon microscopy in the mouse somatosensory barrel cortex, we found that acute whisker stimulation leads to a significant increase in the surface expression of the AMPAR GluA1 subunit (sGluA1) in both spines and dendritic shafts and small increases in spine size. Interestingly, initial spine properties bias spine changes following whisker stimulation. Changes in spine sGluA1 are positively correlated with changes in spine size and dendritic shaft sGluA1 following whisker stimulation. The increase in spine sGluA1 evoked by whisker stimulation is NMDA receptor dependent and long lasting, similar to major forms of synaptic plasticity in the brain. These results reveal experience dependent AMPAR trafficking in real time and characterize, in vivo, a major form of synaptic plasticity in the brain. PMID:25643295

  11. PSD-95 regulates synaptic kainate receptors at mouse hippocampal mossy fiber-CA3 synapses.

    PubMed

    Suzuki, Etsuko; Kamiya, Haruyuki

    2016-06-01

    Kainate-type glutamate receptors (KARs) are the third class of ionotropic glutamate receptors whose activation leads to the unique roles in regulating synaptic transmission and circuit functions. In contrast to AMPA receptors (AMPARs), little is known about the mechanism of synaptic localization of KARs. PSD-95, a major scaffold protein of the postsynaptic density, is a candidate molecule that regulates the synaptic KARs. Although PSD-95 was shown to bind directly to KARs subunits, it has not been tested whether PSD-95 regulates synaptic KARs in intact synapses. Using PSD-95 knockout mice, we directly investigated the role of PSD-95 in the KARs-mediated components of synaptic transmission at hippocampal mossy fiber-CA3 synapse, one of the synapses with the highest density of KARs. Mossy fiber EPSCs consist of AMPA receptor (AMPAR)-mediated fast component and KAR-mediated slower component, and the ratio was significantly reduced in PSD-95 knockout mice. The size of KARs-mediated field EPSP reduced in comparison with the size of the fiber volley. Analysis of KARs-mediated miniature EPSCs also suggested reduced synaptic KARs. All the evidence supports critical roles of PSD-95 in regulating synaptic KARs. Copyright © 2015 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  12. Ionotropic glutamate receptor biology: effect on synaptic connectivity and function in neurological disease.

    PubMed

    Barnes, G N; Slevin, J T

    2003-10-01

    Glutamate receptor signaling is essential to normal synaptic function in the central nervous system. The major ionotropic glutamate receptors (AMPA, Kainic, and NMDA) have different synaptic functions depending upon cellular and subcellular localization, subunit composition, and second messenger systems linked to the receptors. In this review, we examine major advances in glutamate receptor biology whose physiology plays a central role in neurologic disease such as epilepsy and stroke. A key feature of glutamate receptor activation in neurologic disease is the downstream effects on cell survival, genetic expression of axon guidance cues, synaptic connectivity/formation of networks, and neuronal excitability. Identification of therapeutic pharmacologic targets and development of antagonists specific to the disease process remain central themes in epilepsy and stroke research.

  13. Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways

    PubMed Central

    Ledgerwood, CJ; Greenwood, SM; Brett, RR; Pratt, JA; Bushell, TJ

    2011-01-01

    BACKGROUND AND PURPOSE Cannabidiol (CBD) has emerged as an interesting compound with therapeutic potential in several CNS disorders. However, whether it can modulate synaptic activity in the CNS remains unclear. Here, we have investigated whether CBD modulates synaptic transmission in rat hippocampal cultures and acute slices. EXPERIMENTAL APPROACH The effect of CBD on synaptic transmission was examined in rat hippocampal cultures and acute slices using whole cell patch clamp and standard extracellular recordings respectively. KEY RESULTS Cannabidiol decreased synaptic activity in hippocampal cultures in a concentration-dependent and Pertussis toxin-sensitive manner. The effects of CBD in culture were significantly reduced in the presence of the cannabinoid receptor (CB1) inverse agonist, LY320135 but were unaffected by the 5-HT1A receptor antagonist, WAY100135. In hippocampal slices, CBD inhibited basal synaptic transmission, an effect that was abolished by the proposed CB1 receptor antagonist, AM251, in addition to LY320135 and WAY100135. CONCLUSIONS AND IMPLICATIONS Cannabidiol reduces synaptic transmission in hippocampal in vitro preparations and we propose a role for both 5-HT1A and CB1 receptors in these CBD-mediated effects. These data offer some mechanistic insights into the effects of CBD and emphasize that further investigations into the actions of CBD in the CNS are required in order to elucidate the full therapeutic potential of CBD. PMID:20825410

  14. Itinerant Teaching: An Insider's View.

    ERIC Educational Resources Information Center

    Swenson, Anna M.

    1995-01-01

    An itinerant teacher of students with visual impairments describes the itinerant model, in which students who are visually impaired attend their neighborhood schools while periodically receiving special services from a vision teacher. Advantages and disadvantages of the model are considered, a typical day of an itinerant teacher is described, and…

  15. Excitatory Synaptic Responses Mediated by GABA_A Receptors in the Hippocampus

    NASA Astrophysics Data System (ADS)

    Michelson, Hillary B.; Wong, Robert K. S.

    1991-09-01

    Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the cortex. Activation of postsynaptic GABA_A receptors hyperpolarizes cells and inhibits neuronal activity. Synaptic responses mediated by GABA_A receptors also strongly excited hippocampal neurons. This excitatory response was recorded in morphologically identified interneurons in the presence of 4-aminopyridine or after elevation of extracellular potassium concentrations. The synaptic excitation sustained by GABA_A receptors synchronized the activity of inhibitory interneurons. This synchronized discharge of interneurons in turn elicited large-amplitude inhibitory postsynaptic potentials in pyramidal and granule cells. Excitatory synaptic responses mediated by GABA_A receptors may thus provide a mechanism for the recruitment of GABAergic interneurons through their recurrent connections.

  16. 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.

  17. New vistas on synaptic plasticity: the receptor mosaic hypothesis of the engram.

    PubMed

    Agnati, L F; Fuxe, K; Zoli, M; Rondanini, C; Ogren, S O

    1982-08-01

    The concepts of coexistence of transmitters and of receptor-receptor interactions have increased our understanding of the integrative processes regulating synaptic homeostasis and synaptic plasticity. Depending upon the ionotropic or metabotropic characteristics of the cotransmitter, it may be mainly involved in synaptic homeostasis or synaptic plasticity, respectively. A chemical trace of the postsynaptic activity can be obtained because of the plasticity of the receptor molecules. Thus, the heuristic hypothesis is introduced that islands of receptors located on postsynaptic membranes of local circuits can be formed by means of receptor-receptor interactions favouring ordered electrotonic sequences in the local circuits. This hypothesis has been named the receptor mosaic hypothesis of the engram. The islands or clusters of receptors can then store specific and complex information and when activated by the transmitters they may induce unique changes in ion permeability and cell metabolism which, at the local circuit level, can mimic exactly a previous electrotonic sequence. They can therefore represent at least part of the engram. This hypothesis is introduced against the background of the possible existence of different types of encodings of memory.

  18. Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single synaptic activation

    PubMed Central

    Hou, Qingming; Gilbert, James; Man, Heng-Ye

    2011-01-01

    During homeostatic adjustment in response to alterations in neuronal activity, synaptic expression of AMPA receptors (AMPARs) is globally tuned up- or down so that the neuronal activity is restored to a physiological range. Given that a central neuron receives multiple presynaptic inputs, whether and how AMPAR synaptic expression is homeostatically regulated at individual synapses remains unclear. In cultured hippocampal neurons, we report that when activity of an individual presynaptic terminal is selectively elevated by light-controlled excitation, AMPAR abundance at the excited synapses is selectively down-regulated in an NMDAR-dependent manner. The reduction in surface AMPARs is accompanied by enhanced receptor endocytosis and dependent on proteasomal activity. Synaptic activation also leads to a site-specific increase in the ubiquitin ligase Nedd4 and polyubiquitination levels, consistent with AMPAR ubiquitination and degradation in the spine. These results indicate that AMPAR accumulation at individual synapses is subject to autonomous homeostatic regulation in response to synaptic activity. PMID:22153376

  19. TARP modulation of synaptic AMPA receptor trafficking and gating depends on multiple intracellular domains.

    PubMed

    Milstein, Aaron D; Nicoll, Roger A

    2009-07-07

    Previous work has established stargazin and its related family of transmembrane AMPA receptor regulatory proteins (TARPs) as auxiliary subunits of AMPA receptors (AMPARs) that control synaptic strength both by targeting AMPARs to synapses through an intracellular PDZ-binding motif and by modulating their gating through an extracellular domain. However, TARPs gamma-2 and gamma-8 differentially regulate the synaptic targeting of AMPARs, despite having identical PDZ-binding motifs. Here, we investigate the structural elements that contribute to this functional difference between TARP subtypes by using domain transplantation and truncation. We identify a component of synaptic AMPAR trafficking that is independent of the TARP C-terminal PDZ-binding motif, and we establish previously uncharacterized roles for the TARP intracellular N terminus, loop, and C terminus in modulating both the trafficking and gating of synaptic AMPARs.

  20. NMDA receptor phosphorylation at a site affected in schizophrenia controls synaptic and behavioral plasticity

    PubMed Central

    Li, Bo; Devidze, Nino; Barengolts, Denis; Prostak, Naseem; Sphicas, Eleana; Apicella, Alfonso; Malinow, Roberto; Emamian, Effat S.

    2009-01-01

    Phosphorylation of the NR1 subunit of NMDA receptors (NMDAR) at serine (S) 897 is markedly reduced in schizophrenia patients. However, the role of NR1 S897 phosphorylation in normal synaptic function and adaptive behaviors are unknown. To address these questions we generated mice in which the NR1 S897 is replaced with alanine (A). This knock-in mutation causes severe impairment in NMDAR synaptic incorporation and NMDAR-mediated synaptic transmission. Furthermore, the phosphomutant animals have reduced AMPA receptor (AMPAR)-mediated synaptic transmission, decreased AMPAR GluR1 subunit in the synapse, and impaired long-term potentiation (LTP). Finally, the mutant mice exhibit behavioral deficits in social interaction and sensorimotor gating. Our results suggest that an impairment in NR1 phosphorylation leads to glutamatergic hypofunction that can contribute to behavioral deficits associated with psychiatric disorders. PMID:19776282

  1. Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5

    PubMed Central

    Hou, Hailong; Sun, Lu; Siddoway, Benjamin A.; Petralia, Ronald S.; Yang, Hongtian; Gu, Hua; Nairn, Angus C.

    2013-01-01

    The serine/threonine protein phosphatase protein phosphatase 1 (PP1) is known to play an important role in learning and memory by mediating local and downstream aspects of synaptic signaling, but how PP1 activity is controlled in different forms of synaptic plasticity remains unknown. We find that synaptic N-methyl-d-aspartate (NMDA) receptor stimulation in neurons leads to activation of PP1 through a mechanism involving inhibitory phosphorylation at Thr320 by Cdk5. Synaptic stimulation led to proteasome-dependent degradation of the Cdk5 regulator p35, inactivation of Cdk5, and increased auto-dephosphorylation of Thr320 of PP1. We also found that neither inhibitor-1 nor calcineurin were involved in the control of PP1 activity in response to synaptic NMDA receptor stimulation. Rather, the PP1 regulatory protein, inhibitor-2, formed a complex with PP1 that was controlled by synaptic stimulation. Finally, we found that inhibitor-2 was critical for the induction of long-term depression in primary neurons. Our work fills a major gap regarding the regulation of PP1 in synaptic plasticity. PMID:24189275

  2. Role of motor cortex NMDA receptors in learning-dependent synaptic plasticity of behaving mice.

    PubMed

    Hasan, Mazahir T; Hernández-González, Samuel; Dogbevia, Godwin; Treviño, Mario; Bertocchi, Ilaria; Gruart, Agnès; Delgado-García, José M

    2013-01-01

    The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, here we generate mice with deletion of the Grin1 gene, encoding the essential NMDA receptor subunit 1 (GluN1), specifically in the primary motor cortex. The loss of NMDA receptor function impairs primary motor cortex long-term potentiation in vivo. Importantly, it impairs the synaptic efficacy between the primary somatosensory and primary motor cortices and significantly reduces classically conditioned eyeblink responses. Furthermore, compared with wild-type littermates, mice lacking NMDA receptors in the [corrected] primary motor cortex show slower learning in Skinner-box tasks. Thus, primary motor cortex NMDA receptors are necessary for activity-dependent synaptic strengthening and associative learning.

  3. Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity.

    PubMed

    Goel, Anubhuti; Xu, Linda W; Snyder, Kevin P; Song, Lihua; Goenaga-Vazquez, Yamila; Megill, Andrea; Takamiya, Kogo; Huganir, Richard L; Lee, Hey-Kyoung

    2011-03-31

    Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca(2+)-permeable AMPA receptors (CP-AMPARs). However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1) subunit at the serine 845 (S845) site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants), which is a substrate of cAMP-dependent kinase (PKA), show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

  4. 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.

  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. Functional localization of neurotransmitter receptors and synaptic inputs to mature neurons of the medial superior olive.

    PubMed

    Couchman, Kiri; Grothe, Benedikt; Felmy, Felix

    2012-02-01

    Neurons of the medial superior olive (MSO) code for the azimuthal location of low-frequency sound sources via a binaural coincidence detection system operating on microsecond time scales. These neurons are morphologically simple and stereotyped, and anatomical studies have indicated a functional segregation of excitatory and inhibitory inputs between cellular compartments. It is thought that this morphological arrangement holds important implications for the computational task of these cells. To date, however, there has been no functional investigation into synaptic input sites or functional receptor distributions on mature neurons of the MSO. Here, functional neurotransmitter receptor maps for amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA), N-methyl-D-aspartate (NMDA), glycine (Gly), and ionotropic γ-aminobutyric acid (GABA(A)) receptors (Rs) were compared and complemented by their corresponding synaptic input map. We find in MSO neurons from postnatal day 20-35 gerbils that AMPARs and their excitatory inputs target the soma and dendrites. Functional GlyRs and their inhibitory inputs are predominantly refined to the somata, although a pool of functional GlyRs is present extrasynaptically on MSO dendrites. GABA(A)R responses are present throughout the cell but lack direct synaptic contact indicating an involvement in volume transmission. NMDARs are present both synaptically and extrasynaptically with an overall distribution similar to GlyRs. Interestingly, even at physiological temperatures these functional NMDARs can be potentiated by synaptically released Gly. The functional receptor and synaptic input maps produced here led to the identification of a cross talk between transmitter systems and raises the possibility that extrasynaptic receptors could be modulating leak conductances as a homeostatic mechanism.

  7. Dopamine and Norepinephrine Receptors Participate in Methylphenidate Enhancement of In Vivo Hippocampal Synaptic Plasticity

    PubMed Central

    Jenson, Daniel; Yang, Kechun; Acevedo-Rodriguez, Alexandra; Levine, Amber; Broussard, John I.; Tang, Jianrong; Dani, John A.

    2014-01-01

    Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and β-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors. PMID:25445492

  8. 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.

  9. LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery

    PubMed Central

    Brachet, Anna; Norwood, Stephanie; Brouwers, Jos F.; Palomer, Ernest; Helms, J. Bernd

    2015-01-01

    Neurotransmitter receptor trafficking during synaptic plasticity requires the concerted action of multiple signaling pathways and the protein transport machinery. However, little is known about the contribution of lipid metabolism during these processes. In this paper, we addressed the question of the role of cholesterol in synaptic changes during long-term potentiation (LTP). We found that N-methyl-d-aspartate–type glutamate receptor (NMDAR) activation during LTP induction leads to a rapid and sustained loss or redistribution of intracellular cholesterol in the neuron. A reduction in cholesterol, in turn, leads to the activation of Cdc42 and the mobilization of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptors (AMPARs) from Rab11-recycling endosomes into the synaptic membrane, leading to synaptic potentiation. This process is accompanied by an increase of NMDAR function and an enhancement of LTP. These results imply that cholesterol acts as a sensor of NMDAR activation and as a trigger of downstream signaling to engage small GTPase (guanosine triphosphatase) activation and AMPAR synaptic delivery during LTP. PMID:25753037

  10. 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

  11. 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

  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. Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics

    PubMed Central

    Rust, Marco B; Gurniak, Christine B; Renner, Marianne; Vara, Hugo; Morando, Laura; Görlich, Andreas; Sassoè-Pognetto, Marco; Banchaabouchi, Mumna Al; Giustetto, Maurizio; Triller, Antoine; Choquet, Daniel; Witke, Walter

    2010-01-01

    Neuronal plasticity is an important process for learning, memory and complex behaviour. Rapid remodelling of the actin cytoskeleton in the postsynaptic compartment is thought to have an important function for synaptic plasticity. However, the actin-binding proteins involved and the molecular mechanisms that in vivo link actin dynamics to postsynaptic physiology are not well understood. Here, we show that the actin filament depolymerizing protein n-cofilin is controlling dendritic spine morphology and postsynaptic parameters such as late long-term potentiation and long-term depression. Loss of n-cofilin-mediated synaptic actin dynamics in the forebrain specifically leads to impairment of all types of associative learning, whereas exploratory learning is not affected. We provide evidence for a novel function of n-cofilin function in synaptic plasticity and in the control of extrasynaptic excitatory AMPA receptors diffusion. These results suggest a critical function of actin dynamics in associative learning and postsynaptic receptor availability. PMID:20407421

  14. Modulation of neurotransmitter receptors and synaptic differentiation by proteins containing complement-related domains.

    PubMed

    Nakayama, Minoru; Hama, Chihiro

    2011-02-01

    Neurotransmitter receptors play central roles in basic neurotransmission and synaptic plasticity. Recent studies have revealed that some transmembrane and extracellular proteins bind to neurotransmitter receptors, forming protein complexes that are required for proper synaptic localization or gating of core receptor molecules. Consequently, the components of these complexes contribute to long-term potentiation, a process that is critical for learning and memory. Here, we review factors that regulate neurotransmitter receptors, with a focus on proteins containing CUB (complement C1r/C1s, Uegf, Bmp1) or CCP (complement control protein) domains, which are frequently found in complement system proteins. Proteins that contain these domains are structurally distinct from TARPs (transmembrane AMPA receptor regulatory proteins), and may constitute new protein families that modulate either the localization or function of neurotransmitter receptors. In addition, other CCP domain-containing proteins participate in dendritic patterning and/or synaptic differentiation, although current evidence has not identified any direct activities on neurotransmitter receptors. Some of these proteins are involved in pathologic conditions such as epileptic seizure and mental retardation. Together, these lines of information have shown that CUB and CCP domain-containing proteins contribute to a wide variety of neuronal events that ultimately establish neural circuits.

  15. Adenosine A2A receptors enable the synaptic effects of cannabinoid CB1 receptors in the rodent striatum.

    PubMed

    Tebano, Maria Teresa; Martire, Alberto; Chiodi, Valentina; Pepponi, Rita; Ferrante, Antonella; Domenici, Maria Rosaria; Frank, Claudio; Chen, Jiang-Fan; Ledent, Catherine; Popoli, Patrizia

    2009-09-01

    Adenosine A(2A), cannabinoid CB(1) and metabotropic glutamate 5 (mGlu(5)) receptors are all highly expressed in the striatum. The aim of the present work was to investigate whether, and by which mechanisms, the above receptors interact in the regulation of striatal synaptic transmission. By extracellular field potentials (FPs) recordings in corticostriatal slices, we demonstrated that the ability of the selective type 1 cannabinoid receptor (CB(1)R) agonist WIN55,212-2 to depress synaptic transmission was prevented by the pharmacological blockade or the genetic inactivation of A(2A)Rs. Such a permissive effect of A(2A)Rs towards CB(1)Rs does not seem to occur pre-synaptically as the ability of WIN55,212-2 to increase the R2/R1 ratio under a protocol of paired-pulse stimulation was not modified by ZM241385. Furthermore, the effects of WIN55,212-2 were reduced in slices from mice lacking post-synaptic striatal A(2A)Rs. The selective mGlu(5)R agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) potentiated the synaptic effects of WIN55,212-2, and such a potentiation was abolished by A(2A)R blockade. Unlike the synaptic effects, the ability of WIN55,212-2 to prevent NMDA-induced toxicity was not influenced by ZM241385. Altogether, these results show that the state of activation of A(2A)Rs regulates the synaptic effects of CB(1)Rs and that A(2A)Rs may control CB(1) effects also indirectly, namely through mGlu(5)Rs.

  16. Nicotinic receptors, amyloid-beta, and synaptic failure in Alzheimer's disease.

    PubMed

    Jürgensen, Sofia; Ferreira, Sergio T

    2010-01-01

    Dysfunctional cholinergic transmission is thought to underlie, at least in part, memory impairment and cognitive deficits in Alzheimer's disease (AD). However, it is still unclear whether this is a consequence of the loss of cholinergic neurons and elimination of nicotinic acetycholine receptors (nAChRs) in AD brain or of a direct impact of molecular interactions of the amyloid-beta (Abeta) peptide with nAChRs, leading to dysregulation of receptor function. This review examines recent progress in our understanding of the roles of nicotinic receptors in mechanisms of synaptic plasticity, molecular interactions of Abeta with nAChRs, and how Abeta-induced dysregulation of nicotinic receptor function may underlie synaptic failure in AD.

  17. Anesthetic action on extra-synaptic receptors: effects in neural population models of EEG activity

    PubMed Central

    Hashemi, Meysam; Hutt, Axel; Sleigh, Jamie

    2014-01-01

    The role of extra-synaptic receptors in the regulation of excitation and inhibition in the brain has attracted increasing attention. Because activity in the extra-synaptic receptors plays a role in regulating the level of excitation and inhibition in the brain, they may be important in determining the level of consciousness. This paper reviews briefly the literature on extra-synaptic GABA and NMDA receptors and their affinity to anesthetic drugs. We propose a neural population model that illustrates how the effect of the anesthetic drug propofol on GABAergic extra-synaptic receptors results in changes in neural population activity and the electroencephalogram (EEG). Our results show that increased tonic inhibition in inhibitory cortical neurons cause a dramatic increase in the power of both δ− and α− bands. Conversely, the effects of increased tonic inhibition in cortical excitatory neurons and thalamic relay neurons have the opposite effect and decrease the power in these bands. The increased δ-activity is in accord with observed data for deepening propofol anesthesia; but is absolutely dependent on the inclusion of extrasynaptic (tonic) GABA action in the model. PMID:25540612

  18. Regulation of muscarinic acetylcholine receptor-mediated synaptic responses by adenosine receptors in the rat hippocampus.

    PubMed Central

    Morton, R A; Davies, C H

    1997-01-01

    1. Intracellular current clamp recordings were made from CA1 pyramidal neurones in rat hippocampal slices. Experiments were performed in the presence of ionotropic glutamate receptor antagonists and gamma-aminobutyric acid (GABA) receptor antagonists to block all fast excitatory and inhibitory synaptic transmission. A single stimulus, delivered extracellularly in the stratum oriens, caused a reduction in spike frequency adaptation in response to a depolarizing current step delivered 2 s after the stimulus. A 2- to 10-fold increase in stimulus intensity evoked a slow excitatory postsynaptic potential (EPSP) which was associated with a small increase in input resistance. The peak amplitude of the EPSP occurred approximately 2.5 s after the stimulus and its magnitude (up to 30 mV) and duration (10-50 s) increased with increasing stimulus intensity. 2. The slow EPSP was unaffected by the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG; 1000 microM) but was greatly enhanced by the acetylcholinesterase inhibitor physostigmine (1-5 microM). Both the slow EPSP and the stimulus-evoked reduction in spike frequency adaptation were inhibited by the muscarinic acetylcholine receptor (mAChR) antagonist atropine (1-5 microM). These results are consistent with these effects being mediated by mAChRs. 3. Both the mAChR-mediated EPSP (EPSPm) and the associated reduction in spike frequency adaptation were reversibly depressed (up to 97%) by either adenosine (100 microM) or its non-hydrolysable analogue 2-chloroadenosine (CADO; 0.1-5.0 microM). These effects were often accompanied by postsynaptic hyperpolarization (up to 8 mV) and a reduction in input resistance (up to 11%). The selective adenosine A1 receptor agonists 2-chloro-N6-cyclopentyladenosine (CCPA; 0.1-0.4 microM) and R(-)N6-(2-phenylisopropyl)-adenosine (R-PIA; 1 microM) both depressed the EPSPm. In contrast, the adenosine A2A receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5

  19. 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.

  20. Synaptic and extrasynaptic NMDA receptors differentially modulate neuronal COX-2 function, lipid peroxidation, and neuroprotection

    PubMed Central

    Stark, David T.; Bazan, Nicolas G.

    2011-01-01

    Stimulation of synaptic NMDA receptors (NMDARs) induces neuroprotection, while extrasynaptic NMDARs promote excitotoxic cell death. Neuronal expression of cyclooxygenase-2 (COX-2) is enhanced by synaptic NMDARs, and although this enzyme mediates neuronal functions, COX-2 is also regarded as a key modulator of neuroinflammation and is thought to exacerbate excitotoxicity via overproduction of prostaglandins. This raises an apparent paradox: synaptic NMDARs are pro-survival yet are essential for robust neuronal COX-2 expression. We hypothesized that stimulation of extrasynaptic NMDARs converts COX-2 signaling from a physiological to a potentially pathological process. We combined HPLC-ESI-MS/MS-based mediator lipidomics and unbiased image analysis in mouse dissociated and organotypic cortical cultures to uncover that synaptic and extrasynaptic NMDARs differentially modulate neuronal COX-2 expression and activity. We show that synaptic NMDARs enhance neuronal COX-2 expression, while sustained synaptic stimulation limits COX-2 activity by suppressing cellular levels of the primary COX-2 substrate, arachidonic acid (AA). In contrast, extrasynaptic NMDARs suppress COX-2 expression while activating phospholipase A2 (PLA2), which enhances AA levels by hydrolysis of membrane phospholipids. Thus, sequential activation of synaptic then extrasynaptic NMDARs maximizes COX-2-dependent prostaglandin synthesis. We also show that excitotoxic events only drive induction of COX-2 expression through abnormal synaptic network excitability. Finally, we show that non-enzymatic lipid peroxidation of arachidonic and other polyunsaturated fatty acids is a function of network activity history. A new paradigm emerges from our results suggesting that pathological COX-2 signaling associated with models of stroke, epilepsy, and neurodegeneration requires specific spatio-temporal NMDAR stimulation. PMID:21957234

  1. Pre-synaptic GABA receptors inhibit glutamate release through GIRK channels in rat cerebral cortex.

    PubMed

    Ladera, Carolina; del Carmen Godino, María; José Cabañero, María; Torres, Magdalena; Watanabe, Masahiko; Luján, Rafael; Sánchez-Prieto, José

    2008-12-01

    Neuronal G protein-gated inwardly rectifying potassium (GIRK) channels mediate the slow inhibitory effects of many neurotransmitters post-synaptically. However, no evidence exists that supports that GIRK channels play any role in the inhibition of glutamate release by GABA(B) receptors. In this study, we show for the first time that GABA(B) receptors operate through two mechanisms in nerve terminals from the cerebral cortex. As shown previously, GABA(B) receptors reduces glutamate release and the Ca(2+) influx mediated by N-type Ca(2+) channels in a mode insensitive to the GIRK channel blocker tertiapin-Q and consistent with direct inhibition of this voltage-gated Ca(2+) channel. However, by means of weak stimulation protocols, we reveal that GABA(B) receptors also reduce glutamate release mediated by P/Q-type Ca(2+) channels, and that these responses are reversed by the GIRK channel blocker tertiapin-Q. Consistent with the functional interaction between GABA(B) receptors and GIRK channels at nerve terminals we demonstrate by immunogold electron immunohistochemistry that pre-synaptic boutons of asymmetric synapses co-express GABA(B) receptors and GIRK channels, thus suggesting that the functional interaction of these two proteins, found at the post-synaptic level, also occurs at glutamatergic nerve terminals.

  2. Mathematical modelling of non-stationary fluctuation analysis for studying channel properties of synaptic AMPA receptors.

    PubMed

    Benke, T A; Lüthi, A; Palmer, M J; Wikström, M A; Anderson, W W; Isaac, J T; Collingridge, G L

    2001-12-01

    1. The molecular properties of synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are an important factor determining excitatory synaptic transmission in the brain. Changes in the number (N) or single-channel conductance (gamma) of functional AMPA receptors may underlie synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). These parameters have been estimated using non-stationary fluctuation analysis (NSFA). 2. The validity of NSFA for studying the channel properties of synaptic AMPA receptors was assessed using a cable model with dendritic spines and a microscopic kinetic description of AMPA receptors. Electrotonic, geometric and kinetic parameters were altered in order to determine their effects on estimates of the underlying gamma. 3. Estimates of gamma were very sensitive to the access resistance of the recording (R(A)) and the mean open time of AMPA channels. Estimates of gamma were less sensitive to the distance between the electrode and the synaptic site, the electrotonic properties of dendritic structures, recording electrode capacitance and background noise. Estimates of gamma were insensitive to changes in spine morphology, synaptic glutamate concentration and the peak open probability (P(o)) of AMPA receptors. 4. The results obtained using the model agree with biological data, obtained from 91 dendritic recordings from rat CA1 pyramidal cells. A correlation analysis showed that R(A) resulted in a slowing of the decay time constant of excitatory postsynaptic currents (EPSCs) by approximately 150 %, from an estimated value of 3.1 ms. R(A) also greatly attenuated the absolute estimate of gamma by approximately 50-70 %. 5. When other parameters remain constant, the model demonstrates that NSFA of dendritic recordings can readily discriminate between changes in gamma vs. changes in N or P(o). Neither background noise nor asynchronous activation of multiple synapses prevented reliable

  3. 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

  4. miRNAs in NMDA receptor-dependent synaptic plasticity and psychiatric disorders

    PubMed Central

    Shen, Hongmei; Li, Zheng

    2017-01-01

    The identification and functional delineation of miRNAs (a class of small non-coding RNAs) have added a new layer of complexity to our understanding of the molecular mechanisms underlying synaptic plasticity. Genome-wide association studies in conjunction with investigations in cellular and animal models, moreover, provide evidence that miRNAs are involved in psychiatric disorders. In the present review, we examine the current knowledge about the roles played by miRNAs in NMDA (N-methyl-d-aspartate) receptor-dependent synaptic plasticity and psychiatric disorders. PMID:27252401

  5. Wnt signaling regulates acetylcholine receptor translocation and synaptic plasticity in the adult nervous system.

    PubMed

    Jensen, Michael; Hoerndli, Frédéric J; Brockie, Penelope J; Wang, Rui; Johnson, Erica; Maxfield, Dane; Francis, Michael M; Madsen, David M; Maricq, Andres V

    2012-03-30

    The adult nervous system is plastic, allowing us to learn, remember, and forget. Experience-dependent plasticity occurs at synapses--the specialized points of contact between neurons where signaling occurs. However, the mechanisms that regulate the strength of synaptic signaling are not well understood. Here, we define a Wnt-signaling pathway that modifies synaptic strength in the adult nervous system by regulating the translocation of one class of acetylcholine receptors (AChRs) to synapses. In Caenorhabditis elegans, we show that mutations in CWN-2 (Wnt ligand), LIN-17 (Frizzled), CAM-1 (Ror receptor tyrosine kinase), or the downstream effector DSH-1 (disheveled) result in similar subsynaptic accumulations of ACR-16/α7 AChRs, a consequent reduction in synaptic current, and predictable behavioral defects. Photoconversion experiments revealed defective translocation of ACR-16/α7 to synapses in Wnt-signaling mutants. Using optogenetic nerve stimulation, we demonstrate activity-dependent synaptic plasticity and its dependence on ACR-16/α7 translocation mediated by Wnt signaling via LIN-17/CAM-1 heteromeric receptors. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity

    PubMed Central

    Costello, Derek A.; Claret, Marc; Al-Qassab, Hind; Plattner, Florian; Irvine, Elaine E.; Choudhury, Agharul I.; Giese, K. Peter; Withers, Dominic J.; Pedarzani, Paola

    2012-01-01

    Objective Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits and the corresponding neurophysiological structural and functional alterations are linked to both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. To elucidate the specific role of brain insulin signalling in neuronal functions that are relevant for cognitive processes we have investigated the behaviour of neurons and synaptic plasticity in the hippocampus of mice lacking the insulin receptor substrate protein 2 (IRS-2). Research Design and Methods To study neuronal function and synaptic plasticity in the absence of confounding factors such as hyperglycaemia, we used a mouse model with a central nervous system- (CNS)-restricted deletion of IRS-2 (NesCreIrs2KO). Results We report a deficit in NMDA receptor-dependent synaptic plasticity in the hippocampus of NesCreIrs2KO mice, with a concomitant loss of metaplasticity, the modulation of synaptic plasticity by the previous activity of a synapse. These plasticity changes are associated with reduced basal phosphorylation of the NMDA receptor subunit NR1 and of downstream targets of the PI3K pathway, the protein kinases Akt and GSK-3β. Conclusions These findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to specific defects of neuronal insulin signalling. PMID:22383997

  7. TARP gamma-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity.

    PubMed

    Rouach, Nathalie; Byrd, Keith; Petralia, Ronald S; Elias, Guillermo M; Adesnik, Hillel; Tomita, Susumu; Karimzadegan, Siavash; Kealey, Colin; Bredt, David S; Nicoll, Roger A

    2005-11-01

    Synaptic plasticity involves activity-dependent trafficking of AMPA-type glutamate receptors. Numerous cytoplasmic scaffolding proteins are postulated to control AMPA receptor trafficking, but the detailed mechanisms remain unclear. Here, we show that the transmembrane AMPA receptor regulatory protein (TARP) gamma-8, which is preferentially expressed in the mouse hippocampus, is important for AMPA receptor protein levels and extrasynaptic surface expression. By controlling the number of AMPA receptors, gamma-8 is also important in long-term potentiation, but not long-term depression. This study establishes gamma-8 as a critical protein for basal AMPA receptor expression and localization at extrasynaptic sites in the hippocampus and raises the possibility that TARP-dependent control of AMPA receptors during synapse development and plasticity may be widespread.

  8. Presynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity

    PubMed Central

    Corlew, Rebekah; Brasier, Daniel J.; Feldman, Daniel E.; Philpot, Benjamin D.

    2009-01-01

    Many aspects of synaptic development, plasticity, and neurotransmission are critically influenced by NMDA-type glutamate receptors (NMDARs). Moreover, dysfunction of NMDARs has been implicated in a broad array of neurological disorders, including schizophrenia, stroke, epilepsy, and neuropathic pain. Classically, NMDARs were thought to be exclusively postsynaptic. However, substantial evidence in the last 10 years demonstrates that NMDARs also exist presynaptically, and that presynaptic NMDA receptors (preNMDARs) modulate synapse function and have critical roles in plasticity at many synapses. Here we review current knowledge of the role of preNMDARs in synaptic transmission and plasticity, focusing on the neocortex. We discuss the prevalence, function, and development of these receptors, and their potential modification by experience and in brain pathology. PMID:19029059

  9. Chronic intermittent ethanol exposure enhances NMDA-receptor-mediated synaptic responses and NMDA receptor expression in hippocampal CA1 region.

    PubMed

    Nelson, T E; Ur, C L; Gruol, D L

    2005-06-28

    In previous studies, we found that chronic intermittent ethanol (CIE) treatment-a model of ethanol consumption in which animals are exposed to and withdrawn from intoxicating levels of ethanol on a daily basis-produces neuroadaptive changes in hippocampal area CA1 excitatory synaptic transmission and plasticity. Synaptic responses mediated by N-methyl-D-aspartate (NMDA) receptors are known to be sensitive to ethanol and could play an important role in the neuroadaptive changes induced by CIE treatment. To address this issue, we compared electrophysiological recordings of pharmacologically isolated NMDA-receptor-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 region of hippocampal slices prepared from control rats and rats exposed to 2 weeks of CIE treatment administered by vapor inhalation. We found that fEPSPs induced by NMDA receptor activation were unaltered in slices prepared shortly after cessation of CIE treatment (i.e., < or = 1 day of withdrawal from CIE). However, following 7 days of withdrawal from CIE treatment, NMDA-receptor-mediated fEPSPs were augmented relative to age-matched controls. Western blot analysis of NMDA receptor subunit expression showed that, at 7 days of withdrawal, the level of protein for NR2A and NR2B subunits was elevated in the CA1 region of hippocampal slices from CIE-treated animals compared with slices from age-matched controls. These results are consistent with an involvement of NMDA-receptor-mediated synaptic responses in the neuroadaptive effects of CIE on hippocampal physiology and suggest that such changes may contribute to ethanol-induced changes in processes dependent on NMDA-receptor-mediated synaptic responses such as learning and memory, neural development, hyperexcitability and seizures, and neurotoxicity.

  10. Modulation of synaptic input by GABAB receptors improves coincidence detection for computation of sound location

    PubMed Central

    Fischl, Matthew J; Combs, T Dalton; Klug, Achim; Grothe, Benedikt; Burger, R Michael

    2012-01-01

    Interaural time disparities (ITDs) are the primary cues for localisation of low-frequency sound stimuli. ITDs are computed by coincidence-detecting neurones in the medial superior olive (MSO) in mammals. Several previous studies suggest that control of synaptic gain is essential for maintaining ITD selectivity as stimulus intensity increases. Using acute brain slices from postnatal day 7 to 24 (P7–P24) Mongolian gerbils, we confirm that activation of GABAB receptors reduces the amplitude of excitatory and inhibitory synaptic currents to the MSO and, moreover, show that the decay kinetics of IPSCs are slowed in mature animals. During repetitive stimuli, activation of GABAB receptors reduced the amount of depression observed, while PSC suppression and the slowed kinetics were maintained. Additionally, we used physiological and modelling approaches to test the potential impact of GABAB activation on ITD encoding in MSO neurones. Current clamp recordings from MSO neurones were made while pharmacologically isolated excitatory inputs were bilaterally stimulated using pulse trains that simulate ITDs in vitro. MSO neurones showed strong selectivity for bilateral delays. Application of both GABAB agonists and antagonists demonstrate that GABAB modulation of synaptic input can sharpen ITD selectivity. We confirmed and extended these results in a computational model that allowed for independent manipulation of each GABAB-dependent effect. Modelling suggests that modulation of both amplitude and kinetics of synaptic inputs by GABAB receptors can improve precision of ITD computation. Our studies suggest that in vivo modulation of synaptic input by GABAB receptors may act to preserve ITD selectivity across various stimulus conditions. PMID:22473782

  11. The AAA+ ATPase, Thorase Regulates AMPA Receptor-Dependent Synaptic Plasticity and Behavior

    PubMed Central

    Zhang, Jianmin; Wang, Yue; Chi, Zhikai; Keuss, Matthew J.; Pai, Ying-Min Emily; Kang, Ho Chul; Shin, Jooho; Bugayenko, Artem; Wang, Hong; Xiong, Yulan; Pletnikov, Mikhail V.; Mattson, Mark P.; Dawson, Ted M.; Dawson, Valina L.

    2011-01-01

    SUMMARY The synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the regulation of synaptic activity reflected in the expression of long-term potentiation (LTP) and long-term depression (LTD). The cellular events underlying this important process in learning and memory are still being revealed. Here we describe and characterize the AAA+ ATPase, Thorase, that regulates the expression of surface AMPAR. In an ATPase-dependent manner Thorase mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex. Following genetic deletion of Thorase, the internalization of AMPAR is substantially reduced, leading to increased amplitudes of miniature excitatory postsynaptic currents, enhancement of LTP and elimination of LTD. These molecular events are expressed as deficits in learning and memory in Thorase null mice. This study identifies an AAA+ ATPase that plays a critical role in regulating the surface expression of AMPAR and thereby regulates synaptic plasticity and learning and memory. PMID:21496646

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

    PubMed

    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.

  13. 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

  14. Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors

    PubMed Central

    Mortensen, Martin; Ebert, Bjarke; Wafford, Keith; Smart, Trevor G

    2010-01-01

    The activation characteristics of synaptic and extrasynaptic GABAA receptors are important for shaping the profile of phasic and tonic inhibition in the central nervous system, which will critically impact on the activity of neuronal networks. Here, we study in isolation the activity of three agonists, GABA, muscimol and 4,5,6,7-tetrahydoisoxazolo[5,4-c]pyridin-3(2H)-one (THIP), to further understand the activation profiles of α1β3γ2, α4β3γ2 and α4β3δ receptors that typify synaptic- and extrasynaptic-type receptors expressed in the hippocampus and thalamus. The agonists display an order of potency that is invariant between the three receptors, which is reliant mostly on the agonist dissociation constant. At δ subunit-containing extrasynaptic-type GABAA receptors, both THIP and muscimol additionally exhibited, to different degrees, superagonist behaviour. By comparing whole-cell and single channel currents induced by the agonists, we provide a molecular explanation for their different activation profiles. For THIP at high concentrations, the unusual superagonist behaviour on α4β3δ receptors is a consequence of its ability to increase the duration of longer channel openings and their frequency, resulting in longer burst durations. By contrast, for muscimol, moderate superagonist behaviour was caused by reduced desensitisation of the extrasynaptic-type receptors. The ability to specifically increase the efficacy of receptor activation, by selected exogenous agonists over that obtained with the natural transmitter, may prove to be of therapeutic benefit under circumstances when synaptic inhibition is compromised or dysfunctional. PMID:20176630

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

    PubMed Central

    2011-01-01

    Background Dendritic spines represent the postsynaptic component of the vast majority of excitatory synapses present in the mammalian forebrain. The ability of spines to rapidly alter their shape, size, number and receptor content in response to stimulation is considered to be of paramount importance during the development of synaptic plasticity. Indeed, long-term potentiation (LTP), widely believed to be a cellular correlate of learning and memory, has been repeatedly shown to induce both spine enlargement and the formation of new dendritic spines. In our studies, we focus on Kalirin-7 (Kal7), a Rho GDP/GTP exchange factor (Rho-GEF) localized to the postsynaptic density that plays a crucial role in the development and maintenance of dendritic spines both in vitro and in vivo. Previous studies have shown that mice lacking Kal7 (Kal7KO) have decreased dendritic spine density in the hippocampus as well as focal hippocampal-dependent learning impairments. Results We have performed a detailed electrophysiological characterization of the role of Kal7 in hippocampal synaptic plasticity. We show that loss of Kal7 results in impaired NMDA receptor-dependent LTP and long-term depression, whereas a NMDA receptor-independent form of LTP is shown to be normal in the absence of Kal7. Conclusions These results indicate that Kal7 is an essential and selective modulator of NMDA receptor-dependent synaptic plasticity in the hippocampus. PMID:22182308

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

    PubMed Central

    Henley, Jeremy M.; Wilkinson, Kevin A.

    2013-01-01

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

  17. Structural Basis for Integration of GluD Receptors within Synaptic Organizer Complexes

    PubMed Central

    Elegheert, Jonathan; Kakegawa, Wataru; Clay, Jordan E.; Shanks, Natalie F.; Behiels, Ester; Matsuda, Keiko; Kohda, Kazuhisa; Miura, Eriko; Rossmann, Maxim; Mitakidis, Nikolaos; Motohashi, Junko; Chang, Veronica T.; Siebold, Christian; Greger, Ingo H.; Nakagawa, Terunaga; Yuzaki, Michisuke; Aricescu, A. Radu

    2017-01-01

    Ionotropic glutamate receptor family members (iGluRs) are integrated into supramolecular complexes that modulate their location and function at excitatory synapses. However, a lack of structural information beyond isolated receptors or fragments thereof currently limits the mechanistic understanding of physiological iGluR signaling. Here, we report structural and functional analyses of the prototypical molecular bridge linking post-synaptic iGluR δ2 (GluD2) and pre-synaptic β-neurexin-1 (β-NRX1) via Cbln1, a C1q-like synaptic organizer. We show how Cbln1 hexamers “anchor” GluD2 amino-terminal domain dimers to monomeric β-NRX1. This arrangement promotes synaptogenesis, and is essential for D-Serine-dependent GluD2 signaling in vivo, underlying long-term depression of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses and motor coordination in developing mice. These results lead to a model where protein and small-molecule ligands synergistically control synaptic iGluR function. PMID:27418511

  18. Synaptic plasticity through activation of GluA3-containing AMPA-receptors

    PubMed Central

    Gutierrez-Castellanos, Nicolas; Reinders, Niels R; van Huijstee, Aile N; Xiong, Hui; Lodder, Tessa R

    2017-01-01

    Excitatory synaptic transmission is mediated by AMPA-type glutamate receptors (AMPARs). In CA1 pyramidal neurons of the hippocampus two types of AMPARs predominate: those that contain subunits GluA1 and GluA2 (GluA1/2), and those that contain GluA2 and GluA3 (GluA2/3). Whereas subunits GluA1 and GluA2 have been extensively studied, the contribution of GluA3 to synapse physiology has remained unclear. Here we show in mice that GluA2/3s are in a low-conductance state under basal conditions, and although present at synapses they contribute little to synaptic currents. When intracellular cyclic AMP (cAMP) levels rise, GluA2/3 channels shift to a high-conductance state, leading to synaptic potentiation. This cAMP-driven synaptic potentiation requires the activation of both protein kinase A (PKA) and the GTPase Ras, and is induced upon the activation of β-adrenergic receptors. Together, these experiments reveal a novel type of plasticity at CA1 hippocampal synapses that is expressed by the activation of GluA3-containing AMPARs. PMID:28762944

  19. 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.

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

    PubMed

    Henley, Jeremy M; Wilkinson, Kevin A

    2013-03-01

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

  1. Activation of 5-hyrdoxytryptamine 7 receptors within the rat nucleus tractus solitarii modulates synaptic properties

    PubMed Central

    Matott, Michael P.; Kline, David D.

    2016-01-01

    Serotonin (5-HT) is a potent neuromodulator with multiple receptor types within the cardiorespiratory system, including the nucleus tractus solitarii (nTS) - the central termination site of visceral afferent fibers. The 5-HT7 receptor facilitates cardiorespiratory reflexes through its action in the brainstem and likely in the nTS. However, the mechanism and site of action for these effects is not clear. In this study, we examined the expression and function of 5-HT7 receptors in the nTS of Sprague-Dawley rats. 5-HT7 receptor mRNA and protein were identified across the rostrocaudal extent of the nTS. To determine 5-HT7 receptor function, we examined nTS synaptic properties following 5-HT7 receptor activation in monosynaptic nTS neurons in the in vitro brainstem slice preparation. Application of 5-HT7 receptor agonists altered tractus solitarii evoked and spontaneous excitatory postsynaptic currents which were attenuated with a selective 5-HT7 receptor antagonist. 5-HT7 receptor-mediated changes in excitatory postsynaptic currents were also altered by block of 5-HT1A and GABAA receptors. Interestingly, 5-HT7 receptor activation also reduced the amplitude but not frequency of GABAA-mediated inhibitory currents. Together these results indicate a complex role for 5-HT7 receptors in the nTS that mediate its diverse effects on cardiorespiratory parameters. PMID:26779891

  2. 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

  3. Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission.

    PubMed

    Fukata, Yuko; Adesnik, Hillel; Iwanaga, Tsuyoshi; Bredt, David S; Nicoll, Roger A; Fukata, Masaki

    2006-09-22

    Abnormally synchronized synaptic transmission in the brain causes epilepsy. Most inherited forms of epilepsy result from mutations in ion channels. However, one form of epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF), is characterized by mutations in a secreted neuronal protein, LGI1. We show that ADAM22, a transmembrane protein that when mutated itself causes seizure, serves as a receptor for LGI1. LGI1 enhances AMPA receptor-mediated synaptic transmission in hippocampal slices. The mutated form of LGI1 fails to bind to ADAM22. ADAM22 is anchored to the postsynaptic density by cytoskeletal scaffolds containing stargazin. These studies in rat brain indicate possible avenues for understanding human epilepsy.

  4. Dopamine D1 Receptors Regulate the Light Dependent Development of Retinal Synaptic Responses

    PubMed Central

    He, Quanhua; Xu, Hong-ping; Wang, Ping; Tian, Ning

    2013-01-01

    Retinal synaptic connections and function are developmentally regulated. Retinal synaptic activity plays critical roles in the development of retinal synaptic circuitry. Dopamine receptors have been thought to play important roles in the activity-dependent synaptic plasticity in central nervous system. The primary goal of this study is to determine whether dopamine D1 receptor regulates the activity-dependent development of retinal light responsiveness. Accordingly, we recorded electroretinogram from wild type mice and mice with genetic deletion of D1 dopamine receptor (D1−/− mice) raised under cyclic light conditions and constant darkness. Our results demonstrated that D1−/− mice have reduced amplitudes of all three major components of electroretinogram in adulthood. When the relative strength of the responses is considered, the D1−/− mice have selective reduction of the amplitudes of a-wave and oscillatory potentials evoked by low-intermediate intensities of lights. During postnatal development, D1−/− mice have increased amplitude of b-wave at the time of eye-opening but reduced developmental increase of the amplitude of b-wave after eye opening. Light deprivation from birth significantly reduced the amplitudes of b-wave and oscillatory potentials, increased the outer retinal light response gain and altered the light response kinetics of both a- and b-waves of wild type mice. In D1−/− mice, the effect of dark rearing on the amplitude of oscillatory potentials was diminished and dark rearing induced effects on the response gain of outer retina and the kinetics of a-wave were reversed. These results demonstrated roles of dopamine D1 receptor in the activity-dependent functional development of mouse retina. PMID:24260267

  5. Antagonism of Muscarinic Acetylcholine Receptors Alters Synaptic ERK Phosphorylation in the Rat Forebrain.

    PubMed

    Mao, Li-Min; Wang, Henry H; Wang, John Q

    2016-12-28

    Acetylcholine (ACh) is a key transmitter in the mesocorticolimbic circuit. By interacting with muscarinic ACh receptors (mAChR) enriched in the circuit, ACh actively regulates various neuronal and synaptic activities. The extracellular signal-regulated kinase (ERK) is one of members of the mitogen-activated protein kinase family and is subject to the regulation by dopamine receptors, although the regulation of ERKs by limbic mAChRs is poorly understood. In this study, we investigated the role of mAChRs in the regulation of ERK phosphorylation (activation) in the mesocorticolimbic system of adult rat brains in vivo. We targeted a sub-pool of ERKs at synaptic sites. We found that a systemic injection of the mAChR antagonist scopolamine increased phosphorylation of synaptic ERKs in the striatum (caudate putamen and nucleus accumbens) and medial prefrontal cortex (mPFC). Increases in ERK phosphorylation in both forebrain regions were rapid and transient. Notably, pretreatment with a dopamine D1 receptor (D1R) antagonist SCH23390 blocked the scopolamine-stimulated ERK phosphorylation in these brain regions, while a dopamine D2 receptor antagonist eticlopride did not. Scopolamine and SCH23390 did not change the amount of total ERK proteins. These results demonstrate that mAChRs inhibit synaptic ERK phosphorylation in striatal and mPFC neurons under normal conditions. Blockade of this inhibitory mAChR tone leads to the upregulation of ERK phosphorylation likely through a mechanism involving the level of D1R activity.

  6. Glutamate NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure

    PubMed Central

    Li, Nanxin; Liu, Rong-Jian; Dwyer, Jason M.; Banasr, Mounira; Lee, Boyoung; Son, Hyeon; Li, Xiao-Yuan; Aghajanian, George; Duman, Ronald S.

    2011-01-01

    Background Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants, or the molecular mechanisms that could account for the rapid responses. Methods We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex (PFC) neurons. Results The results demonstrate that acute treatment with the non-competitive NMDA channel blocker ketamine or the selective NR2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonia and anxiogenic behaviors. We also find that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (EPSCs) in layer V pyramidal neurons in the PFC, and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin (mTOR) protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. Conclusions The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in an mTOR-dependent manner. PMID:21292242

  7. Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity.

    PubMed

    Almonte, Antoine G; Qadri, Laura H; Sultan, Faraz A; Watson, Jennifer A; Mount, Daniel J; Rumbaugh, Gavin; Sweatt, J David

    2013-01-01

    Protease-activated receptor-1 (PAR1) is an unusual G-protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. Although previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1's contribution to normal brain function. Here, we used PAR1-/- mice to investigate the contribution of PAR1 function to memory formation and synaptic function. We demonstrate that PAR1-/- mice have deficits in hippocampus-dependent memory. We also show that while PAR1-/- mice have normal baseline synaptic transmission at Schaffer collateral-CA1 synapses, they exhibit severe deficits in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). Mounting evidence indicates that activation of PAR1 leads to potentiation of NMDAR-mediated responses in CA1 pyramidal cells. Taken together, this evidence and our data suggest an important role for PAR1 function in NMDAR-dependent processes subserving memory formation and synaptic plasticity.

  8. Adenosine A1 receptors presynaptically modulate excitatory synaptic input onto subiculum neurons

    PubMed Central

    Hargus, Nicholas J.; Bertram, Edward H.; Patel, Manoj K.

    2009-01-01

    Adenosine is an endogenous neuromodulator previously shown to suppress synaptic transmission and membrane excitability in the CNS. In this study we have determined the actions of adenosine on excitatory synaptic transmission in the subiculum, the main output area for the hippocampus. Adenosine (10 μM) reversibly inhibited excitatory post synaptic currents (EPSCs) recorded from subiculum neurons. These actions were mimicked by the A1 receptor specific agonist, N6-cyclopentyl-adenosine (CPA, 10 nM) and blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 500 nM), but were unaffected by the A2A antagonist ZM 241385 (50 nM). In membrane excitability experiments, bath application of adenosine and CPA reversibly inhibited action potentials (AP) in subiculum neurons that were evoked by stimulation of the pyramidal cell layer of the CA1, but not by depolarizing current injection steps in subiculum neurons, suggesting a presynaptic mechanism of action. In support, adenosine and CPA application reduced mEPSC frequency without modulating mEPSC amplitude. These studies suggest that modulation of subiculum neuron excitability by adenosine is mediated via presynaptic A1 receptors. PMID:19450566

  9. Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity

    PubMed Central

    Almonte, Antoine G.; Qadri, Laura H.; Sultan, Faraz A.; Watson, Jennifer A.; Mount, Daniel J.; Rumbaugh, Gavin; Sweatt, J. David

    2012-01-01

    Protease-activated receptor-1 (PAR1) is an unusual G-protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. While previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1’s contribution to normal brain function. Here we used PAR1 −/− mice to investigate the contribution of PAR1 function to memory formation and synaptic function. We demonstrate that PAR1 −/− mice have deficits in hippocampus-dependent memory. We also show that while PAR1 −/− mice have normal baseline synaptic transmission at Schaffer collateral-CA1 synapses, they exhibit severe deficits in N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). Mounting evidence indicates that activation of PAR1 leads to potentiation of NMDAR-mediated responses in CA1 pyramidal cells. Taken together, this evidence and our data suggest an important role for PAR1 function in NMDAR-dependent processes subserving memory formation and synaptic plasticity. PMID:23113835

  10. Neurosteroid interactions with synaptic and extrasynaptic GABAa receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

    PubMed Central

    Chase Matthew, Carver; Doodipala Samba, Reddy

    2013-01-01

    Rationale Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are three widely explored prototype endogenous neurosteroids. They have very different targets and functions compared to conventional steroid hormones. Neuronal GABAa receptors are one of the prime molecular targets of neurosteroids. Objective This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABAa receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABAa receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABAa receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity γ2-containing synaptic receptors, while high-affinity δ-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABAa receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior. Conclusion The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABAa receptors provide many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions. PMID:24071826

  11. Synaptic localization of. kappa. opioid receptors in guinea pig neostriatum

    SciTech Connect

    Jomary, C.; Beaudet, A. ); Gairin, J.E. )

    1992-01-15

    Distribution of {kappa} opioid receptors was examined by EM radioautography in sections of guinea pig neostriatum with the selective {sup 125}I-labeled dynorphin analog (D-Pro{sup 10})dynorphin-(1-11). Most specifically labeled binding sites were found by probability circle analysis to be associated with neuronal membrane appositions. Because of limitations in resolution of the method, the radioactive sources could not be ascribed directly to either one of the apposed plasma membranes. Nevertheless, three lines of evidence favored a predominant association of ligand with dendrites of intrinsic striatal neurons: (1) the high frequency with which labeled interfaces implicated a dendrite, (2) the enrichment of dendrodendritic interfaces, and (3) the occurrence of dendritic profiles labeled at several contact points along their plasma membranes. A small proportion of labeled sites was associated with axo-axonic interfaces, which may subserve the {kappa} opioid-induced regulation of presynaptic dopamine and acetylcholine release documented in guinea pig neostriatum. These results support the hypothesis that in mammalian brain {kappa} opioid receptors are conformationally and functionally distinct from {mu} and {delta} types.

  12. Pre-synaptic adenosine A2A receptors control cannabinoid CB1 receptor-mediated inhibition of striatal glutamatergic neurotransmission.

    PubMed

    Martire, Alberto; Tebano, Maria Teresa; Chiodi, Valentina; Ferreira, Samira G; Cunha, Rodrigo A; Köfalvi, Attila; Popoli, Patrizia

    2011-01-01

    An interaction between adenosine A(2A) receptors (A(2A) Rs) and cannabinoid CB(1) receptors (CB(1) Rs) has been consistently reported to occur in the striatum, although the precise mechanisms are not completely understood. As both receptors control striatal glutamatergic transmission, we now probed the putative interaction between pre-synaptic CB(1) R and A(2A) R in the striatum. In extracellular field potentials recordings in corticostriatal slices from Wistar rats, A(2A) R activation by CGS21680 inhibited CB(1) R-mediated effects (depression of synaptic response and increase in paired-pulse facilitation). Moreover, in superfused rat striatal nerve terminals, A(2A) R activation prevented, while A(2A) R inhibition facilitated, the CB(1) R-mediated inhibition of 4-aminopyridine-evoked glutamate release. In summary, the present study provides converging neurochemical and electrophysiological support for the occurrence of a tight control of CB(1) R function by A(2A) Rs in glutamatergic terminals of the striatum. In view of the key role of glutamate to trigger the recruitment of striatal circuits, this pre-synaptic interaction between CB(1) R and A(2A) R may be of relevance for the pathogenesis and the treatment of neuropsychiatric disorders affecting the basal ganglia.

  13. NMDA receptor-mediated excitotoxicity depends on the coactivation of synaptic and extrasynaptic receptors.

    PubMed

    Zhou, X; Hollern, D; Liao, J; Andrechek, E; Wang, H

    2013-03-28

    N-methyl-D-aspartate receptors (NMDAR) overactivation is linked to neurodegeneration. The current prevailing theory suggests that synaptic and extrasynaptic NMDAR (syn- and ex-NMDAR) impose counteracting effects on cell fate, and neuronal cell death is mainly mediated by the activation of ex-NMDAR. However, several lines of evidence implicate the limitation of this theory. Here, we demonstrate that activation of NMDAR bi-directionally regulated cell fate through stimulating pro-survival or pro-death signaling. While low-dose NMDA preferentially activated syn-NMDAR and stimulated the extracellular signal-regulated kinase ½-cAMP responsive element-binding protein-brain-derived neurotrophic factor pro-survival signaling, higher doses progressively activated increasing amount of ex-NMDAR along with syn-NMDAR and triggered cell death program. Interestingly, the activation of syn- or ex-NMDAR alone did not cause measurable cell death. Consistently, activation of syn- or ex-NMDAR alone stimulated pro-survival but not pro-death signaling. Next, we found that memantine, which was previously identified as an ex-NMDAR blocker, inhibited intracellular signaling mediated by syn- or ex-NMDAR. Simultaneous blockade of syn- and ex-NMDAR by memantine dose-dependently attenuated NMDAR-mediated death. Moreover, long- but not short-term treatment with high-dose NMDA or oxygen-glucose deprivation triggered cell death and suppressed pro-survival signaling. These data implicate that activation of syn- or ex-NMDAR alone is not neurotoxic. The degree of excitotoxicity depends on the magnitude and duration of syn- and ex-NMDAR coactivation. Finally, genome-wide examination demonstrated that the activation of syn- and ex-NMDAR lead to significant overlapping rather than counteracting transcriptional responses.

  14. Neurotrophin receptor p75(NTR) mediates Huntington's disease-associated synaptic and memory dysfunction.

    PubMed

    Brito, Verónica; Giralt, Albert; Enriquez-Barreto, Lilian; Puigdellívol, Mar; Suelves, Nuria; Zamora-Moratalla, Alfonsa; Ballesteros, Jesús J; Martín, Eduardo D; Dominguez-Iturza, Nuria; Morales, Miguel; Alberch, Jordi; Ginés, Sílvia

    2014-10-01

    Learning and memory deficits are early clinical manifestations of Huntington's disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75(NTR) negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75(NTR) function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75(NTR) are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75(NTR) levels in HD mutant mice heterozygous for p75(NTR) prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75(NTR) in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75(NTR) in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75(NTR) mediates synaptic, learning, and memory dysfunction in HD.

  15. Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

    PubMed Central

    Brito, Verónica; Giralt, Albert; Enriquez-Barreto, Lilian; Puigdellívol, Mar; Suelves, Nuria; Zamora-Moratalla, Alfonsa; Ballesteros, Jesús J.; Martín, Eduardo D.; Dominguez-Iturza, Nuria; Morales, Miguel; Alberch, Jordi; Ginés, Sílvia

    2014-01-01

    Learning and memory deficits are early clinical manifestations of Huntington’s disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75NTR negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75NTR function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75NTR are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75NTR levels in HD mutant mice heterozygous for p75NTR prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75NTR in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75NTR in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75NTR mediates synaptic, learning, and memory dysfunction in HD. PMID:25180603

  16. Differential regulation of synaptic inputs to dentate hilar border interneurons by metabotropic glutamate receptors.

    PubMed

    Doherty, J; Dingledine, R

    1998-06-01

    Regulation of synaptic transmission by metabotropic glutamate receptors (mGluRs) was examined at two excitatory inputs to interneurons with cell bodies at the granule cell-hilus border in hippocampal slices taken from neonatal rats. Subgroup-selective mGluR agonists altered the reliability, or probability of transmitter release, of evoked minimal excitatory synaptic inputs and decreased the amplitudes of excitatory postsynaptic currents (EPSCs) evoked with conventional stimulation. The group II-selective agonist, (2S,1R',2R',3R')-2-(2, 3-dicarboxylcyclopropyl) glycine (DCG-IV; 1 microM), reversibly depressed the reliability of EPSCs evoked by stimulation of the dentate granule cell layer. However, DCG-IV had no significant effect on EPSCs evoked by CA3 stimulation in the majority (82%) of hilar border interneurons. Both the group III-selective agonist, -(+)-2-amino-4-phosphonobutyric acid (-AP4; 3 microM), and the group I-selective agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG; 20 microM) reversibly depressed synaptic input to interneurons from both CA3 and the granule cell layer. We conclude that multiple pharmacologically distinct mGluRs presynaptically regulate synaptic transmission at two excitatory inputs to hilar border interneurons. Further, the degree of mGluR-meditated depression of excitatory drive is greater at synapses from dentate granule cells onto interneurons than at synapses from CA3 pyramidal cells.

  17. Impaired Attention and Synaptic Senescence of the Prefrontal Cortex Involves Redox Regulation of NMDA Receptors

    PubMed Central

    Guidi, Michael

    2015-01-01

    Young (3–6 months) and middle-age (10–14 months) rats were trained on the five-choice serial reaction time task. Attention and executive function deficits were apparent in middle-age animals observed as a decrease in choice accuracy, increase in omissions, and increased response latency. The behavioral differences were not due to alterations in sensorimotor function or a diminished motivational state. Electrophysiological characterization of synaptic transmission in slices from the mPFC indicated an age-related decrease in glutamatergic transmission. In particular, a robust decrease in N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic responses in the mPFC was correlated with several measures of attention. The decrease in NMDAR function was due in part to an altered redox state as bath application of the reducing agent, dithiothreitol, increased the NMDAR component of the synaptic response to a greater extent in middle-age animals. Together with previous work indicating that redox state mediates senescent physiology in the hippocampus, the results indicate that redox changes contribute to senescent synaptic function in vulnerable brain regions involved in age-related cognitive decline. PMID:25740525

  18. Impaired attention and synaptic senescence of the prefrontal cortex involves redox regulation of NMDA receptors.

    PubMed

    Guidi, Michael; Kumar, Ashok; Foster, Thomas C

    2015-03-04

    Young (3-6 months) and middle-age (10-14 months) rats were trained on the five-choice serial reaction time task. Attention and executive function deficits were apparent in middle-age animals observed as a decrease in choice accuracy, increase in omissions, and increased response latency. The behavioral differences were not due to alterations in sensorimotor function or a diminished motivational state. Electrophysiological characterization of synaptic transmission in slices from the mPFC indicated an age-related decrease in glutamatergic transmission. In particular, a robust decrease in N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in the mPFC was correlated with several measures of attention. The decrease in NMDAR function was due in part to an altered redox state as bath application of the reducing agent, dithiothreitol, increased the NMDAR component of the synaptic response to a greater extent in middle-age animals. Together with previous work indicating that redox state mediates senescent physiology in the hippocampus, the results indicate that redox changes contribute to senescent synaptic function in vulnerable brain regions involved in age-related cognitive decline.

  19. Histamine excites rat lateral vestibular nuclear neurons through activation of post-synaptic H2 receptors.

    PubMed

    Zhang, Jun; Han, Xiao-Hu; Li, Hong-Zhao; Zhu, Jing-Ning; Wang, Jian-Jun

    2008-12-19

    Through whole-cell patch recordings in brainstem slices, the effects of histamine on neuronal activity of the lateral vestibular nucleus (LVN) were investigated. Bath application of histamine elicited a concentration-dependent excitation of both spontaneous firing (n=19) and silent (n=7) LVN neurons. Moreover, histamine induced a stable inward current in the LVN neurons (n=5) and the histamine-induced depolarization of membrane potential persisted in the presence of tetrodotoxin (n=4), indicating a direct post-synaptic effect of the histamine on the LVN neurons. Selective histamine H2 receptor antagonist ranitidine effectively blocked the histamine-evoked excitatory responses on the LVN neurons (n=4), but selective histamine H1 receptor antagonist triprolidine did not (n=4). In addition, selective histamine H2 receptor agonist dimaprit (n=3) rather than 2-pyridylethylamine (n=4), a selective histamine H1 receptor agonist, mimicked the excitatory action of histamine on LVN neurons. The results demonstrate that histamine excites the LVN neurons via post-synaptic histamine H2 receptors and suggest that the central histaminergic projection arising from the hypothalamus may modulate LVN neurons activity and actively influence the vestibular reflexes and functions.

  20. Systems biology of synaptic plasticity: a review on N-methyl-D-aspartate receptor mediated biochemical pathways and related mathematical models.

    PubMed

    He, Y; Kulasiri, D; Samarasinghe, S

    2014-08-01

    Synaptic plasticity, an emergent property of synaptic networks, has shown strong correlation to one of the essential functions of the brain, memory formation. Through understanding synaptic plasticity, we hope to discover the modulators and mechanisms that trigger memory formation. In this paper, we first review the well understood modulators and mechanisms underlying N-methyl-D-aspartate receptor dependent synaptic plasticity, a major form of synaptic plasticity in hippocampus, and then comment on the key mathematical modelling approaches available in the literature to understand synaptic plasticity as the integration of the established functionalities of synaptic components.

  1. 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.

  2. A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation

    PubMed Central

    Tozzi, Alessandro; de Iure, Antonio; Marsili, Valentina; Romano, Rosaria; Tantucci, Michela; Di Filippo, Massimiliano; Costa, Cinzia; Napolitano, Francesco; Mercuri, Nicola Biagio; Borsini, Franco; Giampà, Carmen; Fusco, Francesca Romana; Picconi, Barbara; Usiello, Alessandro; Calabresi, Paolo

    2012-01-01

    Background Cocaine increases the level of endogenous dopamine (DA) in the striatum by blocking the DA transporter. Endogenous DA modulates glutamatergic inputs to striatal neurons and this modulation influences motor activity. Since D2 DA and A2A-adenosine receptors (A2A-Rs) have antagonistic effects on striatal neurons, drugs targeting adenosine receptors such as caffeine-like compounds, could enhance psychomotor stimulant effects of cocaine. In this study, we analyzed the electrophysiological effects of cocaine and A2A-Rs antagonists in striatal slices and the motor effects produced by this pharmacological modulation in rodents. Principal Findings Concomitant administration of cocaine and A2A-Rs antagonists reduced glutamatergic synaptic transmission in striatal spiny neurons while these drugs failed to produce this effect when given in isolation. This inhibitory effect was dependent on the activation of D2-like receptors and the release of endocannabinoids since it was prevented by L-sulpiride and reduced by a CB1 receptor antagonist. Combined application of cocaine and A2A-R antagonists also reduced the firing frequency of striatal cholinergic interneurons suggesting that changes in cholinergic tone might contribute to this synaptic modulation. Finally, A2A-Rs antagonists, in the presence of a sub-threshold dose of cocaine, enhanced locomotion and, in line with the electrophysiological experiments, this enhanced activity required activation of D2-like and CB1 receptors. Conclusions The present study provides a possible synaptic mechanism explaining how caffeine-like compounds could enhance psychomotor stimulant effects of cocaine. PMID:22715379

  3. Itinerant teaching: the inside story.

    PubMed

    Yarger, C C; Luckner, J L

    1999-10-01

    The number of students who are deaf or hard of hearing attending local neighborhood schools has increased steadily over the past 20 years (Holden-Pitt & Diaz, 1998). This increase has led to larger numbers of teachers serving these students as itinerant teachers. However, little research has been conducted to examine the efficacy of this model of service delivery (Brelje, 1992; Luckner & Miller, 1994). Qualitative research methods were used to investigate itinerant teachers' perceptions of their responsibilities, job satisfaction, and effectiveness. Individual interviews were conducted with 10 itinerant teachers. Participants reported they preferred working directly with students rather than consulting with general education teachers and families. They noted the primary advantages of working as an itinerant teacher were variety, autonomy, time for reflection, and the diversity of students with whom they worked. Some of the most significant disadvantages they cited were isolation, time and budget constraints, and the distances required to travel from school to school. Essential skills and challenges to being an effective itinerant teacher are identified, recommendations for future itinerant teachers are discussed, and suggestions for future research are presented.

  4. Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory.

    PubMed

    Simões, Ana Patrícia; Machado, Nuno J; Gonçalves, Nélio; Kaster, Manuella P; Simões, Ana T; Nunes, Ana; Pereira de Almeida, Luís; Goosens, Ki Ann; Rial, Daniel; Cunha, Rodrigo A

    2016-11-01

    The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A2A receptors (A2ARs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A2ARs in the amygdala regulate synaptic plasticity and fear memory. We report that A2ARs in the amygdala are enriched in synapses and located to glutamatergic synapses, where they selectively control synaptic plasticity rather than synaptic transmission at a major afferent pathway to the amygdala. Notably, the downregulation of A2ARs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A2AR (shA2AR)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A2ARs in the amygdala after fear acquisition. The importance of A2ARs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A2AR antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; A1R antagonist), treatment for 7 days before fear conditioning onwards, to attenuate the retrieval of context fear after 24-48 h and after 7-8 days. These results demonstrate that amygdala A2ARs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A2AR polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A2ARs to manage fear-related pathologies.

  5. Role of BMP receptor traffic in synaptic growth defects in an ALS model

    PubMed Central

    Deshpande, Mugdha; Feiger, Zachary; Shilton, Amanda K.; Luo, Christina C.; Silverman, Ethan; Rodal, Avital A.

    2016-01-01

    TAR DNA-binding protein 43 (TDP-43) is genetically and functionally linked to amyotrophic lateral sclerosis (ALS) and regulates transcription, splicing, and transport of thousands of RNA targets that function in diverse cellular pathways. In ALS, pathologically altered TDP-43 is believed to lead to disease by toxic gain-of-function effects on RNA metabolism, as well as by sequestering endogenous TDP-43 and causing its loss of function. However, it is unclear which of the numerous cellular processes disrupted downstream of TDP-43 dysfunction lead to neurodegeneration. Here we found that both loss and gain of function of TDP-43 in Drosophila cause a reduction of synaptic growth–promoting bone morphogenic protein (BMP) signaling at the neuromuscular junction (NMJ). Further, we observed a shift of BMP receptors from early to recycling endosomes and increased mobility of BMP receptor–containing compartments at the NMJ. Inhibition of the recycling endosome GTPase Rab11 partially rescued TDP-43–induced defects in BMP receptor dynamics and distribution and suppressed BMP signaling, synaptic growth, and larval crawling defects. Our results indicate that defects in receptor traffic lead to neuronal dysfunction downstream of TDP-43 misregulation and that rerouting receptor traffic may be a viable strategy for rescuing neurological impairment. PMID:27535427

  6. A novel fibroblast growth factor receptor family member promotes neuronal outgrowth and synaptic plasticity in aplysia.

    PubMed

    Pollak, Daniela D; Minh, Bui Quang; Cicvaric, Ana; Monje, Francisco J

    2014-11-01

    Fibroblast Growth Factor (FGF) Receptors (FGFRs) regulate essential biological processes, including embryogenesis, angiogenesis, cellular growth and memory-related long-term synaptic plasticity. Whereas canonical FGFRs depend exclusively on extracellular Immunoglobulin (Ig)-like domains for ligand binding, other receptor types, including members of the tropomyosin-receptor-kinase (Trk) family, use either Ig-like or Leucine-Rich Repeat (LRR) motifs, or both. Little is known, however, about the evolutionary events leading to the differential incorporation of LRR domains into Ig-containing tyrosine kinase receptors. Moreover, although FGFRs have been identified in many vertebrate species, few reports describe their existence in invertebrates. Information about the biological relevance of invertebrate FGFRs and evolutionary divergences between them and their vertebrate counterparts is therefore limited. Here, we characterized ApLRRTK, a neuronal cell-surface protein recently identified in Aplysia. We unveiled ApLRRTK as the first member of the FGFRs family deprived of Ig-like domains that instead contains extracellular LRR domains. We describe that ApLRRTK exhibits properties typical of canonical vertebrate FGFRs, including promotion of FGF activity, enhancement of neuritic outgrowth and signaling via MAPK and the transcription factor CREB. ApLRRTK also enhanced the synaptic efficiency of neurons known to mediate in vivo memory-related defensive behaviors. These data reveal a novel molecular regulator of neuronal function in invertebrates, provide the first evolutionary linkage between LRR proteins and FGFRs and unveil an unprecedented mechanism of FGFR gene diversification in primeval central nervous systems.

  7. Serine proteases, serine protease inhibitors, and protease-activated receptors: roles in synaptic function and behavior.

    PubMed

    Almonte, Antoine G; Sweatt, J David

    2011-08-17

    Serine proteases, serine protease inhibitors, and protease-activated receptors have been intensively investigated in the periphery and their roles in a wide range of processes-coagulation, inflammation, and digestion, for example-have been well characterized (see Coughlin, 2000; Macfarlane et al., 2001; Molinari et al., 2003; Wang et al., 2008; Di Cera, 2009 for reviews). A growing number of studies demonstrate that these protein systems are widely expressed in many cell types and regions in mammalian brains. Accumulating lines of evidence suggest that the brain has co-opted the activities of these interesting proteins to regulate various processes underlying synaptic activity and behavior. In this review, we discuss emerging roles for serine proteases in the regulation of mechanisms underlying synaptic plasticity and memory formation.

  8. Serine proteases, serine protease inhibitors, and protease-activated receptors: roles in synaptic function and behavior

    PubMed Central

    Almonte, Antoine G.; Sweatt, J. David

    2011-01-01

    Serine proteases, serine protease inhibitors, and protease-activated receptors have been intensively investigated in the periphery and their roles in a wide range of processes—coagulation, inflammation, and digestion, for example—have been well characterized (see Coughlin, 2000; Macfarlane et al., 2001; Molinari et al., 2003; Wang et al., 2008; Di Cera, 2009 for reviews). A growing number of studies demonstrate that these protein systems are widely expressed in many cell types and regions in mammalian brains. Accumulating lines of evidence suggest that the brain has co-opted the activities of these interesting proteins to regulate various processes underlying synaptic activity and behavior. In this review, we discuss emerging roles for serine proteases in the regulation of mechanisms underlying synaptic plasticity and memory formation. PMID:21782155

  9. A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior

    PubMed Central

    De Rossi, P; Harde, E; Dupuis, J P; Martin, L; Chounlamountri, N; Bardin, M; Watrin, C; Benetollo, C; Pernet-Gallay, K; Luhmann, H J; Honnorat, J; Malleret, G; Groc, L; Acker-Palmer, A; Salin, P A; Meissirel, C

    2016-01-01

    Vascular endothelial growth factor (VEGF) is known to be required for the action of antidepressant therapies but its impact on brain synaptic function is poorly characterized. Using a combination of electrophysiological, single-molecule imaging and conditional transgenic approaches, we identified the molecular basis of the VEGF effect on synaptic transmission and plasticity. VEGF increases the postsynaptic responses mediated by the N-methyl-D-aspartate type of glutamate receptors (GluNRs) in hippocampal neurons. This is concurrent with the formation of new synapses and with the synaptic recruitment of GluNR expressing the GluN2B subunit (GluNR-2B). VEGF induces a rapid redistribution of GluNR-2B at synaptic sites by increasing the surface dynamics of these receptors within the membrane. Consistently, silencing the expression of the VEGF receptor 2 (VEGFR2) in neural cells impairs hippocampal-dependent synaptic plasticity and consolidation of emotional memory. These findings demonstrated the direct implication of VEGF signaling in neurons via VEGFR2 in proper synaptic function. They highlight the potential of VEGF as a key regulator of GluNR synaptic function and suggest a role for VEGF in new therapeutic approaches targeting GluNR in depression. PMID:26728568

  10. Pathophysiology of Huntington’s Disease: Time-Dependent Alterations in Synaptic and Receptor Function

    PubMed Central

    Raymond, Lynn A.; André, Véronique M.; Cepeda, Carlos; Gladding, Clare M.; Milnerwood, Austen J.; Levine, Michael S.

    2011-01-01

    Huntington’s disease (HD) is a progressive, fatal neurological condition caused by an expansion of CAG (glutamine) repeats in the coding region of the Huntington gene. To date, there is no cure but great strides have been made to understand pathophysiological mechanisms. In particular, genetic animal models of HD have been instrumental in elucidating the progression of behavioral and physiological alterations, which had not been possible using classic neurotoxin models. Our groups have pioneered the use of transgenic HD mice to examine the excitotoxicity hypothesis of striatal neuronal dysfunction and degeneration, as well as alterations in excitation and inhibition in striatum and cerebral cortex. In this review, we focus on synaptic and receptor alterations of striatal medium-sized spiny (MSNs) and cortical pyramidal neurons in genetic HD mouse models. We demonstrate a complex series of alterations that are region-specific and time-dependent. In particular, many changes are bidirectional depending on the degree of disease progression, i.e., early versus late, and also on the region examined. Early synaptic dysfunction is manifested by dysregulated glutamate release in striatum followed by progressive disconnection between cortex and striatum. The differential effects of altered glutamate release on MSNs originating the direct and indirect pathways is also elucidated, with the unexpected finding that cells of the direct striatal pathway are involved early in the course of the disease. In addition, we review evidence for early N-methyl-D-aspartate receptor (NMDAR) dysfunction leading to enhanced sensitivity of extrasynaptic receptors and a critical role of GluN2B subunits. Some of the alterations in late HD could be compensatory mechanisms designed to cope with early synaptic and receptor dysfunctions. The main findings indicate that HD treatments need to be designed according to the stage of disease progression and should consider regional differences. PMID

  11. D2 receptor regulation of synaptic burst firing in prefrontal cortical pyramidal neurons

    PubMed Central

    Wang, Yun; Goldman-Rakic, Patricia S.

    2004-01-01

    The efficacy of antipsychotics in the treatment of schizophrenia depends on their ability to block dopamine (DA) D2 receptors. D2 receptor excitatory mediation of glutamatergic receptors has been implicated in in vivo studies. However, D2 receptor enhancement of glutamatergic transmission has rarely been reported in slice recordings. Instead, D2 receptor depression of both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) action was obtained in previous slice studies. To obtain insight into this paradox, we examined DA's actions on synaptic responses of layer V pyramidal cells to minimal extracellular stimulation in layer III of ferret prefrontal cortical slices under NMDA and γ-aminobutyric acid type A blockade. This experimental design models the proposed hypofunction of NMDA receptor and γ-aminobutyric acid type A deficiency in schizophrenia. We found that DA and D2 receptor agonists promoted burst firing in a subset of pyramidal cells, which was reversed by haloperidol, a D2 antagonist and a D3 agonist, compounds having antipsychotic efficacy. In contrast, a D4 antagonist, which has not proven clinically effective, was not effective in blocking DA-promoted bursts. These results revealed excitatory effects of DA mediated mainly via D2 receptors, potentially providing a cellular mechanism for the D2 antagonism in treating schizophrenia. PMID:15051874

  12. Neto2 Interacts with the Scaffolding Protein GRIP and Regulates Synaptic Abundance of Kainate Receptors

    PubMed Central

    Tang, Man; Ivakine, Evgueni; Mahadevan, Vivek; Salter, Michael W.; McInnes, Roderick R.

    2012-01-01

    Kainate receptors (KARs) are a class of ionotropic glutamate receptors that are expressed throughout the central nervous system. The function and subcellular localization of KARs are tightly regulated by accessory proteins. We have previously identified the single-pass transmembrane proteins, Neto1 and Neto2, to be associated with native KARs. In the hippocampus, Neto1, but not Neto2, controls the abundance and modulates the kinetics of postsynaptic KARs. Here we evaluated whether Neto2 regulates synaptic KAR levels in the cerebellum where Neto1 expression is limited to the deep cerebellar nuclei. In the cerebellum, where Neto2 is present abundantly, we found a ∼40% decrease in GluK2-KARs at the postsynaptic density (PSD) of Neto2-null mice. No change, however, was observed in total level of GluK2-KARs, thereby suggesting a critical role of Neto2 on the synaptic localization of cerebellar KARs. The presence of a putative class II PDZ binding motif on Neto2 led us to also investigate whether it interacts with PDZ domain-containing proteins previously implicated in regulating synaptic abundance of KARs. We identified a PDZ-dependent interaction between Neto2 and the scaffolding protein GRIP. Furthermore, coexpression of Neto2 significantly increased the amount of GRIP associated with GluK2, suggesting that Neto2 may promote and/or stabilize GluK2:GRIP interactions. Our results demonstrate that Neto2, like Neto1, is an important auxiliary protein for modulating the synaptic levels of KARs. Moreover, we propose that the interactions of Neto1/2 with various scaffolding proteins is a critical mechanism by which KARs are stabilized at diverse synapses. PMID:23236500

  13. Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses.

    PubMed

    Park, Hoyong; Kim, Sungmin; Rhee, Jeehae; Kim, Hyeon-Joong; Han, Jung-Soo; Nah, Seung-Yeol; Chung, ChiHye

    2015-03-01

    Lysophosphatidic acid (LPA) is one of the well-characterized, ubiquitous phospholipid molecules. LPA exerts its effect by activating G protein-coupled receptors known as LPA receptors (LPARs). So far, LPAR signaling has been critically implicated during early development stages, including the regulation of synapse formation and the morphology of cortical and hippocampal neurons. In adult brains, LPARs seem to participate in cognitive as well as emotional learning and memory. Recent studies using LPAR1-deficient mice reported impaired performances in a number of behavioral tasks, including the hippocampus-dependent spatial memory and fear conditioning tests. Nevertheless, the effect of LPAR activation in the synaptic transmission of central synapses after the completion of embryonic development has not been investigated. In this study, we took advantage of a novel extracellular agonist for LPARs called gintonin to activate LPARs in adult brain systems. Gintonin, a recently identified active ingredient in ginseng, has been shown to activate LPARs and mobilize Ca(2+) in an artificial cell system. We found that the activation of LPARs by application of gintonin acutely enhanced both excitatory and inhibitory transmission in central synapses, albeit through tentatively distinct mechanisms. Gintonin-mediated LPAR activation primarily resulted in synaptic enhancement and an increase in neuronal excitability in a phospholipase C-dependent manner. Our findings suggest that LPARs are able to directly potentiate synaptic transmission in central synapses when stimulated exogenously. Therefore, LPARs could serve as a useful target to modulate synaptic activity under pathological conditions, including neurodegenerative diseases. Copyright © 2015 the American Physiological Society.

  14. Homeostatic regulation of synaptic excitability: tonic GABAA receptor currents replace Ih in cortical pyramidal neurons of HCN1 knockout mice

    PubMed Central

    Chen, Xiangdong; Shu, Shaofang; Schwartz, Lauren C.; Sun, Chengsan; Kapur, Jaideep; Bayliss, Douglas A.

    2010-01-01

    Homeostatic control of synaptic efficacy is often mediated by dynamic regulation of excitatory synaptic receptors. Here, we report a novel form of homeostatic synaptic plasticity based on regulation of shunt currents that control dendritosomatic information transfer. In cortical pyramidal neurons from wild type mice, HCN1 channels underlie a dendritic hyperpolarization-activated cationic current (Ih) that serves to limit temporal summation of synaptic inputs. In HCN1 knockout mice, as expected, Ih is reduced in pyramidal neurons and its effects on synaptic summation are strongly diminished. Unexpectedly, we found a markedly enhanced bicuculline- and L-655,708-sensitive background GABAA current in these cells that could be attributed to selective up-regulation of GABAA α5 subunit expression in the cortex of HCN1 knockout mice. Strikingly, despite diminished Ih, baseline sub-linear summation of evoked EPSPs was unchanged in pyramidal neurons from HCN1 knockout mice; however, blocking tonic GABAA currents with bicuculline enhanced synaptic summation more strongly in pyramidal cells from HCN1 knockout mice than in those cells from wild type mice. Increasing tonic GABAA receptor conductance in the context of reduced Ih, using computational or pharmacological approaches, restored normal baseline synaptic summation, as observed in neurons from HCN1 knockout mice. These data indicate that up-regulation of α5 subunit-mediated GABAA receptor tonic current compensates quantitatively for loss of dendritic Ih in cortical pyramidal neurons from HCN1 knockout mice to maintain normal synaptic summation; they further imply that dendritosomatic synaptic efficacy is a controlled variable for homeostatic regulation of cortical neuron excitability in vivo. PMID:20164346

  15. Synaptic expression of glutamate receptor after encoding of fear memory in the rat amygdala.

    PubMed

    Yeh, Shiu-Hwa; Mao, Sheng-Chun; Lin, Hui-Ching; Gean, Po-Wu

    2006-01-01

    Fear conditioning has been ascribed to presynaptic mechanisms, particularly presynaptic facilitation of transmission at thalamo- and cortico-amygdala synapses. Here, by labeling surface receptors with biotin or using membrane fractionation approaches, we report that fear conditioning resulted in an increase in surface expression of GluR1 subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in the amygdala, whereas total GluR1 mRNA and protein levels were unchanged. The control group that received conditioned stimulus (CS) and unconditioned stimulus in an unpaired fashion did not present any increase, indicating that GluR1 increase was specific to the learning component of the task. Conditioning-induced increase in surface expression of GluR1 depended on the activation of N-methyl-d-aspartate receptors and protein kinases and required the synthesis of new proteins. CS-alone trials applied 24 h before training attenuated fear-potentiated startle and prevented conditioning-induced increase in surface expression of GluR1. Increase in GluR1 was also observed in the amygdala slices after delivery of tetanic stimulation that elicited long-term potentiation of synaptic transmission. Proteasome inhibitor increased surface expression of GluR1 in a time- and dose-dependent manner. Furthermore, pretraining administration of proteasome inhibitor into the amygdala facilitated the fear-potentiated startle. These results suggest that long-term memory formation is correlated with the change in synaptic expression of GluR1, and trafficking of GluR1 to the synaptic sites contributes at least in part to the expression of fear memory.

  16. AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability

    PubMed Central

    Brechet, Aline; Buchert, Rebecca; Schwenk, Jochen; Boudkkazi, Sami; Zolles, Gerd; Siquier-Pernet, Karine; Schaber, Irene; Bildl, Wolfgang; Saadi, Abdelkrim; Bole-Feysot, Christine; Nitschke, Patrick; Reis, Andre; Sticht, Heinrich; Al-Sanna’a, Nouriya; Rolfs, Arndt; Kulik, Akos; Schulte, Uwe; Colleaux, Laurence; Abou Jamra, Rami; Fakler, Bernd

    2017-01-01

    AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function. PMID:28675162

  17. 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. © 2016 Wiley Periodicals, Inc.

  18. Imidazoleacetic acid-ribotide induces depression of synaptic responses in hippocampus through activation of imidazoline receptors

    PubMed Central

    Bozdagi, O.; Wang, X. B.; Martinelli, G. P.; Prell, G.; Friedrich, V. L.; Huntley, G. W.

    2011-01-01

    Imidazole-4-acetic acid-ribotide (IAA-RP), an endogenous agonist at imidazoline receptors (I-Rs), is a putative neurotransmitter/regulator in mammalian brain. We studied the effects of IAA-RP on excitatory transmission by performing extracellular and whole cell recordings at Schaffer collateral-CA1 synapses in rat hippocampal slices. Bath-applied IAA-RP induced a concentration-dependent depression of synaptic transmission that, after washout, returned to baseline within 20 min. Maximal decrease occurred with 10 μM IAA-RP, which reduced the slope of field extracellular postsynaptic potentials (fEPSPs) to 51.2 ± 5.7% of baseline at 20 min of exposure. Imidazole-4-acetic acid-riboside (IAA-R; 10 μM), the endogenous dephosphorylated metabolite of IAA-RP, also produced inhibition of fEPSPs. This effect was smaller than that produced by IAA-RP (to 65.9 ± 3.8% of baseline) and occurred after a further 5- to 8-min delay. The frequency, but not the amplitude, of miniature excitatory postsynaptic currents was decreased, and paired-pulse facilitation (PPF) was increased after application of IAA-RP, suggesting a principally presynaptic site of action. Since IAA-RP also has low affinity for α2-adrenergic receptors (α2-ARs), we tested synaptic depression induced by IAA-RP in the presence of α2-ARs, I1-R, or I3-R antagonists. The α2-AR antagonist rauwolscine (100 nM), which blocked the actions of the α2-AR agonist clonidine, did not affect either the IAA-RP-induced synaptic depression or the increase in PPF. In contrast, efaroxan (50 μM), a mixed I1-R and α2-AR antagonist, abolished the synaptic depression induced by IAA-RP and abolished the related increase in PPF. KU-14R, an I3-R antagonist, partially attenuated responses to IAA-RP. Taken together, these data support a role for IAA-RP in modulating synaptic transmission in the hippocampus through activation of I-Rs. PMID:21228308

  19. Intrinsic and synaptic homeostatic plasticity in motoneurons from mice with glycine receptor mutations

    PubMed Central

    Tadros, M. A.; Farrell, K. E.; Schofield, P. R.; Brichta, A. M.; Graham, B. A.; Fuglevand, A. J.

    2014-01-01

    Inhibitory synaptic inputs to hypoglossal motoneurons (HMs) are important for modulating excitability in brainstem circuits. Here we ask whether reduced inhibition, as occurs in three murine mutants with distinct naturally occurring mutations in the glycine receptor (GlyR), leads to intrinsic and/or synaptic homeostatic plasticity. Whole cell recordings were obtained from HMs in transverse brainstem slices from wild-type (wt), spasmodic (spd), spastic (spa), and oscillator (ot) mice (C57Bl/6, approximately postnatal day 21). Passive and action potential (AP) properties in spd and ot HMs were similar to wt. In contrast, spa HMs had lower input resistances, more depolarized resting membrane potentials, higher rheobase currents, smaller AP amplitudes, and slower afterhyperpolarization current decay times. The excitability of HMs, assessed by “gain” in injected current/firing-frequency plots, was similar in all strains whereas the incidence of rebound spiking was increased in spd. The difference between recruitment and derecruitment current (i.e., ΔI) for AP discharge during ramp current injection was more negative in spa and ot. GABAA miniature inhibitory postsynaptic current (mIPSC) amplitude was increased in spa and ot but not spd, suggesting diminished glycinergic drive leads to compensatory adjustments in the other major fast inhibitory synaptic transmitter system in these mutants. Overall, our data suggest long-term reduction in glycinergic drive to HMs results in changes in intrinsic and synaptic properties that are consistent with homeostatic plasticity in spa and ot but not in spd. We propose such plasticity is an attempt to stabilize HM output, which succeeds in spa but fails in ot. PMID:24401707

  20. Role of the CaMKII/NMDA-receptor complex in the maintenance of synaptic strength

    PubMed Central

    Sanhueza, Magdalena; Fernandez-Villalobos, German; Stein, Ivar S.; Kasumova, Gyulnara; Zhang, Peng; Bayer, K. Ulrich; Otmakhov, Nikolai; Hell, Johannes W.; Lisman, John

    2011-01-01

    During long-term potentiation (LTP), synapses undergo stable changes in synaptic strength. The molecular memory processes that maintain strength have not been identified. One hypothesis is that the complex formed by the Ca2+/Calmodulin -dependent protein kinase II (CaMKII) and the NMDA-type glutamate receptor (NMDAR) is a molecular memory at the synapse. To establish a molecule as a molecular memory, it must be shown that interfering with the molecule produces a persistent reversal of LTP. We used the CN class of peptides that inhibit CaMKII binding to the NR2B subunit in vitro to test this prediction in rat hippocampal slices. We found that CN peptides can reverse saturated LTP, allowing additional LTP to be induced. The peptide also produced a persistent reduction in basal transmission. We then tested whether CN compounds actually affect CaMKII binding in living cells. Application of CN peptide to slice cultures reduced the amount of CaMKII concentrated in spines, consistent with delocalization of the kinase from a binding partner in the spine. To more specifically assay the binding of CaMKII to the NMDAR, we used coimmunoprecipitation methods. We found that CN peptide decreased synaptic strength only at concentrations necessary to disrupt the CaMKII/NMDAR complex, but not at lower concentrations sufficient to inhibit CaMKII activity. Importantly, both the reduction of the complex and the reduction of synaptic strength persisted after removal of the inhibitor. These results support the hypothesis that the CaMKII/NMDAR complex has switch-like properties that are important in the maintenance of synaptic strength. PMID:21697368

  1. AMPA receptor trafficking and synaptic plasticity require SQSTM1/p62.

    PubMed

    Jiang, Jianxiong; Parameshwaran, Kodeeswaran; Seibenhener, M Lamar; Kang, Myoung-Goo; Suppiramaniam, Vishnu; Huganir, Richard L; Diaz-Meco, Maria T; Wooten, Marie W

    2009-04-01

    SQSTM1/p62 is a multidomain/scaffold for the atypical protein kinase Cs (aPKC). Phosphorylation of AMPA receptors by PKC has been shown to regulate their insertion in the postsynaptic membrane. Here, we directly tested whether p62 could interact with AMPA receptor subunits and influence their trafficking and phosphorylation. GluR1 receptor intracellular loop L2-3 and the ZZ-type zinc finger domain of p62 are essential for the interaction between these two proteins. In this context, both p62 and aPKC-mediated phosphorylation were necessary for surface delivery of the receptor. Our findings reveal that p62 is the first protein identified that interacts with a region of the GluR receptor other than the C-terminal tail. Furthermore, mice deficient in p62 displayed impaired hippocampal CA1 long-term potentiation (LTP), along with diminished surface expression of GluR1 and phosphorylation of S818. Lastly, we identify a conserved sequence (ISExSL) shared by all p62 interacting-aPKC substrates. These findings support a model where p62 interaction and aPKC phosphorylation act together to mediate AMPA receptor trafficking and long-term synaptic plasticity in the hippocampus.

  2. Stargazin (TARP gamma-2) is required for compartment-specific AMPA receptor trafficking and synaptic plasticity in cerebellar stellate cells.

    PubMed

    Jackson, Alexander C; Nicoll, Roger A

    2011-03-16

    In the cerebellar cortex, parallel fiber-to-stellate cell (PF-SC) synapses exhibit a form of synaptic plasticity manifested as a switch in the subunit composition of synaptic AMPA receptors (AMPARs) from calcium-permeable, GluA2-lacking to calcium-impermeable, GluA2-containing receptors. Here, we examine the role of stargazin (γ-2), canonical member of the transmembrane AMPAR regulatory protein (TARP) family, in the regulation of GluA2-lacking AMPARs and synaptic plasticity in SCs from epileptic and ataxic stargazer mutant mice. We found that AMPAR-mediated synaptic transmission is severely diminished in stargazer SCs, and that the rectification index (RI) of AMPAR current is reduced. Activity-dependent plasticity in the rectification of synaptic AMPARs is also impaired in stargazer SCs. Despite the dramatic loss in synaptic AMPARs, extrasynaptic AMPARs are preserved. We then examined the role of stargazin in regulating the rectification of extrasynaptic AMPARs in nucleated patches and found, in contrast to previous reports, that wild-type extrasynaptic AMPARs have moderate RI values (average RI = 0.38), while those in stargazer SCs are low (average RI = 0.24). The GluA2-lacking AMPAR blocker, philanthotoxin-433 (PhTx-433), was used as an alternative measure of GluA2 content in wild-type and stargazer SCs. Despite the difference in RI, PhTx-433 sensitivity of both synaptic and extrasynaptic AMPARs remains unchanged, suggesting that the dramatic changes in RI and the impairment in synaptic plasticity observed in the stargazer mouse are not the result of a specific impairment in GluA2 trafficking. Together, these data suggest that stargazin regulates compartment-specific AMPAR trafficking, as well as activity-dependent plasticity in synaptic AMPAR rectification at cerebellar PF-SC synapses.

  3. Synaptic mechanism for functional synergism between delta- and mu-opioid receptors

    PubMed Central

    Zhang, Zhi; Pan, Zhizhong Z.

    2010-01-01

    By sustained activation of mu-opioid receptors (MOR), chronic opioids cause analgesic tolerance, physical dependence and opioid addiction, common clinical problems for which an effective treatment is still lacking. Chronic opioids recruit delta-opioid receptors (DOR) to plasma membrane through exocytotic trafficking, but the role of this new DOR and its interaction with existing MOR in brain functions and in the clinical problems remains largely unknown. In this study, we investigated the mechanisms underlying synaptic and behavioral actions of chronic morphine-induced DOR and its interaction with MOR in Nucleus Raphe Magnus (NRM) neurons important for opioid analgesia. We found that the emerged DOR inhibited GABAergic IPSCs through both the phospholipase A2 (PLA2) and cAMP/PKA signaling pathways. MOR inhibition of IPSCs, normally mediated predominantly by the PLA2 pathway, was additionally mediated by the cAMP/PKA pathway, with MOR potency significantly increased after chronic morphine treatment. Isobologram analysis revealed a synergistic DOR-MOR interaction in their IPSC inhibition, which was dependent on upregulated activities of both the PLA2 and cAMP/PKA pathways. Furthermore, DOR and MOR agonists microinjected into the NRM in vivo also produced a PLA2–dependent synergism in their antinociceptive effects. These findings suggest that the cAMP/PKA pathway, upregulated by chronic opioids, becomes more important in the mechanisms of both MOR and DOR inhibition of GABA synaptic transmission after chronic opioid exposure, and DOR and MOR are synergic both synaptically and behaviorally in producing analgesic effects in a PLA2-dependent fashion, supporting the potential therapeutic use of DOR agonists in pain management under chronic opioid conditions. PMID:20357124

  4. Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation

    PubMed Central

    Adasme, Tatiana; Haeger, Paola; Paula-Lima, Andrea C.; Espinoza, Italo; Casas-Alarcón, M. Mercedes; Carrasco, M. Angélica; Hidalgo, Cecilia

    2011-01-01

    Ryanodine receptors (RyR) amplify activity-dependent calcium influx via calcium-induced calcium release. Calcium signals trigger postsynaptic pathways in hippocampal neurons that underlie synaptic plasticity, learning, and memory. Recent evidence supports a role of the RyR2 and RyR3 isoforms in these processes. Along with calcium signals, brain-derived neurotrophic factor (BDNF) is a key signaling molecule for hippocampal synaptic plasticity and spatial memory. Upon binding to specific TrkB receptors, BDNF initiates complex signaling pathways that modify synaptic structure and function. Here, we show that BDNF-induced remodeling of hippocampal dendritic spines required functional RyR. Additionally, incubation with BDNF enhanced the expression of RyR2, RyR3, and PKMζ, an atypical protein kinase C isoform with key roles in hippocampal memory consolidation. Consistent with their increased RyR protein content, BDNF-treated neurons generated larger RyR-mediated calcium signals than controls. Selective inhibition of RyR-mediated calcium release with inhibitory ryanodine concentrations prevented the PKMζ, RyR2, and RyR3 protein content enhancement induced by BDNF. Intrahippocampal injection of BDNF or training rats in a spatial memory task enhanced PKMζ, RyR2, RyR3, and BDNF hippocampal protein content, while injection of ryanodine at concentrations that stimulate RyR-mediated calcium release improved spatial memory learning and enhanced memory consolidation. We propose that RyR-generated calcium signals are key features of the complex neuronal plasticity processes induced by BDNF, which include increased expression of RyR2, RyR3, and PKMζ and the spine remodeling required for spatial memory formation. PMID:21282625

  5. A critical role for PSD-95/AKAP interactions in endocytosis of synaptic AMPA receptors.

    PubMed

    Bhattacharyya, Samarjit; Biou, Virginie; Xu, Weifeng; Schlüter, Oliver; Malenka, Robert C

    2009-02-01

    The endocytosis of AMPA receptors (AMPARs) underlies several forms of synaptic plasticity, including NMDA receptor (NMDAR)-dependent long-term depression (LTD), but the molecular mechanisms responsible for this trafficking remain unknown. We found that PSD-95, a major postsynaptic density protein, is important for NMDAR-triggered endocytosis of synaptic AMPARs in rat neuron cultures because of its binding to A kinase-anchoring protein 150 (AKAP150), a scaffold for specific protein kinases and phosphatases. Knockdown of PSD-95 with shRNA blocked NMDAR-triggered, but not constitutive or mGluR-triggered, endocytosis of AMPARs. Deletion of PSD-95's Src homology 3 and guanylate kinase-like domains, as well as a point mutation (L460P), both of which inhibit binding of PSD-95 to AKAP150, also blocked NMDAR-triggered AMPAR endocytosis. Furthermore, expression of a mutant AKAP150 that does not bind calcineurin inhibited this NMDAR-triggered trafficking event. Our results suggest that PSD-95's interaction with AKAP150 is critical for NMDAR-triggered AMPAR endocytosis and LTD, possibly because these scaffolds position calcineurin in the appropriate subsynaptic domain.

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

    PubMed Central

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

    2016-01-01

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

  7. Structural basis for integration of GluD receptors within synaptic organizer complexes.

    PubMed

    Elegheert, Jonathan; Kakegawa, Wataru; Clay, Jordan E; Shanks, Natalie F; Behiels, Ester; Matsuda, Keiko; Kohda, Kazuhisa; Miura, Eriko; Rossmann, Maxim; Mitakidis, Nikolaos; Motohashi, Junko; Chang, Veronica T; Siebold, Christian; Greger, Ingo H; Nakagawa, Terunaga; Yuzaki, Michisuke; Aricescu, A Radu

    2016-07-15

    Ionotropic glutamate receptor (iGluR) family members are integrated into supramolecular complexes that modulate their location and function at excitatory synapses. However, a lack of structural information beyond isolated receptors or fragments thereof currently limits the mechanistic understanding of physiological iGluR signaling. Here, we report structural and functional analyses of the prototypical molecular bridge linking postsynaptic iGluR δ2 (GluD2) and presynaptic β-neurexin 1 (β-NRX1) via Cbln1, a C1q-like synaptic organizer. We show how Cbln1 hexamers "anchor" GluD2 amino-terminal domain dimers to monomeric β-NRX1. This arrangement promotes synaptogenesis and is essential for D: -serine-dependent GluD2 signaling in vivo, which underlies long-term depression of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses and motor coordination in developing mice. These results lead to a model where protein and small-molecule ligands synergistically control synaptic iGluR function.

  8. Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus

    PubMed Central

    Ribeiro, Luís F.; Catarino, Tatiana; Santos, Sandra D.; Benoist, Marion; van Leeuwen, J. Fiona; Esteban, José A.; Carvalho, Ana Luísa

    2014-01-01

    Ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. These effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary. However, GHS-R1a is expressed in other brain regions, including the hippocampus, where its activation enhances memory retention. Herein we explore the molecular mechanism underlying the action of ghrelin on hippocampal-dependent memory. Our data show that GHS-R1a is localized in the vicinity of hippocampal excitatory synapses, and that its activation increases delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-type receptors (AMPARs) to synapses, producing functional modifications at excitatory synapses. Moreover, GHS-R1a activation enhances two different paradigms of long-term potentiation in the hippocampus, activates the phosphatidylinositol 3-kinase, and increases GluA1 AMPAR subunit and stargazin phosphorylation. We propose that GHS-R1a activation in the hippocampus enhances excitatory synaptic transmission and synaptic plasticity by regulating AMPAR trafficking. Our study provides insights into mechanisms that may mediate the cognition-enhancing effect of ghrelin, and suggests a possible link between the regulation of energy metabolism and learning. PMID:24367106

  9. Synaptic inhibition by glycine acting at a metabotropic receptor in tiger salamander retina.

    PubMed

    Hou, Mingli; Duan, Lei; Slaughter, Malcolm M

    2008-06-15

    Glycine is the lone fast neurotransmitter for which a metabotropic pathway has not been identified. In retina, we found a strychnine-insensitive glycine response in bipolar and ganglion cells. This glycine response reduced high voltage-activated calcium current. It was G-protein mediated and protein kinase A dependent. The EC(50) of the metabotropic glycine response is 3 mum, an order of magnitude lower than the ionotropic glycine receptor in the same retina. The bipolar cell glutamatergic input to ganglion cells was suppressed by metabotropic glycine action. The synaptic output of about two-thirds of bipolar cells and calcium current in two-thirds of ganglion cells are sensitive to the action of glycine at metabotropic receptors, suggesting this signal regulates specific synaptic pathways in proximal retina. This study resolves the curious absence of a metabotropic glycine pathway in the nervous system and reveals that the major fast inhibitory neurotransmitters, GABA and glycine, both activate G-protein-coupled pathways as well.

  10. Efficient Integration of Synaptic Events by NMDA Receptors in Three-Dimensional Neuropil

    PubMed Central

    Zheng, Kaiyu; Rusakov, Dmitri A.

    2015-01-01

    Sustained activation of NMDA receptors (NMDARs) plays an important role in controlling activity of neural circuits in the brain. However, whether this activation reflects the ambient level of excitatory neurotransmitter glutamate in brain tissue or whether it depends mainly on local synaptic discharges remains poorly understood. To shed light on the underlying biophysics here we developed and explored a detailed Monte Carlo model of a realistic three-dimensional neuropil fragment containing 54 excitatory synapses. To trace individual molecules and their individual receptor interactions on this scale, we have designed and implemented a dedicated computer cluster and the appropriate software environment. Our simulations have suggested that sparse synaptic discharges are 20–30 times more efficient than nonsynaptic (stationary, leaky) supply of glutamate in controlling sustained NMDAR occupancy in the brain. This mechanism could explain how the brain circuits provide substantial background activation of NMDARs while maintaining a negligible ambient glutamate level in the extracellular space. Thus the background NMDAR occupancy, rather than the background glutamate level, is likely to reflect the ongoing activity in local excitatory networks. PMID:25992724

  11. Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength.

    PubMed

    Mackie, K

    2006-04-01

    The CB1 cannabinoid receptor has attracted much recent interest because of the observation that CB1 receptor antagonists have efficacy in treating metabolic syndrome and obesity. CB1 receptors also mediate most of the psychotropic effects of Delta9-tetrahydrocannabinol (Delta9THC), the principal psychoactive component of cannabis. In addition, they are one component of an interesting and widespread paracrine signaling system, the endocannabinoid system. The endocannabinoid system is comprised of cannabinoid receptors, endogenous cannabinoids, and the metabolic pathways responsible for their synthesis and degradation. The details of the endocannabinoid system have been most thoroughly studied in the brain. Here it has been shown to be intimately involved in several forms of neuronal plasticity. That is, activation of CB1 receptors by endocannabinoids produces either short- or long-term changes in the efficacy of synaptic transmission. The behavioral consequences of these changes are many, but some of the most striking and relevant to the current symposium are those associated with endogenous reward and consumptive behavior.

  12. N-terminal SAP97 isoforms differentially regulate synaptic structure and postsynaptic surface pools of AMPA receptors.

    PubMed

    Goodman, Lucy; Baddeley, David; Ambroziak, Wojciech; Waites, Clarissa L; Garner, Craig C; Soeller, Christian; Montgomery, Johanna M

    2017-02-28

    The location and density of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is controlled by scaffolding proteins within the postsynaptic density (PSD). SAP97 is a PSD protein with two N-terminal isoforms, α and β, that have opposing effects on synaptic strength thought to result from differential targeting of AMPA receptors into distinct synaptic versus extrasynaptic locations, respectively. In this study, we have applied dSTORM super resolution imaging in order to localize the synaptic and extrasynaptic pools of AMPA receptors in neurons expressing α or βSAP97. Unexpectedly, we observed that both α and βSAP97 enhanced the localization of AMPA receptors at synapses. However, this occurred via different mechanisms: αSAP97 increased PSD size and consequently the number of receptor binding sites, whilst βSAP97 increased synaptic receptor cluster size and surface AMPA receptor density at the PSD edge and surrounding perisynaptic sites without changing PSD size. αSAP97 also strongly enlarged presynaptic active zone protein clusters, consistent with both presynaptic and postsynaptic enhancement underlying the previously observed αSAP97-induced increase in AMPA receptor-mediated currents. In contrast, βSAP97-expressing neurons increased the proportion of immature filopodia that express higher levels of AMPA receptors, decreased the number of functional presynaptic terminals, and also reduced the size of the dendritic tree and delayed the maturation of mushroom spines. Our data reveal that SAP97 isoforms can specifically regulate surface AMPA receptor nanodomain clusters, with βSAP97 increasing extrasynaptic receptor domains at peri-synaptic and filopodial sites. Moreover, βSAP97 negatively regulates synaptic maturation both structurally and functionally. These data support diverging presynaptic and postsynaptic roles of SAP97 N-terminal isoforms in synapse maturation and plasticity. As numerous splice isoforms exist in

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

    PubMed Central

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

    2015-01-01

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

  14. Pin1 Modulates the Synaptic Content of NMDA Receptors via Prolyl-Isomerization of PSD-95.

    PubMed

    Antonelli, Roberta; De Filippo, Roberto; Middei, Silvia; Stancheva, Stefka; Pastore, Beatrice; Ammassari-Teule, Martine; Barberis, Andrea; Cherubini, Enrico; Zacchi, Paola

    2016-05-18

    Phosphorylation of serine/threonine residues preceding a proline regulates the fate of its targets through postphosphorylation conformational changes catalyzed by the peptidyl-prolyl cis-/trans isomerase Pin1. By flipping the substrate between two different functional conformations, this enzyme exerts a fine-tuning of phosphorylation signals. Pin1 has been detected in dendritic spines and shafts where it regulates protein synthesis required to sustain the late phase of long-term potentiation (LTP). Here, we demonstrate that Pin1 residing in postsynaptic structures can interact with postsynaptic density protein-95 (PSD-95), a key scaffold protein that anchors NMDA receptors (NMDARs) in PSD via GluN2-type receptor subunits. Pin1 recruitment by PSD-95 occurs at specific serine-threonine/proline consensus motifs localized in the linker region connecting PDZ2 to PDZ3 domains. Upon binding, Pin1 triggers structural changes in PSD-95, thus negatively affecting its ability to interact with NMDARs. In electrophysiological experiments, larger NMDA-mediated synaptic currents, evoked in CA1 principal cells by Schaffer collateral stimulation, were detected in hippocampal slices obtained from Pin1(-/-) mice compared with controls. Similar results were obtained in cultured hippocampal cells expressing a PSD-95 mutant unable to undergo prolyl-isomerization, thus indicating that the action of Pin1 on PSD-95 is critical for this effect. In addition, an enhancement in spine density and size was detected in CA1 principal cells of Pin1(-/-) or in Thy-1GFP mice treated with the pharmacological inhibitor of Pin1 catalytic activity PiB.Our data indicate that Pin1 controls synaptic content of NMDARs via PSD-95 prolyl-isomerization and the expression of dendritic spines, both required for LTP maintenance. PSD-95, a membrane-associated guanylate kinase, is the major scaffolding protein at excitatory postsynaptic densities and a potent regulator of synaptic strength and plasticity. The

  15. Changes in Synaptic Plasticity and Glutamate Receptors in Type 2 Diabetic KK-Ay Mice.

    PubMed

    Yin, Huajing; Wang, Weiping; Yu, Wenwen; Li, Jiang; Feng, Nan; Wang, Ling; Wang, Xiaoliang

    2017-01-01

    In the present study, the progressive alteration of cognition and the mechanisms of reduction in long-term potentiation (LTP) in spontaneous obese KK-Ay type 2 diabetic mice were investigated. In the study, 3-, 5-, and 7-month-old KK-Ay mice were used. The results indicated that KK-Ay mice showed cognitive deficits in the Morris water maze test beginning at the age of 3 months. LTP was significantly impaired in KK-Ay mice during whole study period (3 to 7 months). The above deficits were reversible at an early stage (3 to 5 months old) by diet intervention. Moreover, we found the underlying mechanisms of LTP impairment in KK-Ay mice might be attributed to abnormal phosphorylation or expression of postsynaptic glutamate receptor subunits instead of alteration of basal synaptic transmission. The expression levels of NR1, NR2A, and NR2B subunits of N-methyl-d-aspartate receptors (NMDARs) were unchanged while the Tyr-dependent phosphorylation of both NR2A and NR2B subunits were significantly reduced in KK-Ay mice. The level of p-Src expression mediating this process was decreased, and the level of αCaMKII autophosphorylation was also reduced. Meanwhile, the GluR1 of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) was decreased, and GluR2 was significantly increased. These data suggest that deficits in synaptic plasticity in KK-Ay mice may arise from the abnormal phosphorylation of the NR2 subunits and the alteration of subunit composition of AMPARs. Diet intervention at an early stage of diabetes might alleviate the cognitive deficits and LTP reduction in KK-Ay mice.

  16. CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum.

    PubMed

    Gerdeman, G; Lovinger, D M

    2001-01-01

    CB1 cannabinoid receptors in the neostriatum mediate profound motor deficits induced when cannabinoid drugs are administered to rodents. Because the CB1 receptor has been shown to inhibit neurotransmitter release in various brain areas, we investigated the effects of CB1 activation on glutamatergic synaptic transmission in the dorsolateral striatum of the rat where the CB1 receptor is highly expressed. We performed whole cell voltage-clamp experiments in striatal brain slices and applied the CB1 agonists HU-210 or WIN 55,212-2 during measurement of synaptic transmission. Excitatory postsynaptic currents (EPSCs), evoked by electrical stimulation of afferent fibers, were significantly reduced in a dose-dependent manner by CB1 agonist application. EPSC inhibition was accompanied by an increase in two separate indices of presynaptic release, the paired-pulse response ratio and the coefficient of variation, suggesting a decrease in neurotransmitter release. These effects were prevented by application of the CB1 antagonist SR141716A. When Sr(2+) was substituted for Ca(2+) in the extracellular solution, application of HU-210 (1 microM) significantly reduced the frequency, but not amplitude, of evoked, asynchronous quantal release events. Spontaneous release events were similarly decreased in frequency with no change in amplitude. These findings further support the interpretation that CB1 activation leads to a decrease of glutamate release from afferent terminals in the striatum. These results reveal a novel potential role for cannabinoids in regulating striatal function and thus basal ganglia output and may suggest CB1-targeted drugs as potential therapeutic agents in the treatment of Parkinson's disease and other basal ganglia disorders.

  17. Role of Nicotinic and Muscarinic Receptors on Synaptic Plasticity and Neurological Diseases.

    PubMed

    Fuenzalida, Marco; Pérez, Miguel Ángel; Arias, Hugo R

    2016-01-01

    The cholinergic activity in the brain is fundamental for cognitive functions. The modulatory activity of the neurotransmitter acetylcholine (ACh) is mediated by activating a variety of nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). Accumulating evidence indicates that both nAChR and mAChRs can modulate the release of several other neurotransmitters, modify the threshold of long-term plasticity, finally improving learning and memory processes. Importantly, the expression, distribution, and/or function of these systems are altered in several neurological diseases. The aim of this review is to discuss our current knowledge on cholinergic receptors and their regulating synaptic functions and neuronal network activities as well as their use as targets for the development of new and clinically useful cholinergic ligands. These new therapies involve the development of novel and more selective cholinergic agonists and allosteric modulators as well as selective cholinesterase inhibitors, which may improve cognitive and behavioral symptoms, and also provide neuroprotection in several brain diseases. The review will focus on two nAChR receptor subtypes found in the mammalian brain and the most commonly targeted in drug discovery programs for neuropsychiatric disorder, the ligands of α4β2 nAChR and α7 nAChRs.

  18. GABA type a receptor trafficking and the architecture of synaptic inhibition.

    PubMed

    Lorenz-Guertin, Joshua M; Jacob, Tija C

    2017-09-13

    Ubiquitous expression of GABA type A receptors (GABAA R) in the central nervous system establishes their central role in coordinating most aspects of neural function and development. Dysregulation of GABAergic neurotransmission manifests in a number of human health disorders and conditions that in certain cases can be alleviated by drugs targeting these receptors. Precise changes in the quantity or activity of GABAA Rs localized at the cell surface and at GABAergic postsynaptic sites directly impact the strength of inhibition. The molecular mechanisms constituting receptor trafficking to and from these compartments therefore dictate the efficacy of GABAA R function. Here we review the current understanding of how GABAA Rs traffic through biogenesis, plasma membrane transport, and degradation. Emphasis is placed on discussing novel GABAergic synaptic proteins, receptor and scaffolding post-translational modifications, activity-dependent changes in GABAA R confinement, and neuropeptide and neurosteroid mediated changes. We further highlight modern techniques currently advancing the knowledge of GABAA R trafficking and clinically relevant neurodevelopmental diseases connected to GABAergic dysfunction. © 2017 Wiley Periodicals, Inc. Develop Neurobiol, 2017. © 2017 Wiley Periodicals, Inc.

  19. Filamin, a synaptic organizer in Drosophila, determines glutamate receptor composition and membrane growth

    PubMed Central

    Lee, GaYoung; Schwarz, Thomas L

    2016-01-01

    Filamin is a scaffolding protein that functions in many cells as an actin-crosslinker. FLN90, an isoform of the Drosophila ortholog Filamin/cheerio that lacks the actin-binding domain, is here shown to govern the growth of postsynaptic membrane folds and the composition of glutamate receptor clusters at the larval neuromuscular junction. Genetic and biochemical analyses revealed that FLN90 is present surrounding synaptic boutons. FLN90 is required in the muscle for localization of the kinase dPak and, downstream of dPak, for localization of the GTPase Ral and the exocyst complex to this region. Consequently, Filamin is needed for growth of the subsynaptic reticulum. In addition, in the absence of filamin, type-A glutamate receptor subunits are lacking at the postsynapse, while type-B subunits cluster correctly. Receptor composition is dependent on dPak, but independent of the Ral pathway. Thus two major aspects of synapse formation, morphological plasticity and subtype-specific receptor clustering, require postsynaptic Filamin. DOI: http://dx.doi.org/10.7554/eLife.19991.001 PMID:27914199

  20. Itinerant magnetism without magnetic elements

    NASA Astrophysics Data System (ADS)

    Morosan, Emilia

    The origin of magnetism in metals has been traditionally discussed in two diametrically opposite limits: itinerant and local moments. Surprisingly, there are very few known examples of materials that are close to the itinerant limit, and their properties are not universally understood. In the case of the two such examples discovered several decades ago, both itinerant ferromagnets (IFMs) ZrZn2 and Sc3In, the understanding of their magnetic ground states draws on the existence of 3d electrons subject to strong spin fluctuations. In this talk I will contrast the physical properties of these two IFMs without magnetic elements with those of the recently discovered first itinerant antiferromagnetic (IAFM) metal with no magnetic constituents, TiAu. The IFMs have surprisingly different properties, with ZrZn2 showing signatures of mean field, Fermi liquid behavior, while the Sc3In compound is characterized by non-mean field magnetization exponents, and displays non fermi liquid behavior in both the FM and the paramagnetic states. The IAFM TiAu orders below a Neel temperature TN ~ K, about an order of magnitude smaller than in the IAFM Cr, rendering the spin fluctuations in TiAu more important at low temperatures. Like in the two IFMs, doping induces a quantum phase transition in TiAu, and the quantum critical behavior in all three systems is discussed and compared. This work is supported by NSF DMR-1506704.

  1. Recruitment of calcium-permeable AMPA receptors during synaptic potentiation is regulated by CaM-kinase I.

    PubMed

    Guire, Eric S; Oh, Michael C; Soderling, Thomas R; Derkach, Victor A

    2008-06-04

    Ca(2+)-permeable AMPA receptors (CP-AMPARs) at central glutamatergic synapses are of special interest because of their unique biophysical and signaling properties that contribute to synaptic plasticity and their roles in multiple neuropathologies. However, intracellular signaling pathways that recruit synaptic CP-AMPARs are unknown, and involvement of CP-AMPARs in hippocampal region CA1 synaptic plasticity is controversial. Here, we report that intracellular infusion of active CaM-kinase I (CaMKI) into cultured hippocampal neurons enhances miniature EPSC amplitude because of recruitment of CP-AMPARs, likely from an extrasynaptic pool. The ability of CaMKI, which regulates the actin cytoskeleton, to recruit synaptic CP-AMPARs was blocked by inhibiting actin polymerization with latrunculin A. CaMK regulation of CP-AMPARs was also confirmed in hippocampal slices. CA1 long-term potentiation (LTP) after theta bursts, but not high-frequency tetani, produced a rapid, transient expression of synaptic CP-AMPARs that facilitated LTP. This component of TBS LTP was blocked by inhibition of CaM-kinase kinase (CaMKK), the upstream activator of CaMKI. Our calculations show that adding CP-AMPARs numbering <5% of existing synaptic AMPARs is sufficient to account for the potentiation observed in LTP. Thus, synaptic expression of CP-AMPARs is a very efficient mechanism for rapid enhancement of synaptic strength that depends on CaMKK/CaMKI signaling, actin dynamics, and the pattern of synaptic activity used to induce CA1 LTP.

  2. γ1-Containing GABA-A Receptors Cluster at Synapses Where they Mediate Slower Synaptic Currents than γ2-Containing GABA-A Receptors.

    PubMed

    Dixon, Christine L; Sah, Pankaj; Keramidas, Angelo; Lynch, Joseph W; Durisic, Nela

    2017-01-01

    GABA-A receptors (GABAARs) are pentameric ligand-gated ion channels that are assembled mainly from α (α1-6), β (β1-3) and γ (γ1-3) subunits. Although GABAARs containing γ2L subunits mediate most of the inhibitory neurotransmission in the brain, significant expression of γ1 subunits is seen in the amygdala, pallidum and substantia nigra. However, the location and function of γ1-containing GABAARs in these regions remains unclear. In "artificial" synapses, where the subunit composition of postsynaptic receptors is specifically controlled, γ1 incorporation slows the synaptic current decay rate without affecting channel deactivation, suggesting that γ1-containing receptors are not clustered and therefore activated by diffuse neurotransmitter. However, we show that γ1-containing receptors are localized at neuronal synapses and form clusters in both synaptic and extrasynaptic regions. In addition, they exhibit rapid membrane diffusion and a higher frequency of exchange between synaptic and perisynaptic populations compared to γ2L-containing GABAARs. A point mutation in the large intracellular domain and a pharmacological analysis reveal that when a single non-conserved γ2L residue is mutated to its γ1 counterpart (T349L), the synaptic current decay is slowed from γ2L- to γ1-like without changing the clustering or diffusion properties of the receptors. In addition, previous fast perfusion and single channel kinetic experiments revealed no difference in the intrinsic closing rates of γ2L- and γ1-containing receptors when expressed in HEK293 cells. These observations together with Monte Carlo simulations of synaptic function confirm that decreased clustering does not control γ1-containing GABAAR kinetics. Rather, they suggest that γ1- and γ2L-containing receptors exhibit differential synaptic current decay rates due to differential gating dynamics when localized at the synapse.

  3. Distinct perisynaptic and synaptic localization of NMDA and AMPA receptors on ganglion cells in rat retina

    PubMed Central

    Zhang, Jun; Diamond, Jeffrey S.

    2008-01-01

    At most excitatory synapses, AMPA and NMDA receptors (AMPARs and NMDARs) occupy the postsynaptic density (PSD) and contribute to miniature excitatory postsynaptic currents (mEPSCs) elicited by single transmitter quanta. Juxtaposition of AMPARs and NMDARs may be crucial for certain types of synaptic plasticity, although extrasynaptic NMDARs also may contribute. AMPARs and NMDARs also contribute to evoked EPSCs in retinal ganglion cells (RGCs), but mEPSCs are mediated solely by AMPARs. Previous work indicates that an NMDAR component emerges in mEPSCs when glutamate uptake is reduced, suggesting that NMDARs are located near the release site but perhaps not directly beneath in the PSD. Consistent with this idea, NMDARs on RGCs encounter a lower glutamate concentration during synaptic transmission than do AMPARs. To understand better the roles of NMDARs in RGC function, we have used immunohistochemical and electron microscopic techniques to determine the precise subsynaptic localization of NMDARs in RGC dendrites. RGC dendrites were labeled retrogradely with cholera toxin B subunit (CTB) injected into the superior colliculus (SC) and identified using postembedding immunogold methods. Co-labeling with antibodies directed toward AMPARs and/or NMDARs, we found that nearly all AMPARs are located within the PSD, while most NMDARs are located perisynaptically, 100–300 nm from the PSD. This morphological evidence for exclusively perisynaptic NMDARs localizations suggests a distinct role for NMDARs in RGC function. PMID:16927255

  4. A Role for Calcium-Permeable AMPA Receptors in Synaptic Plasticity and Learning

    PubMed Central

    Gray, Erin E.; Abdipranoto, Andrea; Thangthaeng, Nopporn; Jacobs, Nate; Saab, Faysal; Tonegawa, Susumu; Heinemann, Stephen F.; O'Dell, Thomas J.; Fanselow, Michael S.; Vissel, Bryce

    2010-01-01

    A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca2+-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice). Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP) that was independent of NMDARs and mediated by GluR2-lacking Ca2+-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca2+-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs. PMID:20927382

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

    PubMed Central

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

    2016-01-01

    In response to environmental and physiological changes, the synapse manifests plasticity while simultaneously maintains homeostasis. Here, we analyzed mutant synapses of henji, also known as dbo, at the Drosophila neuromuscular junction (NMJ). In henji mutants, NMJ growth is defective with appearance of satellite boutons. Transmission electron microscopy analysis indicates that the synaptic membrane region is expanded. The postsynaptic density (PSD) houses glutamate receptors GluRIIA and GluRIIB, which have distinct transmission properties. In henji mutants, GluRIIA abundance is upregulated but that of GluRIIB is not. Electrophysiological results also support a GluR compositional shift towards a higher IIA/IIB ratio at henji NMJs. Strikingly, dPAK, a positive regulator for GluRIIA synaptic localization, accumulates at the henji PSD. Reducing the dpak gene dosage suppresses satellite boutons and GluRIIA accumulation at henji NMJs. In addition, dPAK associated with Henji through the Kelch repeats which is the domain essential for Henji localization and function at postsynapses. We propose that Henji acts at postsynapses to restrict both presynaptic bouton growth and postsynaptic GluRIIA abundance by modulating dPAK. PMID:27736876

  6. Fingolimod Limits Acute Aβ Neurotoxicity and Promotes Synaptic Versus Extrasynaptic NMDA Receptor Functionality in Hippocampal Neurons

    PubMed Central

    Joshi, Pooja; Gabrielli, Martina; Ponzoni, Luisa; Pelucchi, Silvia; Stravalaci, Matteo; Beeg, Marten; Mazzitelli, Sonia; Braida, Daniela; Sala, Mariaelvina; Boda, Enrica; Buffo, Annalisa; Gobbi, Marco; Gardoni, Fabrizio; Matteoli, Michela; Marcello, Elena; Verderio, Claudia

    2017-01-01

    Fingolimod, also known as FTY720, is an analogue of the sphingolipid sphingosine, which has been proved to be neuroprotective in rodent models of Alzheimer’s disease (AD). Several cellular and molecular targets underlying the neuroprotective effects of FTY720 have been recently identified. However, whether the drug directly protects neurons from toxicity of amyloid-beta (Aβ) still remains poorly defined. Using a combination of biochemical assays, live imaging and electrophysiology we demonstrate that FTY720 induces a rapid increase in GLUN2A-containing neuroprotective NMDARs on the surface of dendritic spines in cultured hippocampal neurons. In addition, the drug mobilizes extrasynaptic GLUN2B-containing NMDARs, which are coupled to cell death, to the synapses. Altered ratio of synaptic/extrasynaptic NMDARs decreases calcium responsiveness of neurons to neurotoxic soluble Aβ 1–42 and renders neurons resistant to early alteration of calcium homeostasis. The fast defensive response of FTY720 occurs through a Sphingosine-1-phosphate receptor (S1P-R) -dependent mechanism, as it is lost in the presence of S1P-R1 and S1P-R3 antagonists. We propose that rapid synaptic relocation of NMDARs might have direct impact on amelioration of cognitive performance in transgenic APPswe/PS1dE9 AD mice upon sub-chronic treatment with FTY720. PMID:28134307

  7. Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule.

    PubMed

    Zhang, H; Etherington, L-A; Hafner, A-S; Belelli, D; Coussen, F; Delagrange, P; Chaouloff, F; Spedding, M; Lambert, J J; Choquet, D; Groc, L

    2013-04-01

    The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions of such adaptations have been linked to psychiatric disorders such as depression. Although the intracellular cascades that are altered in models of depression and stress-related disorders have been under considerable scrutiny, the molecular interplay between antidepressants and glutamatergic signaling remains elusive. Using a combination of electrophysiological and single nanoparticle tracking approaches, we here report that the cognitive enhancer and antidepressant tianeptine (S 1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) favors synaptic plasticity in hippocampal neurons both under basal conditions and after acute stress. Strikingly, tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced AMPAR surface dispersal and restores long-term potentiation of acutely stressed mice. Collectively, these data provide the first evidence that a therapeutically used drug targets the surface diffusion of AMPAR through a CaMKII-stargazin-PSD-95 pathway, to promote long-term synaptic plasticity.

  8. Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity

    PubMed Central

    Klaassen, Remco V.; Stroeder, Jasper; Coussen, Françoise; Hafner, Anne-Sophie; Petersen, Jennifer D.; Renancio, Cedric; Schmitz, Leanne J. M.; Normand, Elisabeth; Lodder, Johannes C.; Rotaru, Diana C.; Rao-Ruiz, Priyanka; Spijker, Sabine; Mansvelder, Huibert D.; Choquet, Daniel; Smit, August B.

    2016-01-01

    Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs. The Shisa6 C-terminus harbours a PDZ domain ligand that binds to PSD-95, constraining mobility of AMPARs in the plasma membrane and confining them to postsynaptic densities. Shisa6 expressed in HEK293 cells alters GluA1- and GluA2-mediated currents by prolonging decay times and decreasing the extent of AMPAR desensitization, while slowing the rate of recovery from desensitization. Using gene deletion, we show that Shisa6 increases rise and decay times of hippocampal CA1 miniature excitatory postsynaptic currents (mEPSCs). Shisa6-containing AMPARs show prominent sustained currents, indicating protection from full desensitization. Accordingly, Shisa6 prevents synaptically trapped AMPARs from depression at high-frequency synaptic transmission. PMID:26931375

  9. 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.

  10. The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity

    PubMed Central

    Chater, Thomas E.; Goda, Yukiko

    2014-01-01

    In the mammalian central nervous system, excitatory glutamatergic synapses harness neurotransmission that is mediated by ion flow through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs, which are enriched in the postsynaptic membrane on dendritic spines, are highly dynamic, and shuttle in and out of synapses in an activity-dependent manner. Changes in their number, subunit composition, phosphorylation state, and accessory proteins can all regulate AMPARs and thus modify synaptic strength and support cellular forms of learning. Furthermore, dysregulation of AMPAR plasticity has been implicated in various pathological states and has important consequences for mental health. Here we focus on the mechanisms that control AMPAR plasticity, drawing particularly from the extensive studies on hippocampal synapses, and highlight recent advances in the field along with considerations for future directions. PMID:25505875

  11. Muscarinic M1 receptors modulate endotoxemia-induced loss of synaptic plasticity.

    PubMed

    Zivkovic, Aleksandar R; Sedlaczek, Oliver; von Haken, Rebecca; Schmidt, Karsten; Brenner, Thorsten; Weigand, Markus A; Bading, Hilmar; Bengtson, C Peter; Hofer, Stefan

    2015-11-04

    Septic encephalopathy is associated with rapid deterioration of cortical functions. Using magnetic resonance imaging (MRI) we detected functional abnormalities in the hippocampal formation of patients with septic delirium. Hippocampal dysfunction was further investigated in an animal model for sepsis using lipopolysaccharide (LPS) injections to induce endotoxemia in rats, followed by electrophysiological recordings in brain slices. Endotoxemia induced a deficit in long term potentiation which was completely reversed by apamin, a blocker of small conductance calcium-activated potassium (SK) channels, and partly restored by treatment with physostigmine (eserine), an acetylcholinesterase inhibitor, or TBPB, a selective M1 muscarinic acetylcholine receptor agonist. These results suggest a novel role for SK channels in the etiology of endotoxemia and explain why boosting cholinergic function restores deficits in synaptic plasticity. Drugs which enhance cholinergic or M1 activity in the brain may prove beneficial in treatment of septic delirium in the intensive care unit.

  12. Neuronal and synaptic organization in the gravity receptor system of the statocyst of Octopus vulgaris.

    PubMed

    Colmers, W F

    1977-12-28

    The neuronal and synaptic organization of the sensory epithelium (macula) of the gravity receptor system of Octopus vulgaris was investigated by serial electron microscopic reconstruction. Three different types of afferent neurons, unipolar, bipolar, and multipolar, are described. Afferent synapses exist between the secondary sensory cells (hair cells) and the afferent neurons. Consequently, the neurons are first-order neurons. Two morphologically distinct types of afferent synapses could be identified: the most common type, present on every hair cell, has a finger-like postsynaptic process; the second type, which does not occur on every hair cell, has a flat or somewhat curved postsynaptic process. As a rule, the hair cells each form synapses with more than one afferent neuron. The neurons, in turn, form synapses with more than one hair cell. A complicated arrangement of efferent synapses was found at the level of both the hair cells and the neurons. The results are discussed with reference to their physiological consequences.

  13. Effect of chronic psychogenic stress on characteristics of some rat brain synaptic membrane receptors

    SciTech Connect

    Nikuradze, V.O.; Kozlovskaya, M.M.; Rozhanets, V.V.; Val'dman, A.V.

    1986-02-01

    This paper studies characteristics of alpha- and beta-adrenoreceptors, and imipramine and bensodiazepine receptors in brain synaptic membranes of rats after exposure to combined stress for 15 days by a modified Hecht's method. Before the experiment the suspension was thawed and centrifuged. Specific binding of tritium-WB-4101 (30 Ci/mmole), tritium-dihydroalprenolol, tritium-flunitrazepam, and tritium-imipramine was carried out by known methods with certain modifications. The results suggest that pathology of behavior in rats observed in the model may be classed as a depressive-like state rather than a neurosis-like state, and the model itself may be more appropriate for the study of the mechanisms of action of compounds with marked tranquilizing activity.

  14. Fine-tuning of synaptic upscaling at excitatory synapses by endocannabinoid signaling is mediated via the CB1 receptor

    PubMed Central

    Song, Yunping; Zhang, Jian; Chen, Chu

    2015-01-01

    The endocannabinoid 2-arachidonoylglycerol (2-AG) functions as a retrograde signaling molecule mediating synaptic transmission and plasticity at both inhibitory and excitatory synapses. However, little is known about whether 2-AG signaling is involved in homeostatic regulation of miniature synaptic events at excitatory synapses in response to activity deprivation. Here, we report that chronic blockade of firing by tetrodotoxin (TTX) for two days resulted in increases both in the frequency and amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in cultured mouse hippocampal neurons. However, treatment with 2-AG alone or JZL184, a potent and selective inhibitor for monoacylglycerol lipase (MAGL) that hydrolyzes 2-AG, induced a CB1 receptor-dependent reduction of the frequency of mEPSCs, but not the amplitude. The TTX-increased frequency was blunted by 2-AG or JZL184 and this effect was eliminated by pharmacological or genetic inhibition of CB1 receptors. In addition, TTX still increased frequency and amplitude of mEPSCs in the presence of CB1 receptor inhibition. Our results suggest that while endocannabinoids are not required for induction of synaptic scaling at excitatory glutamate synapses after chronic activity deprivation, 2-AG signaling may play a role in fine-tuning of synaptic strengths via presynaptically-expressed CB1 receptors. PMID:26541090

  15. 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

  16. 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.

  17. Altered AMPA receptor expression plays an important role in inducing bidirectional synaptic plasticity during contextual fear memory reconsolidation.

    PubMed

    Bhattacharya, Subhrajit; Kimble, Whitney; Buabeid, Manal; Bhattacharya, Dwipayan; Bloemer, Jenna; Alhowail, Ahmad; Reed, Miranda; Dhanasekaran, Muralikrishnan; Escobar, Martha; Suppiramaniam, Vishnu

    2017-03-01

    Retrieval of a memory appears to render it unstable until the memory is once again re-stabilized or reconsolidated. Although the occurrence and consequences of reconsolidation have received much attention in recent years, the specific mechanisms that underlie the process of reconsolidation have not been fully described. Here, we present the first electrophysiological model of the synaptic plasticity changes underlying the different stages of reconsolidation of a conditioned fear memory. In this model, retrieval of a fear memory results in immediate but transient alterations in synaptic plasticity, mediated by modified expression of the glutamate receptor subunits GluA1 and GluA2 in the hippocampus of rodents. Retrieval of a memory results in an immediate impairment in LTP, which is enhanced 6h following memory retrieval. Conversely, memory retrieval results in an immediate enhancement of LTD, which decreases with time. These changes in plasticity are accompanied by decreased expression of GluA2 receptor subunits. Recovery of LTP and LTD correlates with progressive overexpression of GluA2 receptor subunits. The contribution of the GluA2 receptor was confirmed by interfering with receptor expression at the postsynaptic sites. Blocking GluA2 endocytosis restored LTP and attenuated LTD during the initial portion of the reconsolidation period. These findings suggest that altered GluA2 receptor expression is one of the mechanisms that controls different forms of synaptic plasticity during reconsolidation.

  18. 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.

  19. 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

  20. Myosin IIb-dependent Regulation of Actin Dynamics Is Required for N-Methyl-D-aspartate Receptor Trafficking during Synaptic Plasticity.

    PubMed

    Bu, Yunfei; Wang, Ning; Wang, Shaoli; Sheng, Tao; Tian, Tian; Chen, Linlin; Pan, Weiwei; Zhu, Minsheng; Luo, Jianhong; Lu, Wei

    2015-10-16

    N-Methyl-d-aspartate receptor (NMDAR) synaptic incorporation changes the number of NMDARs at synapses and is thus critical to various NMDAR-dependent brain functions. To date, the molecules involved in NMDAR trafficking and the underlying mechanisms are poorly understood. Here, we report that myosin IIb is an essential molecule in NMDAR synaptic incorporation during PKC- or θ burst stimulation-induced synaptic plasticity. Moreover, we demonstrate that myosin light chain kinase (MLCK)-dependent actin reorganization contributes to NMDAR trafficking. The findings from additional mutual occlusion experiments demonstrate that PKC and MLCK share a common signaling pathway in NMDAR-mediated synaptic regulation. Because myosin IIb is the primary substrate of MLCK and can regulate actin dynamics during synaptic plasticity, we propose that the MLCK- and myosin IIb-dependent regulation of actin dynamics is required for NMDAR trafficking during synaptic plasticity. This study provides important insights into a mechanical framework for understanding NMDAR trafficking associated with synaptic plasticity.

  1. Striatopallidal Neuron NMDA Receptors Control Synaptic Connectivity, Locomotor, and Goal-Directed Behaviors

    PubMed Central

    Lambot, Laurie; Chaves Rodriguez, Elena; Houtteman, Delphine; Li, Yuquing; Schiffmann, Serge N.; Gall, David

    2016-01-01

    The basal ganglia (BG) control action selection, motor programs, habits, and goal-directed learning. The striatum, the principal input structure of BG, is predominantly composed of medium-sized spiny neurons (MSNs). Arising from these spatially intermixed MSNs, two inhibitory outputs form two main efferent pathways, the direct and indirect pathways. Striatonigral MSNs give rise to the activating, direct pathway MSNs and striatopallidal MSNs to the inhibitory, indirect pathway (iMSNs). BG output nuclei integrate information from both pathways to fine-tune motor procedures and to acquire complex habits and skills. Therefore, balanced activity between both pathways is crucial for harmonious functions of the BG. Despite the increase in knowledge concerning the role of glutamate NMDA receptors (NMDA-Rs) in the striatum, understanding of the specific functions of NMDA-R iMSNs is still lacking. For this purpose, we generated a conditional knock-out mouse to address the functions of the NMDA-R in the indirect pathway. At the cellular level, deletion of GluN1 in iMSNs leads to a reduction in the number and strength of the excitatory corticostriatopallidal synapses. The subsequent scaling down in input integration leads to dysfunctional changes in BG output, which is seen as reduced habituation, delay in goal-directed learning, lack of associative behavior, and impairment in action selection or skill learning. The NMDA-R deletion in iMSNs causes a decrease in the synaptic strength of striatopallidal neurons, which in turn might lead to a imbalanced integration between direct and indirect MSN pathways, making mice less sensitive to environmental change. Therefore, their ability to learn and adapt to the environment-based experience was significantly affected. SIGNIFICANCE STATEMENT The striatum controls habits, locomotion, and goal-directed behaviors by coordinated activation of two antagonistic pathways. Insofar as NMDA receptors (NMDA-Rs) play a key role in synaptic

  2. SYNAPTIC TRANSLATION OF STRIATAL-ENRICHED TYROSINE PHOSPHATASE (STEP) AFTER β1-ADRENERGIC RECEPTOR STIMULATION

    PubMed Central

    Hu, Yaer; Zhang, Yang; Venkitaramani, Deepa V.; Lombroso, Paul J.

    2009-01-01

    The β-adrenergic system is implicated in long-term synaptic plasticity in the central nervous system, a process that requires protein synthesis. To identify proteins that are translated in response to β-adrenergic receptor stimulation and the pathways that regulate this process, we investigated the effects of isoproterenol on the translation of striatal-enriched protein tyrosine phosphatase (STEP) in both cortico-striatal slices and primary neuronal cultures. Isoproterenol stimulation induced a rapid dose-dependent increase in STEP expression. Anisomycin blocked the increase in STEP expression while actinomycin D had no effect, suggesting a translation-dependent mechanism. Isoproterenol-induced STEP translation required activation of β1 receptors. Application of the MEK inhibitor SL327 blocked both isoproterenol-induced activation of pERK and subsequent STEP translation. Inhibitors of PI3K (LY294002) or mTOR (rapamycin) also completely blocked STEP translation. These results suggest that co-activation of both the ERK and PI3K-Akt-mTOR pathways are required for STEP translation. As the substrates of STEP include ERK itself, these results suggest that STEP is translated upon β-adrenergic activation as part of a negative feedback mechanism. PMID:17623046

  3. 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

  4. Sensitivities of dopamine D1 and D2 receptor radioligands to changes in synaptic dopamine

    SciTech Connect

    Gifford, A.N.; Gatley, S.J.; Shea, C.

    1996-05-01

    Prior studies have shown that the in vivo binding of D2 radioligands such as raclopride and IBZM is subject to competition with synaptic DA. D2 radioligands can thus be used to evaluate both direct effects of drugs at DAergic synapses, and indirect effects at these synapses mediated via neurotransmitter interactions. Competition with DA must also be a potential confounding factor in studies designed to evaluate changes in D2 receptor number. We evaluated the sensitivity of the D1 radioligands for susceptibility to alterations in synaptic DA. We evaluated the sensitivity of the D1 radioligand SCH 23390 using three different models: rat brain slices in which DA release is controlled by electrically simulation, ex vivo mouse brain uptake, and PET in the baboon brain. In slices, the order of sensitivity of DA system radioligands to synaptic DA was D1>D2>DA transporter, and the sensitivity of the low affinity (Kd = 1 nM) D2 ligand, [H-3]raclopride, was greater than that of the high affinity (Kd = 0.05 nM) D2 ligand, [I-123]epidepride (Gifford et al., Synapse, in press). In mice, striatal [H-3]SCH 23390 was decreased after administration of the DA transporter blocker RTI-55 ({beta}-CIT, 0.5 mg/kg, i/v), to a similar extent as that of co-administered [I-123]epidepride. In these experiments RTI-55 was given four hours after injection of radiotracers, after peak striatal radioactivity, to avoid the effects of the increase in delivery of radiotracer to the brain caused by RTI-55. In PET experiments, striatal binding of the D1 radioligand [C-11]SCH23390 was less sensitive to challenge with the DA transporter blocker methylphenidate (0.5 mg/kg, 7-10 min before radiotracer) than is [C-11]raclopride. Our results together indicate that SCH 23390 is not very sensitive to pharmacological challenges which decrease the in vivo binding of labeled raclopride.

  5. The modulation of synaptic GABA(A) receptors in the thalamus by eszopiclone and zolpidem.

    PubMed

    Jia, Fan; Goldstein, Peter A; Harrison, Neil L

    2009-03-01

    Eszopiclone (Lunesta; Sepracor, Marlborough, MA) and zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)-imidazo(1,2-a)pyridine-3-acetamide] are among the most commonly prescribed hypnotics in use in the United States. The thalamus plays a pivotal role in sleep regulation and rhythmicity. Two distinct subtypes of synaptic GABA(A) receptors (GABA(A)-Rs), alpha(1)beta(2)gamma(2) and alpha(3)beta(3)gamma(2), are expressed in thalamocortical relay neurons and in interneurons of the RTN (reticular thalamic nucleus), respectively. Thalamocortical neurons also express extrasynaptic GABA(A)-Rs composed of alpha(4)beta(2)delta subunits. In this study, we compared the effects of eszopiclone and zolpidem on miniature inhibitory postsynaptic currents (IPSCs), spontaneous IPSCs, and tonic inhibition in the mouse thalamus. Eszopiclone (0.1-1 microM) slowed the decay phase of IPSCs recorded from RTN neurons, whereas zolpidem was less effective and increased the decay time constant only at > or = 0.3 microM. IPSCs of RTN neurons were more sensitive to eszopiclone than zolpidem at all concentrations tested. On the other hand, IPSCs of relay neurons in the ventrobasal nucleus (VB) were more sensitive to zolpidem than eszopiclone. Zolpidem (0.1-1 microM) prolonged the decay of IPSCs from VB neurons, whereas eszopiclone increased the decay time constant only at > or = 0.3 microM. Neither of these two hypnotics affected tonic inhibition in relay neurons. Our results demonstrate that eszopiclone has greater efficacy at synaptic GABA(A)-Rs of RTN neurons than in relay neurons, whereas zolpidem exerts bigger effects on relay neurons than RTN neurons. This distinct pattern of activity on thalamic neurons may contribute to some of the observed differences in the clinical effects of these two hypnotics.

  6. Indistinguishable Synaptic Pharmacodynamics of the N-Methyl-d-Aspartate Receptor Channel Blockers Memantine and Ketamine

    PubMed Central

    Emnett, Christine M.; Eisenman, Lawrence N.; Taylor, Amanda M.; Izumi, Yukitoshi; Zorumski, Charles F.

    2013-01-01

    Memantine and ketamine, voltage- and activation-dependent channel blockers of N-methyl-d-aspartate (NMDA) receptors (NMDARs), have enjoyed a recent resurgence in clinical interest. Steady-state pharmacodynamic differences between these blockers have been reported, but it is unclear whether the compounds differentially affect dynamic physiologic signaling. In this study, we explored nonequilibrium conditions relevant to synaptic transmission in hippocampal networks in dissociated culture and hippocampal slices. Equimolar memantine and ketamine had indistinguishable effects on the following measures: steady-state NMDA currents, NMDAR excitatory postsynaptic current (EPSC) decay kinetics, progressive EPSC inhibition during repetitive stimulation, and extrasynaptic NMDAR inhibition. Therapeutic drug efficacy and tolerability of memantine have been attributed to fast kinetics and strong voltage dependence. However, pulse depolarization in drug presence revealed a surprisingly slow and similar time course of equilibration for the two compounds, although memantine produced a more prominent fast component (62% versus 48%) of re-equilibration. Simulations predicted that low gating efficacy underlies the slow voltage–dependent relief from block. This prediction was empirically supported by faster voltage-dependent blocker re-equilibration with several experimental manipulations of gating efficacy. Excitatory postsynaptic potential–like voltage commands produced drug differences only with large, prolonged depolarizations unlikely to be attained physiologically. In fact, we found no difference between drugs on measures of spontaneous network activity or acute effects on plasticity in hippocampal slices. Despite indistinguishable synaptic pharmacodynamics, ketamine provided significantly greater neuroprotection from damage induced by oxygen glucose deprivation, consistent with the idea that under extreme depolarizing conditions, the biophysical difference between drugs

  7. Control of excitatory synaptic transmission by capsaicin is unaltered in TRPV1 vanilloid receptor knockout mice

    PubMed Central

    Benninger, Felix; Freund, Tamás F.; Hájos, Norbert

    2008-01-01

    Several studies have shown that capsaicin could effectively regulate excitatory synaptic transmission in the central nervous system, but the assumption that this effect is mediated by TRPV1 vanilloid receptors (TRPV1Rs) has not been tested directly. To provide direct evidence, we compared the effect of capsaicin on excitatory synapses in wild type mice and TRPV1R knockouts. Using whole-cell patch-clamp techniques, excitatory postsynaptic currents (EPSCs) were recorded in granule cells of the dentate gyrus. First, we investigated the effect of capsaicin on EPSCs evoked by focal stimulation of fibers in the stratum moleculare. Bath application of 10 μM capsaicin reduced the amplitude of evoked EPSCs both in wild type and TRPV1R knockout animals to a similar extent. Treatment of the slices with the TRPV1R antagonist capsazepine (10 μM) alone, or together with the agonist capsaicin, also caused a decrease in the EPSC amplitude both in wild type and TRPV1R knockout animals. Both drugs appeared to affect the efficacy of excitatory synapses at presynaptic sites, since a significant increase was observed in paired-pulse ratio of EPSC amplitude after drug treatment. Next we examined the effect of capsaicin on spontaneously occurring EPSCs. This prototypic vanilloid ligand increased the frequency of events without changing their amplitude in wild type mice. Similar enhancement in the frequency without altering the amplitude of spontaneous EPSCs was observed in TRPV1R knockout mice. These data strongly argue against the hypothesis that capsaicin modulates excitatory synaptic transmission by activating TRPV1Rs, at least in the hippocampal network. PMID:17651868

  8. The coexistence of multiple receptors in a single nerve terminal provides evidence for pre-synaptic integration.

    PubMed

    Ladera, Carolina; Godino, María Del Carmen; Martín, Ricardo; Luján, Rafael; Shigemoto, Ryuichi; Ciruela, Francisco; Torres, Magdalena; Sánchez-Prieto, José

    2007-12-01

    Excitatory synaptic transmission is inhibited by G protein coupled receptors, including the adenosine A(1), GABA(B), and metabotropic glutamate receptor 7. These receptors are present in nerve terminals where they reduce the release of glutamate through activating signaling pathways negatively coupled to Ca(2+) channels and adenylyl cyclase. However, it is not clear whether these receptors operate in distinct subpopulations of nerve terminals or if they are co-expressed in the same nerve terminals, despite the functional consequences that such distributions may have on synaptic transmission. Applying Ca(2+) imaging and immunocytochemistry, we show that these three G protein coupled receptors coexist in a subpopulation of cerebrocortical nerve terminals. The three receptors share an intracellular signaling pathway through which their inhibitory responses are integrated and coactivation of these receptors produced an integrated response. Indeed, this response was highly variable, from a synergistic response at subthreshold agonist concentrations to an occluded response at high agonist concentrations. The presence of multiple receptors in a nerve terminal could be responsible for the physiological effects of neurotransmitter spillover from neighboring synapses or alternatively, the co-release of transmitters by the same nerve terminal.

  9. GABAA and glutamate receptor involvement in dendrodendritic synaptic interactions from salamander olfactory bulb.

    PubMed

    Wellis, D P; Kauer, J S

    1993-09-01

    lateral inhibition. 6. CNQX and AP5 attenuated the optical signals within the bulb supporting the contention that in these conditions, optical signals arise mainly from granule cell dendritic activity. Furthermore, AP5 or removal of bath Mg2+ reduced or enlarged the spatial distribution of activity respectively, suggesting that in some cases the NMDA receptor may be involved in generating or stabilizing spatial patterns of activity. 7. It is concluded that in the salamander olfactory bulb, both GABAA- and glutamate receptor-mediated synaptic transmission shape the different temporal and spatial patterns of neural activity associated with olfactory coding.

  10. Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain

    PubMed Central

    Sheffler-Collins, Sean I.; Xia, Nan L.; Henderson, Nathan; Tillu, Dipti V.; Hassler, Shayne; Spellman, Daniel S.; Zhang, Guoan; Neubert, Thomas A.; Price, Theodore J.

    2017-01-01

    Extracellular phosphorylation of proteins was suggested in the late 1800s when it was demonstrated that casein contains phosphate. More recently, extracellular kinases that phosphorylate extracellular serine, threonine, and tyrosine residues of numerous proteins have been identified. However, the functional significance of extracellular phosphorylation of specific residues in the nervous system is poorly understood. Here we show that synaptic accumulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) and pathological pain are controlled by ephrin-B-induced extracellular phosphorylation of a single tyrosine (p*Y504) in a highly conserved region of the fibronectin type III (FN3) domain of the receptor tyrosine kinase EphB2. Ligand-dependent Y504 phosphorylation modulates the EphB-NMDAR interaction in cortical and spinal cord neurons. Furthermore, Y504 phosphorylation enhances NMDAR localization and injury-induced pain behavior. By mediating inducible extracellular interactions that are capable of modulating animal behavior, extracellular tyrosine phosphorylation of EphBs may represent a previously unknown class of mechanism mediating protein interaction and function. PMID:28719605

  11. Presynaptic GABAB and adenosine A1 receptors regulate synaptic transmission to rat substantia nigra reticulata neurones.

    PubMed Central

    Shen, K Z; Johnson, S W

    1997-01-01

    1. Patch pipettes were used to record whole-cell currents under voltage clamp in substantia nigra zona reticulata (SNR) neurones in the rat midbrain slice. Bipolar electrodes evoked synaptic currents mediated by glutamate (EPSCs) and GABAA receptors (IPSCs). 2. Baclofen reduced the amplitude of IPSCs by 48% at its IC50 value of 0.60 microM. The GABAB antagonist CGP 35348 blocked this effect with a Kd value estimated by Schild analysis of 5 microM. 3. Adenosine reduced IPSCs by 48% at its IC50 value of 56 microM. Adenosine agonists reduced IPSCs with the following rank order of potency: CPA (N6-cyclopentyladenosine) > R-PIA (R(-)N6-(2-phenylisopropyl)adenosine) > CHA (N6-cyclohexyladenosine) = NECA (5'-N-ethylcarboxamidoadenosine) > 2-CADO (2-chloroadenosine) > adenosine. Schild analysis yielded a Kd value of 0.4 nM for antagonism of CPA by the adenosine A1 receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine). 4. Both baclofen and adenosine reduced the magnitude of paired-pulse depression of IPSCs, and neither blocked currents evoked by GABA, which was pressure-ejected from micropipettes. 5. Glutamate EPSCs were reduced by baclofen (IC50 = 0.78 microM) and adenosine (IC50 = 57 microM). Schild analysis yielded a Kd value of 11 microM for antagonism of baclofen-induced inhibition of EPSCs by CGP 35348. DPCPX (1 microM) completely blocked the inhibitory effects of adenosine (100 microM) and CPA (100 nM) on EPSCs. Neither adenosine nor baclofen reduced inward currents evoked by glutamate which was pressure-ejected from micropipettes. 6. These results show that presynaptic GABAB and A1 receptors reduce glutamate and GABA release from nerve terminals in the SNR. PMID:9409479

  12. 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

  13. Subchronic glucocorticoid receptor inhibition rescues early episodic memory and synaptic plasticity deficits in a mouse model of Alzheimer's disease.

    PubMed

    Lanté, Fabien; Chafai, Magda; Raymond, Elisabeth Fabienne; Pereira, Ana Rita Salgueiro; Mouska, Xavier; Kootar, Scherazad; Barik, Jacques; Bethus, Ingrid; Marie, Hélène

    2015-06-01

    The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by the elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis, circadian rhythm, and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by subchronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, whereas LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset.

  14. Tumor necrosis factor (TNF)-receptor 1 and 2 mediate homeostatic synaptic plasticity of denervated mouse dentate granule cells

    PubMed Central

    Becker, Denise; Deller, Thomas; Vlachos, Andreas

    2015-01-01

    Neurological diseases are often accompanied by neuronal cell death and subsequent deafferentation of connected brain regions. To study functional changes after denervation we generated entorhino-hippocampal slice cultures, transected the entorhinal pathway, and denervated dentate granule cells in vitro. Our previous work revealed that partially denervated neurons respond to the loss of input with a compensatory, i.e., homeostatic, increase in their excitatory synaptic strength. TNFα maintains this denervation-induced homeostatic strengthening of excitatory synapses. Here, we used pharmacological approaches and mouse genetics to assess the role of TNF-receptor 1 and 2 in lesion-induced excitatory synaptic strengthening. Our experiments disclose that both TNF-receptors are involved in the regulation of denervation-induced synaptic plasticity. In line with this result TNF-receptor 1 and 2 mRNA-levels were upregulated after deafferentation in vitro. These findings implicate TNF-receptor signaling cascades in the regulation of homeostatic plasticity of denervated networks and suggest an important role for TNFα-signaling in the course of neurological diseases accompanied by deafferentation. PMID:26246237

  15. G-protein-coupled estrogen receptor 1 is anatomically positioned to modulate synaptic plasticity in the mouse hippocampus.

    PubMed

    Waters, Elizabeth M; Thompson, Louisa I; Patel, Parth; Gonzales, Andreina D; Ye, Hector Zhiyu; Filardo, Edward J; Clegg, Deborah J; Gorecka, Jolanta; Akama, Keith T; McEwen, Bruce S; Milner, Teresa A

    2015-02-11

    Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors α and β, and synaptic levels in the rodent dorsal hippocampus. Here, we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and interspersed interneurons, especially those in the hilus of the dentate gyrus. Diffuse GPER1-IR was found in all lamina but was most dense in stratum lucidum of CA3. Ultrastructural analysis revealed discrete extranuclear GPER1-IR affiliated with the plasma membrane and endoplasmic reticulum of neuronal perikarya and dendritic shafts, synaptic specializations in dendritic spines, and clusters of vesicles in axon terminals. Moreover, GPER1-IR was found in unmyelinated axons and glial profiles. Overall, the types and amounts of GPER1-labeled profiles were similar between males and females; however, in females elevated estrogen levels generally increased axonal labeling. Some estradiol-induced changes observed in previous studies were replicated by the GPER agonist G1: G1 increased PSD95-IR in strata oriens, lucidum, and radiatum of CA3 in ovariectomized mice 6 h after administration. In contrast, estradiol but not G1 increased Akt phosphorylation levels. Instead, GPER1 actions in the synapse may be due to interactions with synaptic scaffolding proteins, such as SAP97. These results suggest that although estrogen's actions via GPER1 may converge on the same synaptic elements, different pathways are used to achieve these actions. Copyright © 2015 the authors 0270-6474/15/352384-14$15.00/0.

  16. G-Protein-Coupled Estrogen Receptor 1 Is Anatomically Positioned to Modulate Synaptic Plasticity in the Mouse Hippocampus

    PubMed Central

    Thompson, Louisa I.; Patel, Parth; Gonzales, Andreina D.; Ye, Hector (Zhiyu); Filardo, Edward J.; Clegg, Deborah J.; Gorecka, Jolanta; Akama, Keith T.; McEwen, Bruce S.; Milner, Teresa A.

    2015-01-01

    Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors α and β, and synaptic levels in the rodent dorsal hippocampus. Here, we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and interspersed interneurons, especially those in the hilus of the dentate gyrus. Diffuse GPER1-IR was found in all lamina but was most dense in stratum lucidum of CA3. Ultrastructural analysis revealed discrete extranuclear GPER1-IR affiliated with the plasma membrane and endoplasmic reticulum of neuronal perikarya and dendritic shafts, synaptic specializations in dendritic spines, and clusters of vesicles in axon terminals. Moreover, GPER1-IR was found in unmyelinated axons and glial profiles. Overall, the types and amounts of GPER1-labeled profiles were similar between males and females; however, in females elevated estrogen levels generally increased axonal labeling. Some estradiol-induced changes observed in previous studies were replicated by the GPER agonist G1: G1 increased PSD95-IR in strata oriens, lucidum, and radiatum of CA3 in ovariectomized mice 6 h after administration. In contrast, estradiol but not G1 increased Akt phosphorylation levels. Instead, GPER1 actions in the synapse may be due to interactions with synaptic scaffolding proteins, such as SAP97. These results suggest that although estrogen's actions via GPER1 may converge on the same synaptic elements, different pathways are used to achieve these actions. PMID:25673833

  17. NMDA receptors in the midbrain play a critical role in dopamine-mediated hippocampal synaptic potentiation caused by morphine.

    PubMed

    Hu, Ling; Jing, Xiang-Hong; Cui, Cai-Lian; Xing, Guo-Gang; Zhu, Bing

    2014-05-01

    A single exposure to drugs of abuse produces an NMDAR (N-methyl-D-aspartate receptor)-dependent synaptic potentiation at excitatory synapses of dopamine (DA) neurons in the ventral tegmental area (VTA) of the midbrain. All addictive drugs can increase DA concentrations in projection areas of the midbrain, including the hippocampus. Hippocampal DA release subsequently modulates hippocampal plasticity and drug-associated memories. Using in vivo electrophysiological recording techniques in anesthetized rats, we show that systemic injection of morphine induced hippocampal synaptic potentiation in a dose-dependent manner. Intra-VTA but not intra-hippocampus injection of morphine evoked this potentiation. Local hippocampal dopamine D1 receptors (D1R) are required in the morphine-induced synaptic potentiation and conditioned place preference (CPP). Moreover, both NMDAR activation in the VTA and VTA/hippocampus dopaminergic connections are essential for the morphine-evoked potentiation and CPP. These findings suggest that NMDAR signalings in the midbrain play a key role in regulating dopamine-mediated hippocampal synaptic plasticity underlying drug-induced associative memory.

  18. Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction via modulation of glutamate receptor recycling in Down syndrome

    PubMed Central

    Wang, Xin; Zhao, Yingjun; Zhang, Xiaofei; Badie, Hedieh; Zhou, Ying; Mu, Yangling; Loo, Li Shen; Cai, Lei; Thompson, Robert C.; Yang, Bo; Chen, Yaomin; Johnson, Peter F.; Wu, Chengbiao; Bu, Guojun; Mobley, William C.; Zhang, Dongxian; Gage, Fred H.; Ranscht, Barbara; Zhang, Yun-wu; Lipton, Stuart A.; Hong, Wanjin; Xu, Huaxi

    2014-01-01

    Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here, we show that Snx27−/− mice exhibit severe neuronal deficits in the hippocampus and cortex. While Snx27+/− mice exhibit grossly normal neuroanatomy, we find defects in synaptic function, learning and memory, and a reduction in ionotropic glutamate receptors (NMDARs and AMPARs). SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduction of SNX27 and C/EBPβ in Down syndrome brains and identify C/EBPβ as a transcription factor for SNX27. Down syndrome causes over-expression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBPβ, thereby reducing SNX27 and resulting in synaptic dysfunction. Up-regulating SNX27 in the hippocampus of Down syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a novel molecular mechanism of Down syndrome pathogenesis. PMID:23524343

  19. Distinct roles of D1 and D5 dopamine receptors in motor activity and striatal synaptic plasticity.

    PubMed

    Centonze, Diego; Grande, Cristina; Saulle, Emilia; Martin, Ana B; Gubellini, Paolo; Pavón, Nancy; Pisani, Antonio; Bernardi, Giorgio; Moratalla, Rosario; Calabresi, Paolo

    2003-09-17

    Stimulation of dopamine (DA) receptors in the striatum is essential for voluntary motor activity and for the generation of plasticity at corticostriatal synapses. In the present study, mice lacking DA D1 receptors have been used to investigate the involvement of the D1-like class (D1 and D5) of DA receptors in locomotion and corticostriatal long-term depression (LTD) and long-term potentiation (LTP). Our results suggest that D1 and D5 receptors exert distinct actions on both activity-dependent synaptic plasticity and spontaneous motor activity. Accordingly, the ablation of D1 receptors disrupted corticostriatal LTP, whereas pharmacological blockade of D5 receptors prevented LTD. On the other side, genetic ablation of D1 receptors increased locomotor activity, whereas the D1/D5 receptor antagonist SCH 23390 decreased motor activity in both control mice and mice lacking D1 receptors. Endogenous DA stimulated D1 and D5 receptors in distinct subtypes of striatal neurons to induce, respectively, LTP and LTD. In control mice, in fact, LTP was blocked by inhibiting the D1-protein kinase A pathway in the recorded spiny neuron, whereas the striatal nitric oxide-producing interneuron was presumably the neuronal subtype stimulated by D5 receptors during the induction phase of LTD. Understanding the role of DA receptors in striatal function is essential to gain insights into the neural bases of critical brain functions and of dramatic pathological conditions such as Parkinson's disease, schizophrenia, and drug addiction.

  20. The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons.

    PubMed

    Beckley, Jacob T; Laguesse, Sophie; Phamluong, Khanhky; Morisot, Nadege; Wegner, Scott A; Ron, Dorit

    2016-01-20

    Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1+ neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORC1 is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons and increased synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake. Significance statement: Consuming alcohol for the first time is a learning event that drives further drinking. Here, we identified a mechanism that may underlie the reinforcing learning associated with the initial alcohol experience. We show that the first alcohol experience induces a persistent enhancement of excitatory synaptic transmission on NAc shell D1+ neurons

  1. The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons

    PubMed Central

    Beckley, Jacob T.; Laguesse, Sophie; Phamluong, Khanhky; Morisot, Nadege; Wegner, Scott A.

    2016-01-01

    Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1+ neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORC1 is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons and increased synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake. SIGNIFICANCE STATEMENT Consuming alcohol for the first time is a learning event that drives further drinking. Here, we identified a mechanism that may underlie the reinforcing learning associated with the initial alcohol experience. We show that the first alcohol experience induces a persistent enhancement of excitatory synaptic transmission on NAc shell D1+ neurons

  2. Train stimulation of parallel fibre to Purkinje cell inputs reveals two populations of synaptic responses with different receptor signatures

    PubMed Central

    Devi, Suma Priya Sudarsana; Howe, James R.

    2016-01-01

    Key points Purkinje cells of the cerebellum receive ∼180,000 parallel fibre synapses, which have often been viewed as a homogeneous synaptic population and studied using single action potentials.Many parallel fibre synapses might be silent, however, and granule cells in vivo fire in bursts. Here, we used trains of stimuli to study parallel fibre inputs to Purkinje cells in rat cerebellar slices.Analysis of train EPSCs revealed two synaptic components, phase 1 and 2. Phase 1 is initially large and saturates rapidly, whereas phase 2 is initially small and facilitates throughout the train. The two components have a heterogeneous distribution at dendritic sites and different pharmacological profiles.The differential sensitivity of phase 1 and phase 2 to inhibition by pentobarbital and NBQX mirrors the differential sensitivity of AMPA receptors associated with the transmembrane AMPA receptor regulatory protein, γ‐2, gating in the low‐ and high‐open probability modes, respectively. Abstract Cerebellar granule cells fire in bursts, and their parallel fibre axons (PFs) form ∼180,000 excitatory synapses onto the dendritic tree of a Purkinje cell. As many as 85% of these synapses have been proposed to be silent, but most are labelled for AMPA receptors. Here, we studied PF to Purkinje cell synapses using trains of 100 Hz stimulation in rat cerebellar slices. The PF train EPSC consisted of two components that were present in variable proportions at different dendritic sites: one, with large initial EPSC amplitude, saturated after three stimuli and dominated the early phase of the train EPSC; and the other, with small initial amplitude, increased steadily throughout the train of 10 stimuli and dominated the late phase of the train EPSC. The two phases also displayed different pharmacological profiles. Phase 2 was less sensitive to inhibition by NBQX but more sensitive to block by pentobarbital than phase 1. Comparison of synaptic results with fast glutamate

  3. Train stimulation of parallel fibre to Purkinje cell inputs reveals two populations of synaptic responses with different receptor signatures.

    PubMed

    Devi, Suma Priya Sudarsana; Howe, James R; Auger, Céline

    2016-07-01

    Purkinje cells of the cerebellum receive ∼180,000 parallel fibre synapses, which have often been viewed as a homogeneous synaptic population and studied using single action potentials. Many parallel fibre synapses might be silent, however, and granule cells in vivo fire in bursts. Here, we used trains of stimuli to study parallel fibre inputs to Purkinje cells in rat cerebellar slices. Analysis of train EPSCs revealed two synaptic components, phase 1 and 2. Phase 1 is initially large and saturates rapidly, whereas phase 2 is initially small and facilitates throughout the train. The two components have a heterogeneous distribution at dendritic sites and different pharmacological profiles. The differential sensitivity of phase 1 and phase 2 to inhibition by pentobarbital and NBQX mirrors the differential sensitivity of AMPA receptors associated with the transmembrane AMPA receptor regulatory protein, γ-2, gating in the low- and high-open probability modes, respectively. Cerebellar granule cells fire in bursts, and their parallel fibre axons (PFs) form ∼180,000 excitatory synapses onto the dendritic tree of a Purkinje cell. As many as 85% of these synapses have been proposed to be silent, but most are labelled for AMPA receptors. Here, we studied PF to Purkinje cell synapses using trains of 100 Hz stimulation in rat cerebellar slices. The PF train EPSC consisted of two components that were present in variable proportions at different dendritic sites: one, with large initial EPSC amplitude, saturated after three stimuli and dominated the early phase of the train EPSC; and the other, with small initial amplitude, increased steadily throughout the train of 10 stimuli and dominated the late phase of the train EPSC. The two phases also displayed different pharmacological profiles. Phase 2 was less sensitive to inhibition by NBQX but more sensitive to block by pentobarbital than phase 1. Comparison of synaptic results with fast glutamate applications to recombinant

  4. Muscarinic receptor subtypes differentially control synaptic input and excitability of cerebellum-projecting medial vestibular nucleus neurons.

    PubMed

    Zhu, Yun; Chen, Shao-Rui; Pan, Hui-Lin

    2016-04-01

    Neurons in the vestibular nuclei have a vital function in balance maintenance, gaze stabilization, and posture. Although muscarinic acetylcholine receptors (mAChRs) are expressed and involved in regulating vestibular function, it remains unclear how individual mAChR subtypes regulate vestibular neuronal activity. In this study, we determined which specific subtypes of mAChRs control synaptic input and excitability of medial vestibular nucleus (MVN) neurons that project to the cerebellum. Cerebellum-projecting MVN neurons were labeled by a fluorescent retrograde tracer and then identified in rat brainstem slices. Quantitative PCR analysis suggested that M2 and M3 were the possible major mAChR subtypes expressed in the MVN. The mAChR agonist oxotremorine-M significantly reduced the amplitude of glutamatergic excitatory post-synaptic currents evoked by stimulation of vestibular primary afferents, and this effect was abolished by the M2-preferring antagonist AF-DX 116. However, oxotremorine-M had no effect on GABA-mediated spontaneous inhibitory post-synaptic currents of labeled MVN neurons. Furthermore, oxotremorine-M significantly increased the firing activity of labeled MVN neurons, and this effect was blocked by the M3-preferring antagonist J104129 in most neurons tested. In addition, AF-DX 116 reduced the onset latency and prolonged the excitatory effect of oxotremorine-M on the firing activity of labeled MVN neurons. Our findings suggest that M3 is the predominant post-synaptic mAChR involved in muscarinic excitation of cerebellum-projecting MVN neurons. Pre-synaptic M2 mAChR regulates excitatory glutamatergic input from vestibular primary afferents, which in turn influences the excitability of cerebellum-projecting MVN neurons. This new information has important therapeutic implications for treating vestibular disorders with mAChR subtype-selective agents. Medial vestibular nucleus (MVN) neurons projecting to the cerebellum are involved in balance control. We

  5. An itinerant antiferromagnetic metal without magnetic constituents.

    PubMed

    Svanidze, E; Wang, Jiakui K; Besara, T; Liu, L; Huang, Q; Siegrist, T; Frandsen, B; Lynn, J W; Nevidomskyy, Andriy H; Gamża, Monika B; Aronson, M C; Uemura, Y J; Morosan, E

    2015-07-13

    The origin of magnetism in metals has been traditionally discussed in two diametrically opposite limits: itinerant and local moments. Surprisingly, there are very few known examples of materials that are close to the itinerant limit, and their properties are not universally understood. In the case of the two such examples discovered several decades ago, the itinerant ferromagnets ZrZn2 and Sc3In, the understanding of their magnetic ground states draws on the existence of 3d electrons subject to strong spin fluctuations. Similarly, in Cr, an elemental itinerant antiferromagnet with a spin density wave ground state, its 3d electron character has been deemed crucial to it being magnetic. Here, we report evidence for an itinerant antiferromagnetic metal with no magnetic constituents: TiAu. Antiferromagnetic order occurs below a Néel temperature of 36 K, about an order of magnitude smaller than in Cr, rendering the spin fluctuations in TiAu more important at low temperatures. This itinerant antiferromagnet challenges the currently limited understanding of weak itinerant antiferromagnetism, while providing insights into the effects of spin fluctuations in itinerant-electron systems.

  6. Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system

    PubMed Central

    Baxter, Paul S.; Bell, Karen F.S.; Hasel, Philip; Kaindl, Angela M.; Fricker, Michael; Thomson, Derek; Cregan, Sean P.; Gillingwater, Thomas H.; Hardingham, Giles E.

    2015-01-01

    How the brain's antioxidant defenses adapt to changing demand is incompletely understood. Here we show that synaptic activity is coupled, via the NMDA receptor (NMDAR), to control of the glutathione antioxidant system. This tunes antioxidant capacity to reflect the elevated needs of an active neuron, guards against future increased demand and maintains redox balance in the brain. This control is mediated via a programme of gene expression changes that boosts the synthesis, recycling and utilization of glutathione, facilitating ROS detoxification and preventing Puma-dependent neuronal apoptosis. Of particular importance to the developing brain is the direct NMDAR-dependent transcriptional control of glutathione biosynthesis, disruption of which can lead to degeneration. Notably, these activity-dependent cell-autonomous mechanisms were found to cooperate with non-cell-autonomous Nrf2-driven support from astrocytes to maintain neuronal GSH levels in the face of oxidative insults. Thus, developmental NMDAR hypofunction and glutathione system deficits, separately implicated in several neurodevelopmental disorders, are mechanistically linked. PMID:25854456

  7. Antineuronal antibodies against neurotransmitter receptors and synaptic proteins in schizophrenia: current knowledge and clinical implications.

    PubMed

    Steiner, Johann; Schiltz, Kolja; Bernstein, Hans-Gert; Bogerts, Bernhard

    2015-03-01

    When Eugen Bleuler coined the term 'schizophrenia' he believed that various causes of illness may underlie this disease. Currently, neurodevelopmental abnormalities and consecutive impairments in dopaminergic and glutamatergic neurotransmission are considered as major causes of schizophrenia. However, there are various indications for involvement of immune processes, at least in subgroups of patients. Circulating antineuronal antibodies provide a promising link between the well-described disturbances in neurotransmission and the immune hypothesis of schizophrenia. This review summarizes important studies that have examined the role of glutamate, dopamine, acetylcholine and serotonin receptor autoantibodies, and other antineuronal antibodies against synaptic proteins in the serum of patients diagnosed with schizophrenia. Currently, it is not known whether the presence of antineuronal antibodies in blood should be considered as a causal or disease-modulating factor in schizophrenia. Due to emerging evidence regarding the important role of the blood-brain barrier, combined testing of serum and cerebrospinal fluid is likely to be more appropriate to answer this question than pure serum analyses. We suggest implementation of such testing in first-onset and treatment-resistant patients as part of the diagnostic process. In addition, future clinical trials should evaluate if immunotherapy (e.g. cortisone pulse therapy, intravenous immunoglobulins, plasmapheresis, rituximab, or cyclophosphamide) is helpful in cases with a neuroinflammatory component.

  8. The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK.

    PubMed

    Lippiello, Pellegrino; Hoxha, Eriola; Speranza, Luisa; Volpicelli, Floriana; Ferraro, Angela; Leopoldo, Marcello; Lacivita, Enza; Perrone-Capano, Carla; Tempia, Filippo; Miniaci, Maria Concetta

    2016-02-01

    The 5-HT7 receptor (5-HT7R) mediates important physiological effects of serotonin, such as memory and emotion, and is emerging as a therapeutic target for the treatment of cognitive disorders and depression. Although previous studies have revealed an expression of 5-HT7R in cerebellum, particularly at Purkinje cells, its functional role and signaling mechanisms have never been described. Using patch-clamp recordings in cerebellar slices of adult mice, we investigated the effects of a selective 5-HT7R agonist, LP-211, on the main plastic site of the cerebellar cortex, the parallel fiber-Purkinje cell synapse. Here we show that 5-HT7R activation induces long-term depression of parallel fiber-Purkinje cell synapse via a postsynaptic mechanism that involves the PKC-MAPK signaling pathway. Moreover, a 5-HT7R antagonist abolished the expression of PF-LTD, produced by pairing parallel fiber stimulation with Purkinje cell depolarization; whereas, application of a 5-HT7R agonist impaired LTP induced by 1 Hz parallel fiber stimulation. Our results indicate for the first time that 5-HT7R exerts a fine regulation of cerebellar bidirectional synaptic plasticity that might be involved in cognitive processes and neuropsychiatric disorders involving the cerebellum.

  9. The Downregulation of Somatic A-Type K(+) Channels Requires the Activation of Synaptic NMDA Receptors in Young Hippocampal Neurons of Rats.

    PubMed

    Kang, Moon-Seok; Yang, Yoon-Sil; Kim, Seon-Hee; Park, Joo-Min; Eun, Su-Yong; Jung, Sung-Cherl

    2014-04-01

    The downregulation of A-type K(+) channels (IA channels) accompanying enhanced somatic excitability can mediate epileptogenic conditions in mammalian central nervous system. As IA channels are dominantly targeted by dendritic and postsynaptic processings during synaptic plasticity, it is presumable that they may act as cellular linkers between synaptic responses and somatic processings under various excitable conditions. In the present study, we electrophysiologically tested if the downregulation of somatic IA channels was sensitive to synaptic activities in young hippocampal neurons. In primarily cultured hippocampal neurons (DIV 6~9), the peak of IA recorded by a whole-cell patch was significantly reduced by high KCl or exogenous glutamate treatment to enhance synaptic activities. However, the pretreatment of MK801 to block synaptic NMDA receptors abolished the glutamate-induced reduction of the IA peak, indicating the necessity of synaptic activation for the reduction of somatic IA. This was again confirmed by glycine treatment, showing a significant reduction of the somatic IA peak. Additionally, the gating property of IA channels was also sensitive to the activation of synaptic NMDA receptors, showing the hyperpolarizing shift in inactivation kinetics. These results suggest that synaptic LTP possibly potentiates somatic excitability via downregulating IA channels in expression and gating kinetics. The consequential changes of somatic excitability following the activity-dependent modulation of synaptic responses may be a series of processings for neuronal functions to determine outputs in memory mechanisms or pathogenic conditions.

  10. High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus.

    PubMed

    Baude, A; Nusser, Z; Molnár, E; McIlhinney, R A; Somogyi, P

    1995-12-01

    particles for the GluRA, GluRB/C and GluRD subunits were present at type 1 synaptic membrane specializations on dendritic spines of pyramidal cells throughout all layers of the CA1 and CA3 areas. The most densely labelled synapses tended to be on the largest spines and many smaller spines remained unlabelled. Immunoparticle density at type 1 synapses on dendritic shafts of some non-principal cells was consistently higher than at labelled synapses of dendritic spines of pyramidal cells. Synapses established between dendritic spines and mossy fibre terminals, were immunoreactive for all studied subunits in stratum lucidum of the CA3 area. The postembedding immunogold method revealed that the AMPA type receptors are concentrated within the main body of the anatomically defined type 1 (asymmetrical) synaptic junction. Often only a part of the membrane specialization showed clustered immunoparticles. There was a sharp decrease in immunoreactive receptor density at the edge of the synaptic specialization. Immunolabelling was consistently demonstrated at extrasynaptic sites on dendrites, dendritic spines and somata. The results demonstrate that the GluRA, B/C and D subunits of the AMPA type glutamate receptor are present in many of the glutamatergic synapses formed by the entorhinal, CA3 pyramidal and mossy fibre terminals. Some interneurons have a higher density of AMPA type receptors in their asymmetrical afferent synapses than pyramidal cells. This may contribute to a lower activation threshold of interneurons as compared to principal cells by the same afferents in the hippocampal formation.

  11. Pre-synaptic kainate receptor-mediated facilitation of glutamate release involves PKA and Ca(2+) -calmodulin at thalamocortical synapses.

    PubMed

    Andrade-Talavera, Yuniesky; Duque-Feria, Paloma; Sihra, Talvinder S; Rodríguez-Moreno, Antonio

    2013-09-01

    We have investigated the mechanisms underlying the facilitatory modulation mediated by kainate receptor (KAR) activation in the cortex, using isolated nerve terminals (synaptosomes) and slice preparations. In cortical nerve terminals, kainate (KA, 100 μM) produced an increase in 4-aminopyridine (4-AP)-evoked glutamate release. In thalamocortical slices, KA (1 μM) produced an increase in the amplitude of evoked excitatory post-synaptic currents (eEPSCs) at synapses established between thalamic axon terminals from the ventrobasal nucleus onto stellate neurons of L4 of the somatosensory cortex. In both, synaptosomes and slices, the effect of KA was antagonized by 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted after pre-treatment with a cocktail of antagonists of other receptors whose activation could potentially have produced facilitation of release indirectly. Mechanistically, the observed effects of KA appear to be congruent in synaptosomal and slice preparations. Thus, the facilitation by KA of synaptosomal glutamate release and thalamocortical synaptic transmission were suppressed by the inhibition of protein kinase A and occluded by the stimulation of adenylyl cyclase. Dissecting this G-protein-independent regulation further in thalamocortical slices, the KAR-mediated facilitation of synaptic transmission was found to be sensitive to the block of Ca(2+) permeant KARs by philanthotoxin. Intriguingly, the synaptic facilitation was abrogated by depletion of intracellular Ca(2+) stores by thapsigargin, or inhibition of Ca(2+) -induced Ca(2+) -release by ryanodine. Thus, the KA-mediated modulation was contingent on both Ca(2+) entry through Ca(2+) -permeable KARs and liberation of intracellular Ca(2+) stores. Finally, sensitivity to W-7 indicated that the increased cytosolic [Ca(2+) ] underpinning KAR-mediated regulation of synaptic transmission at thalamocortical synapses, requires downstream activation of calmodulin. We conclude that neocortical pre-synaptic

  12. Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist

    PubMed Central

    Newman-Tancredi, A; Martel, J-C; Assié, M-B; Buritova, J; Lauressergues, E; Cosi, C; Heusler, P; Slot, L Bruins; Colpaert, FC; Vacher, B; Cussac, D

    2009-01-01

    Background and purpose: Activation of post-synaptic 5-HT1A receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT1A receptor agonist. Experimental approach: F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo. Key results: F15599 was highly selective for 5-HT1A receptors in binding experiments and in [35S]-GTPγS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT1A receptors. In cell lines expressing h5-HT1A receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT1A receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [35S]-GTPγS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated Gαi than Gαo activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT1A receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT1A receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT1A receptors in vivo almost as potently as F13714. Conclusions and implications: F15599 showed a distinctive activation profiles for 5-HT1A receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT1A receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition. PMID:19154445

  13. Activity blockade and GABAA receptor blockade produce synaptic scaling through chloride accumulation in embryonic spinal motoneurons and interneurons.

    PubMed

    Lindsly, Casie; Gonzalez-Islas, Carlos; Wenner, Peter

    2014-01-01

    Synaptic scaling represents a process whereby the distribution of a cell's synaptic strengths are altered by a multiplicative scaling factor. Scaling is thought to be a compensatory response that homeostatically controls spiking activity levels in the cell or network. Previously, we observed GABAergic synaptic scaling in embryonic spinal motoneurons following in vivo blockade of either spiking activity or GABAA receptors (GABAARs). We had determined that activity blockade triggered upward GABAergic scaling through chloride accumulation, thus increasing the driving force for these currents. To determine whether chloride accumulation also underlies GABAergic scaling following GABAAR blockade we have developed a new technique. We expressed a genetically encoded chloride-indicator, Clomeleon, in the embryonic chick spinal cord, which provides a non-invasive fast measure of intracellular chloride. Using this technique we now show that chloride accumulation underlies GABAergic scaling following blockade of either spiking activity or the GABAAR. The finding that GABAAR blockade and activity blockade trigger scaling via a common mechanism supports our hypothesis that activity blockade reduces GABAAR activation, which triggers synaptic scaling. In addition, Clomeleon imaging demonstrated the time course and widespread nature of GABAergic scaling through chloride accumulation, as it was also observed in spinal interneurons. This suggests that homeostatic scaling via chloride accumulation is a common feature in many neuronal classes within the embryonic spinal cord and opens the possibility that this process may occur throughout the nervous system at early stages of development.

  14. Status Epilepticus Impairs Synaptic Plasticity in Rat Hippocampus and Is Followed by Changes in Expression of NMDA Receptors.

    PubMed

    Postnikova, T Y; Zubareva, O E; Kovalenko, A A; Kim, K K; Magazanik, L G; Zaitsev, A V

    2017-03-01

    Cognitive deficits and memory loss are frequent in patients with temporal lobe epilepsy. Persistent changes in synaptic efficacy are considered as a cellular substrate underlying memory processes. Electrophysiological studies have shown that the properties of short-term and long-term synaptic plasticity in the cortex and hippocampus may undergo substantial changes after seizures. However, the neural mechanisms responsible for these changes are not clear. In this study, we investigated the properties of short-term and long-term synaptic plasticity in rat hippocampal slices 24 h after pentylenetetrazole (PTZ)-induced status epilepticus. We found that the induction of long-term potentiation (LTP) in CA1 pyramidal cells is reduced compared to the control, while short-term facilitation is increased. The experimental results do not support the hypothesis that status epilepticus leads to background potentiation of hippocampal synapses and further LTP induction becomes weaker due to occlusion, as the dependence of synaptic responses on the strength of input stimulation was not different in the control and experimental animals. The decrease in LTP can be caused by impairment of molecular mechanisms of neuronal plasticity, including those associated with NMDA receptors and/or changes in their subunit composition. Real-time PCR demonstrated significant increases in the expression of GluN1 and GluN2A subunits 3 h after PTZ-induced status epilepticus. The overexpression of obligate GluN1 subunit suggests an increase in the total number of NMDA receptors in the hippocampus. A 3-fold increase in the expression of the GluN2B subunit observed 24 h after PTZ-induced status epilepticus might be indicative of an increase in the proportion of GluN2B-containing NMDA receptors. Increased expression of the GluN2B subunit may be a cause for reducing the magnitude of LTP at hippocampal synapses after status epilepticus.

  15. Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ß production.

    PubMed

    Bordji, Karim; Becerril-Ortega, Javier; Nicole, Olivier; Buisson, Alain

    2010-11-24

    Calcium is a key mediator controlling essential neuronal functions depending on electrical activity. Altered neuronal calcium homeostasis affects metabolism of amyloid precursor protein (APP), leading to increased production of β-amyloid (Aβ), and contributing to the initiation of Alzheimer's disease (AD). A linkage between excessive glutamate receptor activation and neuronal Aβ release was established, and recent reports suggest that synaptic and extrasynaptic NMDA receptor (NMDAR) activation may have distinct consequences in plasticity, gene regulation, and neuronal death. Here, we report for the first time that prolonged activation of extrasynaptic NMDAR, but not synaptic NMDAR, dramatically increased the neuronal production of Aβ. This effect was preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing APPs (KPI-APPs), isoforms exhibiting an important amyloidogenic potential. Conversely, after synaptic NMDAR activation, we failed to detect any KPI-APP expression and neuronal Aβ production was not modified. Calcium imaging data showed that intracellular calcium concentration after extrasynaptic NMDAR stimulation was lower than after synaptic activation. This suggests distinct signaling pathways for each pool of receptors. We found that modification of neuronal APP expression pattern triggered by extrasynaptic NMDAR activation was regulated at an alternative splicing level involving calcium-/calmodulin-dependent protein kinase IV, but overall APP expression remained identical. Finally, memantine dose-dependently inhibited extrasynaptic NMDAR-induced KPI-APPs expression as well as neuronal Aβ release. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR promotes amyloidogenic KPI-APP expression leading to neuronal Aβ release, representing a causal risk factor for developing AD.

  16. S-palmitoylation regulates AMPA receptors trafficking and function: a novel insight into synaptic regulation and therapeutics

    PubMed Central

    Han, Jun; Wu, Pengfei; Wang, Fang; Chen, Jianguo

    2014-01-01

    Glutamate acting on AMPA-type ionotropic glutamate receptor (AMPAR) mediates the majority of fast excitatory synaptic transmission in the mammalian central nervous system. Dynamic regulation of AMPAR by post-translational modifications is one of the key elements that allow the nervous system to adapt to environment stimulations. S-palmitoylation, an important lipid modification by post-translational addition of a long-chain fatty acid to a cysteine residue, regulates AMPA receptor trafficking, which dynamically affects multiple fundamental brain functions, such as learning and memory. In vivo, S-palmitoylation is controlled by palmitoyl acyl transferases and palmitoyl thioesterases. In this review, we highlight advances in the mechanisms for dynamic AMPA receptors palmitoylation, and discuss how palmitoylation affects AMPA receptors function at synapses in recent years. Pharmacological regulation of S-palmitoylation may serve as a novel therapeutic strategy for neurobiological diseases. PMID:26579419

  17. 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

  18. An itinerant antiferromagnetic metal without magnetic constituents

    PubMed Central

    Svanidze, E.; Wang, Jiakui K.; Besara, T.; Liu, L.; Huang, Q.; Siegrist, T.; Frandsen, B.; Lynn, J. W.; Nevidomskyy, Andriy H.; Gamża, Monika B.; Aronson, M. C.; Uemura, Y. J.; Morosan, E.

    2015-01-01

    The origin of magnetism in metals has been traditionally discussed in two diametrically opposite limits: itinerant and local moments. Surprisingly, there are very few known examples of materials that are close to the itinerant limit, and their properties are not universally understood. In the case of the two such examples discovered several decades ago, the itinerant ferromagnets ZrZn2 and Sc3In, the understanding of their magnetic ground states draws on the existence of 3d electrons subject to strong spin fluctuations. Similarly, in Cr, an elemental itinerant antiferromagnet with a spin density wave ground state, its 3d electron character has been deemed crucial to it being magnetic. Here, we report evidence for an itinerant antiferromagnetic metal with no magnetic constituents: TiAu. Antiferromagnetic order occurs below a Néel temperature of 36 K, about an order of magnitude smaller than in Cr, rendering the spin fluctuations in TiAu more important at low temperatures. This itinerant antiferromagnet challenges the currently limited understanding of weak itinerant antiferromagnetism, while providing insights into the effects of spin fluctuations in itinerant–electron systems. PMID:26166042

  19. An itinerant antiferromagnetic metal without magnetic constituents

    SciTech Connect

    Svanidze, E.; Wang, Jiakui K.; Besara, T.; Liu, L.; Huang, Q.; Siegrist, T.; Frandsen, B.; Lynn, J. W.; Nevidomskyy, Andriy H.; Gamża, Monika B.; Aronson, M. C.; Uemura, Y. J.; Morosan, E.

    2015-07-13

    The origin of magnetism in metals has been traditionally discussed in two diametrically opposite limits: itinerant and local moments. Surprisingly, there are very few known examples of materials that are close to the itinerant limit, and their properties are not universally understood. In the case of the two such examples discovered several decades ago, the itinerant ferromagnets ZrZn2 and Sc3In, the understanding of their magnetic ground states draws on the existence of 3d electrons subject to strong spin fluctuations. Similarly, in Cr, an elemental itinerant antiferromagnet with a spin density wave ground state, its 3d electron character has been deemed crucial to it being magnetic. Here, we report evidence for an itinerant antiferromagnetic metal with no magnetic constituents: TiAu. Antiferromagnetic order occurs below a Néel temperature of 36 K, about an order of magnitude smaller than in Cr, rendering the spin fluctuations in TiAu more important at low temperatures. In conclusion, this itinerant antiferromagnet challenges the currently limited understanding of weak itinerant antiferromagnetism, while providing insights into the effects of spin fluctuations in itinerant–electron systems.

  20. An itinerant antiferromagnetic metal without magnetic constituents

    DOE PAGES

    Svanidze, E.; Wang, Jiakui K.; Besara, T.; ...

    2015-07-13

    The origin of magnetism in metals has been traditionally discussed in two diametrically opposite limits: itinerant and local moments. Surprisingly, there are very few known examples of materials that are close to the itinerant limit, and their properties are not universally understood. In the case of the two such examples discovered several decades ago, the itinerant ferromagnets ZrZn2 and Sc3In, the understanding of their magnetic ground states draws on the existence of 3d electrons subject to strong spin fluctuations. Similarly, in Cr, an elemental itinerant antiferromagnet with a spin density wave ground state, its 3d electron character has been deemedmore » crucial to it being magnetic. Here, we report evidence for an itinerant antiferromagnetic metal with no magnetic constituents: TiAu. Antiferromagnetic order occurs below a Néel temperature of 36 K, about an order of magnitude smaller than in Cr, rendering the spin fluctuations in TiAu more important at low temperatures. In conclusion, this itinerant antiferromagnet challenges the currently limited understanding of weak itinerant antiferromagnetism, while providing insights into the effects of spin fluctuations in itinerant–electron systems.« less

  1. Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists.

    PubMed

    Kleschevnikov, Alexander M; Belichenko, Pavel V; Faizi, Mehrdad; Jacobs, Lucia F; Htun, Khin; Shamloo, Mehrdad; Mobley, William C

    2012-07-04

    Cognitive impairment in Down syndrome (DS) is characterized by deficient learning and memory. Mouse genetic models of DS exhibit impaired cognition in hippocampally mediated behavioral tasks and reduced synaptic plasticity of hippocampal pathways. Enhanced efficiency of GABAergic neurotransmission was implicated in those changes. We have recently shown that signaling through postsynaptic GABA(B) receptors is significantly increased in the dentate gyrus of Ts65Dn mice, a genetic model of DS. Here we examined a role for GABA(B) receptors in cognitive deficits in DS by defining the effect of selective GABA(B) receptor antagonists on behavior and synaptic plasticity of adult Ts65Dn mice. Treatment with the GABA(B) receptor antagonist CGP55845 restored memory of Ts65Dn mice in the novel place recognition, novel object recognition, and contextual fear conditioning tasks, but did not affect locomotion and performance in T-maze. The treatment increased hippocampal levels of brain-derived neurotrophic factor, equally in 2N and Ts65Dn mice. In hippocampal slices, treatment with the GABA(B) receptor antagonists CGP55845 or CGP52432 enhanced long-term potentiation (LTP) in the Ts65Dn DG. The enhancement of LTP was accompanied by an increase in the NMDA receptor-mediated component of the tetanus-evoked responses. These findings are evidence for a contribution of GABA(B) receptors to changes in hippocampal-based cognition in the Ts65Dn mouse. The ability to rescue cognitive performance through treatment with selective GABA(B) receptor antagonists motivates studies to further explore the therapeutic potential of these compounds in people with DS.

  2. Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists

    PubMed Central

    Kleschevnikov, A.M.; Belichenko, P.V.; Faizi, M.; Jacobs, L.F.; Htun, K.; Shamloo, M.; Mobley, W.C.

    2012-01-01

    Cognitive impairment in Down syndrome (DS) is characterized by deficient learning and memory. Mouse genetic models of DS exhibit impaired cognition in hippocampally mediated behavioral tasks and reduced synaptic plasticity of hippocampal pathways. Enhanced efficiency of GABAergic neurotransmission was implicated in those changes. We have recently shown that signaling through postsynaptic GABAB receptors is significantly increased in the dentate gyrus (DG) of Ts65Dn mice, a genetic model of DS. Here we examined a role for GABAB receptors in cognitive deficits in DS by defining the effect of selective GABAB receptor antagonists on behavior and synaptic plasticity of adult Ts65Dn mice. Treatment with the GABAB receptor antagonist CGP55845 restored memory of Ts65Dn mice in the novel place recognition, novel object recognition and contextual fear conditioning tasks, but did not affect locomotion and performance in T-maze. The treatment increased hippocampal levels of brain-derived neurotrophic factor (BDNF), equally in 2N and Ts65Dn mice. In hippocampal slices, treatment with the GABAB receptor antagonists CGP55845 or CGP52432 enhanced long-term potentiation (LTP) in the Ts65Dn DG. The enhancement of LTP was accompanied by an increase in the NMDA receptor-mediated component of the tetanus-evoked responses. These findings are evidence for a contribution of GABAB receptors to changes in hippocampal-based cognition in the Ts65Dn mouse. The ability to rescue cognitive performance through treatment with selective GABAB receptor antagonists motivates studies to further explore the therapeutic potential of these compounds in people with DS. PMID:22764230

  3. Corticosterone rapidly increases thorns of CA3 neurons via synaptic/extranuclear glucocorticoid receptor in rat hippocampus

    PubMed Central

    Yoshiya, Miyuki; Komatsuzaki, Yoshimasa; Hojo, Yasushi; Ikeda, Muneki; Mukai, Hideo; Hatanaka, Yusuke; Murakami, Gen; Kawata, Mitsuhiro; Kimoto, Tetsuya; Kawato, Suguru

    2013-01-01

    Modulation of synapses under acute stress is attracting much attention. Exposure to acute stress induces corticosterone (CORT) secretion from the adrenal cortex, resulting in rapid increase of CORT levels in plasma and the hippocampus. We tried to test whether rapid CORT effects involve activation of essential kinases as non-genomic processes. We demonstrated rapid effects (~1 h) of CORT on the density of thorns, by imaging Lucifer Yellow-injected neurons in adult male rat hippocampal slices. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. The application of CORT at 100, 500, and 1000 nM induced a rapid increase in the density of thorns in the stratum lucidum of CA3 pyramidal neurons. Co-administration of RU486, an antagonist of glucocorticoid receptor (GR), abolished the effect of CORT. Blocking a single kinase, including MAPK, PKA, or PKC, suppressed CORT-induced enhancement of thorn-genesis. On the other hand, GSK-3β was not involved in the signaling of thorn-genesis. Blocking AMPA receptors suppressed the CORT effect. Expression of CA3 synaptic/extranuclear GR was demonstrated by immunogold electron microscopic analysis. From these results, stress levels of CORT (100–1000 nM) might drive the rapid thorn-genesis via synaptic/extranuclear GR and multiple kinase pathways, although a role of nuclear GRs cannot be completely excluded. PMID:24348341

  4. In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction

    PubMed Central

    2010-01-01

    Background A severe encephalitis that associates with auto-antibodies to the NR1 subunit of the NMDA receptor (NMDA-R) was recently reported. Patients' antibodies cause a decrease of the density of NMDA-R and synaptic mediated currents, but the in vivo effects on the extracellular glutamate and glutamatergic transmission are unknown. Methods We investigated the acute metabolic effects of patients' CSF and purified IgG injected in vivo. Injections were performed in CA1 area of Ammon's horn and in premotor cortex in rats. Results Patient's CSF increased the concentrations of glutamate in the extracellular space. The increase was dose-dependent and was dramatic with purified IgG. Patients' CSF impaired both the NMDA- and the AMPA-mediated synaptic regulation of glutamate, and did not affect the glial transport of glutamate. Blockade of GABA-A receptors was associated with a marked elevation of extra-cellular levels of glutamate following a pretreatment with patients' CSF. Conclusion These results support a direct role of NMDA-R antibodies upon altering glutamatergic transmission. Furthermore, we provide additional evidence in vivo that NMDA-R antibodies deregulate the glutamatergic pathways and that the encephalitis associated with these antibodies is an auto-immune synaptic disorder. PMID:21110857

  5. In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction.

    PubMed

    Manto, Mario; Dalmau, Josep; Didelot, Adrien; Rogemond, Véronique; Honnorat, Jérôme

    2010-11-26

    A severe encephalitis that associates with auto-antibodies to the NR1 subunit of the NMDA receptor (NMDA-R) was recently reported. Patients' antibodies cause a decrease of the density of NMDA-R and synaptic mediated currents, but the in vivo effects on the extracellular glutamate and glutamatergic transmission are unknown. We investigated the acute metabolic effects of patients' CSF and purified IgG injected in vivo. Injections were performed in CA1 area of Ammon's horn and in premotor cortex in rats. Patient's CSF increased the concentrations of glutamate in the extracellular space. The increase was dose-dependent and was dramatic with purified IgG. Patients' CSF impaired both the NMDA- and the AMPA-mediated synaptic regulation of glutamate, and did not affect the glial transport of glutamate. Blockade of GABA-A receptors was associated with a marked elevation of extra-cellular levels of glutamate following a pretreatment with patients' CSF. These results support a direct role of NMDA-R antibodies upon altering glutamatergic transmission. Furthermore, we provide additional evidence in vivo that NMDA-R antibodies deregulate the glutamatergic pathways and that the encephalitis associated with these antibodies is an auto-immune synaptic disorder.

  6. Learning shapes spontaneous activity itinerating over memorized states.

    PubMed

    Kurikawa, Tomoki; Kaneko, Kunihiko

    2011-03-08

    Learning is a process that helps create neural dynamical systems so that an appropriate output pattern is generated for a given input. Often, such a memory is considered to be included in one of the attractors in neural dynamical systems, depending on the initial neural state specified by an input. Neither neural activities observed in the absence of inputs nor changes caused in the neural activity when an input is provided were studied extensively in the past. However, recent experimental studies have reported existence of structured spontaneous neural activity and its changes when an input is provided. With this background, we propose that memory recall occurs when the spontaneous neural activity changes to an appropriate output activity upon the application of an input, and this phenomenon is known as bifurcation in the dynamical systems theory. We introduce a reinforcement-learning-based layered neural network model with two synaptic time scales; in this network, I/O relations are successively memorized when the difference between the time scales is appropriate. After the learning process is complete, the neural dynamics are shaped so that it changes appropriately with each input. As the number of memorized patterns is increased, the generated spontaneous neural activity after learning shows itineration over the previously learned output patterns. This theoretical finding also shows remarkable agreement with recent experimental reports, where spontaneous neural activity in the visual cortex without stimuli itinerate over evoked patterns by previously applied signals. Our results suggest that itinerant spontaneous activity can be a natural outcome of successive learning of several patterns, and it facilitates bifurcation of the network when an input is provided.

  7. Learning Shapes Spontaneous Activity Itinerating over Memorized States

    PubMed Central

    Kurikawa, Tomoki; Kaneko, Kunihiko

    2011-01-01

    Learning is a process that helps create neural dynamical systems so that an appropriate output pattern is generated for a given input. Often, such a memory is considered to be included in one of the attractors in neural dynamical systems, depending on the initial neural state specified by an input. Neither neural activities observed in the absence of inputs nor changes caused in the neural activity when an input is provided were studied extensively in the past. However, recent experimental studies have reported existence of structured spontaneous neural activity and its changes when an input is provided. With this background, we propose that memory recall occurs when the spontaneous neural activity changes to an appropriate output activity upon the application of an input, and this phenomenon is known as bifurcation in the dynamical systems theory. We introduce a reinforcement-learning-based layered neural network model with two synaptic time scales; in this network, I/O relations are successively memorized when the difference between the time scales is appropriate. After the learning process is complete, the neural dynamics are shaped so that it changes appropriately with each input. As the number of memorized patterns is increased, the generated spontaneous neural activity after learning shows itineration over the previously learned output patterns. This theoretical finding also shows remarkable agreement with recent experimental reports, where spontaneous neural activity in the visual cortex without stimuli itinerate over evoked patterns by previously applied signals. Our results suggest that itinerant spontaneous activity can be a natural outcome of successive learning of several patterns, and it facilitates bifurcation of the network when an input is provided. PMID:21408170

  8. Anandamide-CB1 Receptor Signaling Contributes to Postnatal Ethanol-Induced Neonatal Neurodegeneration, Adult Synaptic and Memory Deficits

    PubMed Central

    Subbanna, Shivakumar; Shivakumar, Madhu; Psychoyos, Delphine; Xie, Shan; Basavarajappa, Balapal S.

    2013-01-01

    The transient exposure of immature rodents to ethanol during postnatal day 7 (P7), which is comparable to the third trimester human pregnancy, induces synaptic dysfunctions. However, the molecular mechanisms underlying these dysfunctions are still poorly understood. Although the endocannabinoid system has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in synaptic dysfunctions in mice exposed to ethanol during early brain development is not examined. In this study, we investigated the potential role of endocannabinoids and the cannabinoid receptor type 1 (CB1R) in neonatal neurodegeneration and adult synaptic dysfunctions in mice exposed to ethanol at P7. Ethanol treatment at P7, which induces neurodegeneration, increased anandamide (AEA) but not 2-arachidonylglycerol biosynthesis and CB1R protein expression in the hippocampus and cortex, two brain areas that are important for memory formation and storage, respectively. N-arachidonoyl phosphatidylethanolamine-phospholipase D (NAPE-PLD), glycerophosphodiesterase (GDE1) and CB1Rs protein expression were enhanced by transcriptional activation of the genes encoding NAPE-PLD, GDE1 and CB1R proteins respectively. In addition, ethanol inhibited ERK1/2 and AKT phosphorylation. The blockade of CB1Rs prior to ethanol treatment at P7 relieved ERK1/2 but not AKT phosphorylation and prevented neurodegeneration. CB1R knockout mice exhibited no ethanol-induced neurodegeneration and inhibition of ERK1/2-phosphorylation. The protective effects of CB1R blockade through pharmacological or genetic deletion resulted in normal adult synaptic plasticity and novel object recognition memory in mice exposed to ethanol at P7. The AEA/CB1R/pERK1/2 signaling pathway may be directly responsible for the synaptic and memory deficits associated with fetal alcohol spectrum disorders. PMID:23575834

  9. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury

    PubMed Central

    Stuck, Ellen D.; Irvine, Karen-Amanda; Bresnahan, Jacqueline C.

    2015-01-01

    Abstract Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity. PMID:26668821

  10. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury.

    PubMed

    Huie, J Russell; Stuck, Ellen D; Lee, Kuan H; Irvine, Karen-Amanda; Beattie, Michael S; Bresnahan, Jacqueline C; Grau, James W; Ferguson, Adam R

    2015-01-01

    Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity.

  11. GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors.

    PubMed

    Chiu, Shu-Ling; Diering, Graham Hugh; Ye, Bing; Takamiya, Kogo; Chen, Chih-Ming; Jiang, Yuwu; Niranjan, Tejasvi; Schwartz, Charles E; Wang, Tao; Huganir, Richard L

    2017-03-22

    Learning depends on experience-dependent modification of synaptic efficacy and neuronal connectivity in the brain. We provide direct evidence for physiological roles of the recycling endosome protein GRASP1 in glutamatergic synapse function and animal behavior. Mice lacking GRASP1 showed abnormal excitatory synapse number, synaptic plasticity, and hippocampal-dependent learning and memory due to a failure in learning-induced synaptic AMPAR incorporation. We identified two GRASP1 point mutations from intellectual disability (ID) patients that showed convergent disruptive effects on AMPAR recycling and glutamate uncaging-induced structural and functional plasticity. Wild-type GRASP1, but not ID mutants, rescued spine loss in hippocampal CA1 neurons in Grasp1 knockout mice. Together, these results demonstrate a requirement for normal recycling endosome function in AMPAR-dependent synaptic function and neuronal connectivity in vivo, and suggest a potential role for GRASP1 in the pathophysiology of human cognitive disorders.

  12. Iron Mediates N-Methyl-d-aspartate Receptor-dependent Stimulation of Calcium-induced Pathways and Hippocampal Synaptic Plasticity*

    PubMed Central

    Muñoz, Pablo; Humeres, Alexis; Elgueta, Claudio; Kirkwood, Alfredo; Hidalgo, Cecilia; Núñez, Marco T.

    2011-01-01

    Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-d-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine-reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP. PMID:21296883

  13. Kalirin binds the NR2B subunit of the NMDA receptor, altering its synaptic localization and function.

    PubMed

    Kiraly, Drew D; Lemtiri-Chlieh, Fouad; Levine, Eric S; Mains, Richard E; Eipper, Betty A

    2011-08-31

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

  14. Kalirin binds the NR2B subunit of the NMDA receptor, altering its synaptic localization and function

    PubMed Central

    Kiraly, Drew D.; Lemtiri-Chlieh, Fouad; Levine, Eric S.; Mains, Richard E.; Eipper, Betty A.

    2011-01-01

    The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor (GEF) localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins including PSD-95, DISC-1, AF-6 and Arf6. Mice genetically lacking Kal7 (Kal7KO) exhibit deficient hippocampal LTP as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7KO mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7KO animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell-surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7KO mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity. PMID:21880917

  15. Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer's Disease

    PubMed Central

    Lanté, Fabien; Chafai, Magda; Raymond, Elisabeth Fabienne; Salgueiro Pereira, Ana Rita; Mouska, Xavier; Kootar, Scherazad; Barik, Jacques; Bethus, Ingrid; Marie, Hélène

    2015-01-01

    The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by the elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis, circadian rhythm, and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by subchronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, whereas LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset. PMID:25622751

  16. Surgical incision-induced nociception causes cognitive impairment and reduction in synaptic NMDA receptor 2B in mice.

    PubMed

    Zhang, Xiaoqin; Xin, Xin; Dong, Yuanlin; Zhang, Yiying; Yu, Buwei; Mao, Jianren; Xie, Zhongcong

    2013-11-06

    Postoperative cognitive dysfunction (POCD) is associated with impairments in daily functioning, and increased morbidity and mortality. However, the causes and neuropathogenesis of POCD remain largely unknown. Uncontrolled pain often occurs postoperatively. We therefore set out to determine the effects of surgical incision-induced nociception on the cognitive function and its underlying mechanisms in 3- and 9-month-old mice. The mice had surgical incision in the hindpaw and then were tested for nociceptive threshold, learning, and memory. Brain levels of NMDA receptor and cyclin-dependent kinase 5 (CDK5) were also assessed. We found that surgical incision-induced nociception in mice led to a decreased freezing time in the tone test (which assesses the hippocampus-independent learning and memory function), but not the context test, of Fear Conditioning System at 3 and 7 d, but not 30 d post incision in 9-month-old, but not 3-month-old mice. Consistently, the surgical incision selectively decreased synaptic NMDA receptor 2B levels in the medial prefrontal cortex, and increased levels of tumor necrosis factor-α and CDK5 in the cortex, but not hippocampus, of the mice. Finally, eutectic mixture of local anesthetics and CDK5 inhibitor, roscovitine, attenuated the surgical incision-induced reduction in the synaptic NMDA receptor 2B levels and learning impairment. These results suggested that surgical incision-induced nociception reduced the synaptic NMDA receptor 2B level in the medial prefrontal cortex of mice, which might lead to hippocampus-independent learning impairment, contributing to POCD. These findings call for further investigation to determine the role of surgical incision-induced nociception in POCD.

  17. The identification of protein tyrosine phosphatase receptor type O (PTPRO) as a synaptic adhesion molecule that promotes synapse formation.

    PubMed

    Jiang, Wei; Wei, Mengping; Liu, Mengna; Pan, Yunlong; Yang, Xiaofei; Zhang, Chen

    2017-09-04

    The proper formation of synapses-specialized unitary structures formed between two neurons-is critical to mediate the information flow in the brain. Synaptic cell adhesion molecules (CAMs) are thought to participate in the initiation of the synapse formation process. However, in-vivo functional analysis demonstrates that most well-known synaptic CAMs regulate synaptic maturation and plasticity rather than synapse formation, suggesting that either CAMs work synergistically in the process of forming synapses or more CAMs remain to be found. By screening for unknown CAMs using a co-culture system, we revealed protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters in co-cultures of human embryonic kidney (HEK) 293 cells and hippocampal neurons cultured from newborn mice irrespective of gender. PTPRO was enriched in the mouse brain and localized to postsynaptic sites at excitatory synapses. The overexpression of PTPRO in cultured hippocampal neurons increased the number of synapses and the frequency of miniature excitatory postsynaptic currents (mEPSCs). The knockdown of PTPRO expression in cultured neurons by short hairpin RNA (shRNA) reduced the number of synapses and the frequencies of the mEPSCs. The effects of shRNA knockdown were rescued by expressing either full-length PTPRO or a truncated PTPRO lacking the cytoplasmic domain. Consistent with these results, the N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in the co-culture assay. Taken together, our data show that PTPRO is a synaptic CAM that serves as a potent initiator of the formation of excitatory synapses.SIGNIFICANCE STATEMENTThe formation of synapses is critical for the brain to execute its function, and synaptic cell adhesion molecules (CAMs) play essential roles in initiating the formation of synapses. By screening for unknown CAMs using a co-culture system, we revealed protein tyrosine

  18. Hunger States Control the Directions of Synaptic Plasticity via Switching Cell Type-Specific Subunits of NMDA Receptors.

    PubMed

    Qi, Yong; Yang, Yunlei

    2015-09-23

    It remains largely unknown whether and how hunger states control activity-dependent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). We here report that both LTP and LTD of excitatory synaptic strength within the appetite control circuits residing in hypothalamic arcuate nucleus (ARC) behave in a manner of hunger states dependence and cell type specificity. For instance, we find that tetanic stimulation induces LTP at orexigenic agouti-related protein (AgRP) neurons in ad libitum fed mice, whereas it induces LTD in food-deprived mice. In an opposite direction, the same induction protocol induces LTD at anorexigenic pro-opiomelanocortin (POMC) neurons in fed mice but weak LTP in deprived mice. Mechanistically, we also find that food deprivation increases the expressions of NR2C/NR2D/NR3-containing NMDA receptors (NMDARs) at AgRP neurons that contribute to the inductions of LTD, whereas it decreases their expressions at POMC neurons. Collectively, our data reveal that hunger states control the directions of activity-dependent synaptic plasticity by switching NMDA receptor subpopulations in a cell type-specific manner, providing insights into NMDAR-mediated interactions between energy states and associative memory. Significance statement: Based on the experiments performed in this study, we demonstrate that activity-dependent synaptic plasticity is also under the control of energy states by regulating NMDAR subpopulations in a cell type-specific manner. We thus propose a reversible memory configuration constructed from energy states-dependent cell type-specific bidirectional conversions of LTP and LTD. Together with the distinct functional roles played by NMDAR signaling in the control of food intake and energy states, these findings reveal a new reciprocal interaction between energy states and associative memory, one that might serve as a target for therapeutic treatments of the energy-related memory disorders or vice versa.

  19. NMDA receptor-dependent synaptic plasticity in dorsal and intermediate hippocampus exhibits distinct frequency-dependent profiles.

    PubMed

    Kenney, Jana; Manahan-Vaughan, Denise

    2013-11-01

    The hippocampus may be functionally differentiated along its dorsoventral axis. In contrast to the wealth of data available on synaptic plasticity mechanisms in the dorsal hippocampus, little is known about synaptic plasticity processes in the intermediate hippocampus. Behavioral data suggest that this structure may play a distinct role in learning and memory. Here, we compared amplitudes, frequency-dependency and persistency of long-term potentiation (LTP) and long-term depression (LTD) in the dorsal (DDG) and intermediate dentate gyrus (IDG). In freely moving rats, high-frequency stimulation (HFS) at 200 Hz (10 burst of 15 stimuli) elicited LTP of similar magnitude in both structures that persisted for over 24 h. The intermediate dentate gyrus is more likely to exhibit persistent LTP than its dorsal counterpart, however: HFS at 200 Hz (3 or 1 burst(s)) or 100 Hz elicited short-term potentiation (STP) in DDG, unlike in the IDG, where LTP could be recorded for at least 4 h. Whereas low frequency stimulation (LFS) at 1 Hz elicited long-lasting LTD (>24 h) in the DDG, it had no significant effect on fEPSP profile in the IDG. LFS at 2 Hz elicited short-term depression in DDG and had no effect in IDG. LTP in both IDG and DDG required activation of N-methyl-D-aspartate receptors. Paired-pulse and input-output responses differed in IDG and DDG. Our data suggest that afferent input from the entorhinal cortex generates a different response profile in the dorsal vs. intermediate DG, which may in turn relate to their postulated distinct roles in synaptic information processing and memory formation. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Target- and input-dependent organization of AMPA and NMDA receptors in synaptic connections of the cochlear nucleus.

    PubMed

    Rubio, María E; Fukazawa, Yugo; Kamasawa, Naomi; Clarkson, Cheryl; Molnár, Elek; Shigemoto, Ryuichi

    2014-12-15

    We examined the synaptic structure, quantity, and distribution of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-type glutamate receptors (AMPARs and NMDARs, respectively) in rat cochlear nuclei by a highly sensitive freeze-fracture replica labeling technique. Four excitatory synapses formed by two distinct inputs, auditory nerve (AN) and parallel fibers (PF), on different cell types were analyzed. These excitatory synapse types included AN synapses on bushy cells (AN-BC synapses) and fusiform cells (AN-FC synapses) and PF synapses on FC (PF-FC synapses) and cartwheel cell spines (PF-CwC synapses). Immunogold labeling revealed differences in synaptic structure as well as AMPAR and NMDAR number and/or density in both AN and PF synapses, indicating a target-dependent organization. The immunogold receptor labeling also identified differences in the synaptic organization of FCs based on AN or PF connections, indicating an input-dependent organization in FCs. Among the four excitatory synapse types, the AN-BC synapses were the smallest and had the most densely packed intramembrane particles (IMPs), whereas the PF-CwC synapses were the largest and had sparsely packed IMPs. All four synapse types showed positive correlations between the IMP-cluster area and the AMPAR number, indicating a common intrasynapse-type relationship for glutamatergic synapses. Immunogold particles for AMPARs were distributed over the entire area of individual AN synapses; PF synapses often showed synaptic areas devoid of labeling. The gold-labeling for NMDARs occurred in a mosaic fashion, with less positive correlations between the IMP-cluster area and the NMDAR number. Our observations reveal target- and input-dependent features in the structure, number, and organization of AMPARs and NMDARs in AN and PF synapses. © 2014 Wiley Periodicals, Inc.

  1. 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.

  2. Presynaptic G protein-coupled receptors dynamically modify vesicle fusion, synaptic cleft glutamate concentrations and motor behavior

    PubMed Central

    Gerachshenko, Tatyana; Schwartz, Eric; Bleckert, Adam; Photowala, Huzefa; Seymour, Andrew; Alford, Simon

    2009-01-01

    Understanding how neuromodulators regulate behavior requires investigating their effects on functional neural systems, but also their underlying cellular mechanisms. Utilizing extensively characterized lamprey motor circuits, and the unique access to reticulospinal presynaptic terminals in the intact spinal cord that initiate these behaviours, we have investigated effects of presynaptic G protein-coupled receptors on locomotion from the systems level, to the molecular control of vesicle fusion. 5-HT inhibits neurotransmitter release via a Gβγ interaction with the SNARE complex that promotes kiss-and-run vesicle fusion. In the lamprey spinal cord we demonstrate that while presynaptic 5-HT receptors inhibit evoked neurotransmitter release from reticulospinal command neurons, their activation does not abolish locomotion, but rather modulates locomotor rhythms. Liberation of presynaptic Gβγ causes substantial inhibition of AMPA receptor-mediated synaptic responses, but leaves NMDA receptor-mediated components of neurotransmission largely intact. Because Gβγ binding to the SNARE complex is displaced by Ca2+-synaptotagmin binding, 5-HT-mediated inhibition displays Ca2+ sensitivity. We show that as Ca2+ accumulates presynaptically during physiological bouts of activity, 5-HT/Gβγ-mediated presynaptic inhibition is relieved leading to a frequency-dependent increase in synaptic concentrations of glutamate. This frequency dependent phenomenon mirrors a shift in the vesicle fusion mode and a recovery of AMPA receptor-mediated EPSCs from inhibition without a modification of NMDA receptor EPSCs. We conclude that activation of presynaptic 5-HT GPCRs state-dependently alters vesicle fusion properties to shift the weight of NMDA vs AMPA receptor-mediated responses at excitatory synapses. We have therefore identified a novel mechanism in which modification of vesicle fusion modes may profoundly alter locomotor behaviour. PMID:19692597

  3. Bidirectional regulation of synaptic plasticity in the basolateral amygdala induced by the D1-like family of dopamine receptors and group II metabotropic glutamate receptors

    PubMed Central

    Li, Chenchen; Rainnie, Donald G

    2014-01-01

    Competing mechanisms of long-term potentiation (LTP) and long-term depression (LTD) in principal neurons of the basolateral amygdala (BLA) are thought to underlie the acquisition and consolidation of fear memories, and their subsequent extinction. However, no study to date has examined the locus of action and/or the cellular mechanism(s) by which these processes interact. Here, we report that synaptic plasticity in the cortical pathway onto BLA principal neurons is frequency-dependent and shows a transition from LTD to LTP at stimulation frequencies of ∼10 Hz. At the crossover point from LTD to LTP induction we show that concurrent activation of D1 and group II metabotropic glutamate (mGluR2/3) receptors act to nullify any net change in synaptic strength. Significantly, blockade of either D1 or mGluR2/3 receptors unmasked 10 Hz stimulation-induced LTD and LTP, respectively. Significantly, prior activation of presynaptic D1 receptors caused a time-dependent attenuation of mGluR2/3-induced depotentiation of previously induced LTP. Furthermore, studies with cell type-specific postsynaptic transgene expression of designer receptors activated by designer drugs (DREADDs) suggest that the interaction results via bidirectional modulation of adenylate cyclase activity in presynaptic glutamatergic terminals. The results of our study raise the possibility that the temporal sequence of activation of either presynaptic D1 receptors or mGluR2/3 receptors may critically regulate the direction of synaptic plasticity in afferent pathways onto BLA principal neurons. Hence, the interaction of these two neurotransmitter systems may represent an important mechanism for bidirectional metaplasticity in BLA circuits and thus modulate the acquisition and extinction of fear memory. PMID:25107924

  4. 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.

  5. 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.

  6. 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

  7. Activity-regulated Somatostatin Expression Reduces Dendritic Spine Density and Lowers Excitatory Synaptic Transmission via Postsynaptic Somatostatin Receptor 4*

    PubMed Central

    Hou, Zai-Hua; Yu, Xiang

    2013-01-01

    Neuronal activity regulates multiple aspects of the morphological and functional development of neural circuits. One mechanism by which it achieves this is through regulation of gene expression. In a screen for activity-induced genes, we identified somatostatin (SST), a neuropeptide secreted by the SST subtype of interneurons. Using real time quantitative PCR and ELISA, we showed that persistent elevation of neuronal activity increased both the gene expression and protein secretion of SST over a relatively prolonged time course of 48 h. Using primary hippocampal neuronal cultures, we found that SST treatment for 1 day significantly reduced the density of dendritic spines, the morphological bases of excitatory synapses. Furthermore, the density of pre- and postsynaptic markers of excitatory synapses was significantly lowered following SST treatment, whereas that of inhibitory synapses was not affected. Consistently, SST treatment reduced the frequency of miniature excitatory postsynaptic currents, without affecting inhibition. Finally, lowering the endogenous level of SST receptor subtype 4 in individual hippocampal pyramidal neurons significantly blocked the effect of SST in reducing spine density and excitatory synaptic transmission in a cell autonomous fashion, suggesting that the effect of SST in regulating excitatory synaptic transmission is mainly mediated by SST receptor subtype 4. Together, our results demonstrated that activity-dependent release of SST reduced the density of dendritic spines and the number of excitatory synapses through postsynaptic activation of SST receptor subtype 4 in pyramidal neurons. To our knowledge, this is the first demonstration of the long term effect of SST on neuronal morphology. PMID:23233668

  8. Synaptic plasticity in the medial vestibular nuclei: role of glutamate receptors and retrograde messengers in rat brainstem slices.

    PubMed

    Grassi, S; Pettorossi, V E

    2001-08-01

    The analysis of cellular-molecular events mediating synaptic plasticity within vestibular nuclei is an attempt to explain the mechanisms underlying vestibular plasticity phenomena. The present review is meant to illustrate the main results, obtained in vitro, on the mechanisms underlying long-term changes in synaptic strength within the medial vestibular nuclei. The synaptic plasticity phenomena taking place at the level of vestibular nuclei could be useful for adapting and consolidating the efficacy of vestibular neuron responsiveness to environmental requirements, as during visuo-vestibular recalibration and vestibular compensation. Following a general introduction on the most salient features of vestibular compensation and visuo-vestibular adaptation, which are two plastic events involving neuronal circuitry within the medial vestibular nuclei, the second and third sections describe the results from rat brainstem slice studies, demonstrating the possibility to induce long-term potentiation and depression in the medial vestibular nuclei, following high frequency stimulation of the primary vestibular afferents. In particular the mechanisms sustaining the induction and expression of vestibular long-term potentiation and depression, such as the role of various glutamate receptors and retrograde messengers have been described. The relevant role of the interaction between the platelet-activating factor, acting as a retrograde messenger, and the presynaptic metabotropic glutamate receptors, in determining the full expression of vestibular long-term potentiation is also underlined. In addition, the mechanisms involved in vestibular long-term potentiation have been compared with those leading to long-term potentiation in the hippocampus to emphasize the most significant differences emerging from vestibular studies. The fourth part, describes recent results demonstrating the essential role of nitric oxide, another retrograde messenger, in the induction of vestibular

  9. Localization of Neuropeptide Y1 Receptor Immunoreactivity in the Rat Retina and the Synaptic Connectivity of Y1 Immunoreactive Cells

    PubMed Central

    D'Angelo, Iona; Oh, Su-Ja; Chun, Myung-Hoon; Brecha, Nicholas C.

    2010-01-01

    Neuropeptide Y (NPY), an inhibitory neuropeptide expressed by a moderately dense population of wide-field amacrine cells in the rat retina, acts through multiple (Y1–y6) G-protein–coupled receptors. This study determined the cellular localization of Y1 receptors and the synaptic connectivity of Y1 processes in the inner plexiform layer (IPL) of the rat retina. Specific Y1 immunoreactivity was localized to horizontal cell bodies in the distal inner nuclear layer and their processes in the outer plexiform layer. Immunoreactivity was also prominent in cell processes located in strata 2 and 4, and puncta in strata 4 and 5 of the IPL. Double-label immunohistochemical experiments with calbindin, a horizontal cell marker, confirmed Y1 immunostaining in all horizontal cells. Double-label immunohistochemical experiments, using antibodies to choline acetyltransferase and vesicular acetylcholine transporter to label cholinergic amacrine cell processes, demonstrated that Y1 immunoreactivity in strata 2 and 4 of the IPL was localized to cholinergic amacrine cell processes. Electron microscopic studies of the inner retina showed that Y1-immunostained amacrine cell processes and puncta received synaptic inputs from unlabeled amacrine cell processes (65.2%) and bipolar cell axon terminals (34.8%). Y1-immunoreactive amacrine cell processes most frequently formed synaptic outputs onto unlabeled amacrine cell processes (34.0%) and ganglion cell dendrites (54.1%). NPY immunoreactivity in the rat retina is distributed primarily to strata 1 and 5 of the IPL, and the present findings, thus, suggest that NPY acts in a paracrine manner on Y1 receptors to influence both horizontal and amacrine cells. PMID:12455004

  10. Ig Superfamily Ligand and Receptor Pairs Expressed in Synaptic Partners in Drosophila.

    PubMed

    Tan, Liming; Zhang, Kelvin Xi; Pecot, Matthew Y; Nagarkar-Jaiswal, Sonal; Lee, Pei-Tseng; Takemura, Shin-Ya; McEwen, Jason M; Nern, Aljoscha; Xu, Shuwa; Tadros, Wael; Chen, Zhenqing; Zinn, Kai; Bellen, Hugo J; Morey, Marta; Zipursky, S Lawrence

    2015-12-17

    Information processing relies on precise patterns of synapses between neurons. The cellular recognition mechanisms regulating this specificity are poorly understood. In the medulla of the Drosophila visual system, different neurons form synaptic connections in different layers. Here, we sought to identify candidate cell recognition molecules underlying this specificity. Using RNA sequencing (RNA-seq), we show that neurons with different synaptic specificities express unique combinations of mRNAs encoding hundreds of cell surface and secreted proteins. Using RNA-seq and protein tagging, we demonstrate that 21 paralogs of the Dpr family, a subclass of immunoglobulin (Ig)-domain containing proteins, are expressed in unique combinations in homologous neurons with different layer-specific synaptic connections. Dpr interacting proteins (DIPs), comprising nine paralogs of another subclass of Ig-containing proteins, are expressed in a complementary layer-specific fashion in a subset of synaptic partners. We propose that pairs of Dpr/DIP paralogs contribute to layer-specific patterns of synaptic connectivity.

  11. Rapid increase of spines by dihydrotestosterone and testosterone in hippocampal neurons: Dependence on synaptic androgen receptor and kinase networks.

    PubMed

    Hatanaka, Yusuke; Hojo, Yasushi; Mukai, Hideo; Murakami, Gen; Komatsuzaki, Yoshimasa; Kim, Jonghyuk; Ikeda, Muneki; Hiragushi, Ayako; Kimoto, Tetsuya; Kawato, Suguru

    2015-09-24

    Rapid modulation of hippocampal synaptic plasticity by locally synthesized androgen is important in addition to circulating androgen. Here, we investigated the rapid changes of dendritic spines in response to the elevation of dihydrotestosterone (DHT) and testosterone (T), by using hippocampal slices from adult male rats, in order to clarify whether these signaling processes include synaptic/extranuclear androgen receptor (AR) and activation of kinases. We found that the application of 10nM DHT and 10nM T increased the total density of spines by approximately 1.3-fold within 2h, by imaging Lucifer Yellow-injected CA1 pyramidal neurons. Interestingly, DHT and T increased different head-sized spines. While DHT increased middle- and large-head spines, T increased small-head spines. Androgen-induced spinogenesis was suppressed by individually blocking Erk MAPK, PKA, PKC, p38 MAPK, LIMK or calcineurin. On the other hand, blocking CaMKII did not inhibit spinogenesis. Blocking PI3K altered the spine head diameter distribution, but did not change the total spine density. Blocking mRNA and protein synthesis did not suppress the enhancing effects induced by DHT or T. The enhanced spinogenesis by androgens was blocked by AR antagonist, which AR was localized postsynaptically. Taken together, these results imply that enhanced spinogenesis by DHT and T is mediated by synaptic/extranuclear AR which rapidly drives the kinase networks. This article is part of a Special Issue entitled SI: Brain and Memory.

  12. 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.

  13. Taurine activates excitatory non-synaptic glycine receptors on dopamine neurones in ventral tegmental area of young rats.

    PubMed

    Wang, Fushun; Xiao, Cheng; Ye, Jiang Hong

    2005-06-01

    The physiological and pharmacological properties of taurine-induced responses were investigated in dopaminergic (DA) neurones from the ventral tegmental area (VTA) of young rats aged 1-13 postnatal days, either in acute brain slices or acutely dissociated neurones. When whole-cell responses were recorded from current-clamped neurones using the gramicidin-perforated technique, the application of taurine (0.01-30 mm) accelerated firings and induced membrane depolarization. In voltage-clamped neurones, taurine induced a current which was antagonized by strychnine and by picrotoxin, but not by bicuculline. In addition, taurine-induced current showed complete cross-desensitization with glycine-activated currents but not with gamma-aminobutyric acid (GABA)-activated currents. Thus, taurine is a full agonist of the glycine receptors (GlyRs) in the VTA. Further studies found that taurine acted mainly on non-synaptic GlyRs. The application of 20 microm bicuculline abolished the spontaneous inhibitory post-synaptic currents (IPSCs) in 40/45 neurones, and 93% of the evoked IPSCs. The addition of 1 microm strychnine completely eliminated the remaining IPSCs. These results suggest that GABAergic IPSCs predominate, and that functional glycinergic synapses are present in a subset of the VTA neurones. The application of 1 mum strychnine alone induced an outward current, suggesting that these neurones were exposed to tonically released taurine/glycine. In conclusion, by activating non-synaptic GlyRs, taurine may act as an excitatory extra-synaptic neurotransmitter in the VTA during early development.

  14. Paired-pulse depression of the N-methyl-D-aspartate receptor-mediated synaptic potentials in the amygdala.

    PubMed Central

    Huang, C C; Gean, P W

    1994-01-01

    1. An in vitro slice preparation of rat amygdala was used to study the paired-pulse depression of the N-methyl-D-aspartate (NMDA) receptor-mediated synaptic potential e.p.s.p.NMDA. 2. The e.p.s.p.NMDA was isolated pharmacologically by applying a solution containing the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the gamma-aminobutyric acidA (GABAA) blocker picrotoxin and increasing the stimulus intensity. 3. When two stimuli of identical strength were applied in close succession, the second e.p.s.p.NMDA was depressed. This paired-pulse depression was seen with interstimulus intervals of between 100 ms and 2000 ms; the maximal depression was observed at interval of 200 ms. 4. Superfusion of phaclofen or 2-hydroxy-saclofen inhibited the paired-pulse depression indicating the involvement of GABAB receptors. 5. Bath applications of Ba2+ or intracellular injection of Cs+ to block post- but not presynaptic GABAB receptors failed to inhibit the paired-pulse depression (PPD). 6. Incubation of slices with pertussis toxin prevented the postsynaptic hyperpolarization induced by baclofen. The PPD of e.p.s.p.NMDA, however, was not affected by pertussis toxin treatment. 7. These results suggest that GABA released by the first stimulus acts on GABAB receptors to suppress the second e.p.s.p.NMDA via mechanisms other than activation of a postsynaptic GABAB receptor-coupled K+ conductance. PMID:7858845

  15. AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes.

    PubMed

    Zhang, Ce; Marek, Gerard J

    2008-01-01

    Glutamate plays an important role in the psychotomimetic effects of both channel blocking N-methyl D-aspartate (NMDA) receptor antagonists and hallucinogenic drugs which activate 5-hydroxytryptamine2A (5-HT2A) receptors. Previous work suggested that activation of non-NMDA ionotropic glutamate receptors mediates the effects of 5-HT-induced excitatory post-synaptic potentials/currents (EPSPs/EPSCs) when recording from layer V pyramidal cells in the rat medial pre-frontal cortex (mPFC). However, those effects are mediated by either alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate receptors of the iGluk5 subtype. To test whether activation of AMPA receptors is sufficient to mediate 5-HT-induced EPSCs, a 2,3-benzodiazepine that selectively blocks AMPA receptors was assessed. This selective AMPA receptor antagonist potently suppressed 5-HT-induced EPSCs. Since phenethylamine hallucinogens induce head shakes by activating 5-HT2A receptors in the mPFC and this action is modulated by glutamate, we also examined whether selective blockade of AMPA receptors would suppress DOI-induced head shakes. As predicted, we found that selective blockade of AMPA receptors suppressed DOI-induced head shakes. Given evidence that activation of AMPA receptors is an important downstream effect for both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens, we also tested multiple doses of DOI with a sub-anesthetic dose of MK-801. Synergistic action between these two classes of psychotomimetic drugs was demonstrated by MK-801 enhancing DOI-induced head shakes and locomotor activity. These findings expand the dependence of both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens on enhancing extracellular glutamate.

  16. Oxygen/glucose deprivation induces a reduction in synaptic AMPA receptors on hippocampal CA3 neurons mediated by mGluR1 and adenosine A3 receptors.

    PubMed

    Dennis, Siobhan H; Jaafari, Nadia; Cimarosti, Helena; Hanley, Jonathan G; Henley, Jeremy M; Mellor, Jack R

    2011-08-17

    Hippocampal CA1 pyramidal neurons are highly sensitive to ischemic damage, whereas neighboring CA3 pyramidal neurons are less susceptible. It is proposed that switching of AMPA receptor (AMPAR) subunits on CA1 neurons during an in vitro model of ischemia, oxygen/glucose deprivation (OGD), leads to an enhanced permeability of AMPARs to Ca(2+), resulting in delayed cell death. However, it is unclear whether the same mechanisms exist in CA3 neurons and whether this underlies the differential sensitivity to ischemia. Here, we investigated the consequences of OGD for AMPAR function in CA3 neurons using electrophysiological recordings in rat hippocampal slices. Following a 15 min OGD protocol, a substantial depression of AMPAR-mediated synaptic transmission was observed at CA3 associational/commissural and mossy fiber synapses but not CA1 Schaffer collateral synapses. The depression of synaptic transmission following OGD was prevented by metabotropic glutamate receptor 1 (mGluR1) or A(3) receptor antagonists, indicating a role for both glutamate and adenosine release. Inhibition of PLC, PKC, or chelation of intracellular Ca(2+) also prevented the depression of synaptic transmission. Inclusion of peptides to interrupt the interaction between GluA2 and PICK1 or dynamin and amphiphysin prevented the depression of transmission, suggesting a dynamin and PICK1-dependent internalization of AMPARs after OGD. We also show that a reduction in surface and total AMPAR protein levels after OGD was prevented by mGluR1 or A(3) receptor antagonists, indicating that AMPARs are degraded following internalization. Thus, we describe a novel mechanism for the removal of AMPARs in CA3 pyramidal neurons following OGD that has the potential to reduce excitotoxicity and promote neuroprotection.

  17. Activation of Synaptic Group II Metabotropic Glutamate Receptors Induces Long-Term Depression at GABAergic Synapses in CNS Neurons

    PubMed Central

    Tang, Zheng-Quan; Liu, Yu-Wei; Shi, Wei; Dinh, Emilie Hoang; Hamlet, William R.; Curry, Rebecca J.

    2013-01-01

    Metabotropic glutamate receptor (mGluR)-dependent homosynaptic long-term depression (LTD) has been studied extensively at glutamatergic synapses in the CNS. However, much less is known about heterosynaptic long-term plasticity induced by mGluRs at inhibitory synapses. Here we report that pharmacological or synaptic activation of group II mGluRs (mGluR II) induces LTD at GABAergic synapses without affecting the excitatory glutamatergic transmission in neurons of the chicken cochlear nucleus. Coefficient of variation and failure rate analysis suggested that the LTD was expressed presynaptically. The LTD requires presynaptic spike activity, but does not require the activation of NMDA receptors. The classic cAMP-dependent protein kinase A signaling is involved in the transduction pathway. Remarkably, blocking mGluR II increased spontaneous GABA release, indicating the presence of tonic activation of mGluR II by ambient glutamate. Furthermore, synaptically released glutamate induced by electrical stimulations that concurrently activated both the glutamatergic and GABAergic pathways resulted in significant and constant suppression of GABA release at various stimulus frequencies (3.3, 100, and 300 Hz). Strikingly, low-frequency stimulation (1 Hz, 15 min) of the glutamatergic synapses induced heterosynaptic LTD of GABAergic transmission, and the LTD was blocked by mGluR II antagonist, indicating that synaptic activation of mGluR II induced the LTD. This novel form of long-term plasticity in the avian auditory brainstem may play a role in the development as well as in temporal processing in the sound localization circuit. PMID:24089501

  18. Serotonin Modulates Developmental Microglia via 5-HT2B Receptors: Potential Implication during Synaptic Refinement of Retinogeniculate Projections.

    PubMed

    Kolodziejczak, Marta; Béchade, Catherine; Gervasi, Nicolas; Irinopoulou, Theano; Banas, Sophie M; Cordier, Corinne; Rebsam, Alexandra; Roumier, Anne; Maroteaux, Luc

    2015-07-15

    Maturation of functional neuronal circuits during central nervous system development relies on sophisticated mechanisms. First, axonal and dendritic growth should reach appropriate targets for correct synapse elaboration. Second, pruning and neuronal death are required to eliminate redundant or inappropriate neuronal connections. Serotonin, in addition to its role as a neurotransmitter, actively participates in postnatal establishment and refinement of brain wiring in mammals. Brain resident macrophages, that is, microglia, also play an important role in developmentally regulated neuronal death as well as in synaptic maturation and elimination. Here, we tested the hypothesis of cross-regulation between microglia and serotonin during postnatal brain development in a mouse model of synaptic refinement. We found expression of the serotonin 5-HT2B receptor on postnatal microglia, suggesting that serotonin could participate in temporal and spatial synchronization of microglial functions. Using two-photon microscopy, acute brain slices, and local delivery of serotonin, we observed that microglial processes moved rapidly toward the source of serotonin in Htr2B(+/+) mice, but not in Htr2B(-/-) mice lacking the 5-HT2B receptor. We then investigated whether some developmental steps known to be controlled by serotonin could potentially result from microglia sensitivity to serotonin. Using an in vivo model of synaptic refinement during early brain development, we investigated the maturation of the retinal projections to the thalamus and observed that Htr2B(-/-) mice present anatomical alterations of the ipsilateral projecting area of retinal axons into the thalamus. In addition, activation markers were upregulated in microglia from Htr2B(-/-) compared to control neonates, in the absence of apparent morphological modifications. These results support the hypothesis that serotonin interacts with microglial cells and these interactions participate in brain maturation.

  19. Selective Requirement for Maintenance of Synaptic Contacts onto Motoneurons by Target-Derived trkB Receptors.

    PubMed

    Zhu, Xiya; Ward, Patricia J; English, Arthur W

    2016-01-01

    Synaptic contacts onto motoneurons were studied in mice in which the gene for the trkB neurotrophin receptor was knocked out selectively in a subset of spinal motoneurons. The extent of contacts by structures immunoreactive for either of two different vesicular glutamate transporters (VGLUT1 and VGLUT2), the vesicular GABA transporter, or glutamic acid decarboxylase 67 (GAD67) with the somata of motoneurons, was studied in wild type and trkB knockout cells in tamoxifen treated male and female SLICK-trkB(-/-) mice. Selective knockout of the trkB gene resulted in a marked reduction in contacts made by VGLUT2- and GAD67-immunoreactive structures in both sexes and a significant reduction in contacts containing only glycine in male mice. No reduction was found for glycinergic contacts in female mice or for VGLUT1 immunoreactive contacts in either sex. Signaling through postsynaptic trkB receptors is considered to be an essential part of a cellular mechanism for maintaining the contacts of some, but not all, synaptic contacts onto motoneurons.

  20. Selective Requirement for Maintenance of Synaptic Contacts onto Motoneurons by Target-Derived trkB Receptors

    PubMed Central

    2016-01-01

    Synaptic contacts onto motoneurons were studied in mice in which the gene for the trkB neurotrophin receptor was knocked out selectively in a subset of spinal motoneurons. The extent of contacts by structures immunoreactive for either of two different vesicular glutamate transporters (VGLUT1 and VGLUT2), the vesicular GABA transporter, or glutamic acid decarboxylase 67 (GAD67) with the somata of motoneurons, was studied in wild type and trkB knockout cells in tamoxifen treated male and female SLICK-trkB−/− mice. Selective knockout of the trkB gene resulted in a marked reduction in contacts made by VGLUT2- and GAD67-immunoreactive structures in both sexes and a significant reduction in contacts containing only glycine in male mice. No reduction was found for glycinergic contacts in female mice or for VGLUT1 immunoreactive contacts in either sex. Signaling through postsynaptic trkB receptors is considered to be an essential part of a cellular mechanism for maintaining the contacts of some, but not all, synaptic contacts onto motoneurons. PMID:27433358

  1. Interaction between gustatory depolarizing receptor potential and efferent-induced slow depolarizing synaptic potential in frog taste cell.

    PubMed

    Sato, Toshihide; Nishishita, Kazuhisa; Okada, Yukio; Toda, Kazuo

    2009-03-01

    Electrical stimulation of parasympathetic nerve (PSN) efferent fibers in the glossopharyngeal nerve induced a slow depolarizing synaptic potential (DSP) in frog taste cells under hypoxia. The objective of this study is to examine the interaction between a gustatory depolarizing receptor potential (GDRP) and a slow DSP. The amplitude of slow DSP added to a tastant-induced GDRP of 10 mV was suppressed to 60% of control slow DSPs for NaCl and acetic acid stimulations, but to 20-30% for quinine-HCl (Q-HCl) and sucrose stimulations. On the other hand, when a GDRP was induced during a prolonged slow DSP, the amplitude of GDRPs induced by 1 M NaCl and 1 M sucrose was suppressed to 50% of controls, but that by 1 mM acetic acid and 10 mM Q-HCl unchanged. It is concluded that the interaction between GDRPs and efferent-induced slow DSPs in frog taste cells under hypoxia derives from the crosstalk between a gustatory receptor current across the receptive membrane and a slow depolarizing synaptic current across the proximal subsynaptic membrane of taste cells.

  2. Two families of TARP isoforms that have distinct effects on the kinetic properties of AMPA receptors and synaptic currents.

    PubMed

    Cho, Chang-Hoon; St-Gelais, Fannie; Zhang, Wei; Tomita, Susumu; Howe, James R

    2007-09-20

    Transmembrane AMPA receptor regulatory proteins (TARPs) are auxiliary AMPA receptor subunits that regulate both the trafficking and gating properties of AMPA receptors, and different TARP isoforms display distinct expression patterns in brain. Here, we compared the effects of four TARP isoforms on the kinetics of AMPA receptor currents. Each isoform slowed the deactivation of GluR1 currents, but the slowing was greatest with gamma-4 and gamma-8. Isoform-specific differences in desensitization were also observed that correlated with effects on deactivation. TARP isoforms also differentially modulated responses to trains of glutamate applications designed to mimic high-frequency presynaptic firing. Importantly, whereas both stargazin and gamma-4 rescued excitatory synaptic transmission in cerebellar granule cells from stargazer mice, the decay of miniature EPSCs was 2-fold slower in neurons expressing gamma-4. The results show that heterogeneity in the composition of AMPA receptor/TARP complexes contributes to synapse-specific differences in EPSC decays and frequency-dependent modulation of neurotransmission.

  3. Diminished neurosteroid sensitivity of synaptic inhibition and altered location of the alpha4 subunit of GABA(A) receptors in an animal model of epilepsy.

    PubMed

    Sun, Chengsan; Mtchedlishvili, Zakaria; Erisir, Alev; Kapur, Jaideep

    2007-11-14

    In animal models of temporal lobe epilepsy (TLE), neurosteroid sensitivity of GABA(A) receptors on dentate granule cells (DGCs) is diminished; the molecular mechanism underlying this phenomenon remains unclear. The current study investigated a mechanism for loss of neurosteroid sensitivity of synaptic GABA(A) receptors in TLE. Synaptic currents recorded from DGCs of epileptic animals (epileptic DGCs) were less frequent, larger in amplitude, and less sensitive to allopregnanolone modulation than those recorded from DGCs of control animals (control DGCs). Synaptic currents recorded from epileptic DGCs were less sensitive to diazepam and had altered sensitivity to benzodiazepine inverse agonist RO 15-4513 (ethyl-8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5alpha][1,4]benzodiazepine-3-carboxylate) and furosemide than those recorded from control DGCs. Properties of synaptic currents recorded from epileptic DGCs appeared similar to those of recombinant receptors containing the alpha4 subunit. Expression of the alpha4 subunit and its colocalization with the synaptic marker GAD65 was increased in epileptic DGCs. Location of the alpha4 subunit in relation to symmetric (inhibitory) synapses on soma and dendrites of control and epileptic DGCs was examined with postembedding immunogold electron microscopy. The alpha4 immunogold labeling was present more commonly within the synapse in epileptic DGCs compared with control DGCs, in which the subunit was extrasynaptic. These studies demonstrate that, in epileptic DGCs, the neurosteroid modulation of synaptic currents is diminished and alpha4 subunit-containing receptors are present at synapses and participate in synaptic transmission. These changes may facilitate seizures in epileptic animals.

  4. Oxygen/glucose Deprivation Induces a Reduction in Synaptic AMPA Receptors on Hippocampal CA3 Neurons Mediated by mGluR1 and A3 Receptors

    PubMed Central

    Dennis, Siobhan H.; Jaafari, Nadia; Cimarosti, Helena; Hanley, Jonathan G.; Henley, Jeremy M.; Mellor, Jack R.

    2011-01-01

    Summary Hippocampal CA1 pyramidal neurons are highly sensitive to ischemic damage, whereas neighbouring CA3 pyramidal neurons are less susceptible. It is proposed that switching of AMPA receptor (AMPAR) subunits on CA1 neurons during an in vitro model of ischemia, oxygen/glucose deprivation (OGD), leads to an enhanced permeability of AMPARs to Ca2+ resulting in delayed cell death. However, it is unclear if the same mechanisms exist in CA3 neurons and whether this underlies the differential sensitivity to ischemia. Here, we investigated the consequences of OGD for AMPAR function in CA3 neurons using electrophysiological recordings in rat hippocampal slices. Following a 15 minute OGD protocol a substantial depression of AMPAR-mediated synaptic transmission was observed at CA3 associational/commissural and mossy fiber synapses but not CA1 Schaffer collateral synapses. The depression of synaptic transmission following OGD was prevented by mGluR1 or A3 receptor antagonists, indicating a role for both glutamate and adenosine release. Inhibition of PLC, PKC or chelation of intracellular Ca2+ also prevented the depression of synaptic transmission. Inclusion of peptides to interrupt the interaction between GluA2 and PICK1 or dynamin and amphiphysin prevented the depression of transmission, suggesting a dynamin and PICK1-dependent internalisation of AMPARs after OGD. We also show a reduction in surface and total AMPAR protein levels after OGD was prevented by mGluR1 or A3 receptor antagonists indicating that AMPARs are degraded following internalisation. Thus, we describe a novel mechanism for the removal of AMPARs in CA3 pyramidal neurons following OGD that has the potential to reduce excitotoxicity and promote neuroprotection. PMID:21849555

  5. Presynaptic 5-HT3 receptor-mediated modulation of synaptic GABA release in the mechanically dissociated rat amygdala neurons

    PubMed Central

    Koyama, Susumu; Matsumoto, Nozomu; Kubo, Chiharu; Akaike, Norio

    2000-01-01

    Nystatin-perforated patch recordings were made from mechanically dissociated basolateral amygdala neurons with preserved intact native presynaptic nerve terminals to study the mechanism of 5-HT3 receptor-mediated serotonergic modulation of GABAergic inhibition. The specific 5-HT3 agonist mCPBG (1 μM) rapidly facilitated the frequency of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) and this facilitation desensitized within 1 min. Tropisetron (30 nM), a specific 5-HT3 antagonist, blocked the mCPBG effect. mCPBG augmented mIPSC amplitude. However, no direct postsynaptic serotonergic currents were evoked by mCPBG. Neither GABA-evoked current amplitude nor the kinetics of individual GABAergic mIPSCs were affected by mCPBG. Therefore, the augmentation is unlikely to be due to postsynaptic effects evoked by mCPBG. At higher concentrations mCPBG produced shorter-duration facilitation of miniature events. While mCPBG increased the mIPSC frequency in calcium-containing solution with Cd2+, this increase was absent in Ca2+-free external solution. It appears that the Ca2+ influx through voltage-dependent calcium channels was not as crucial as that through 5-HT3 receptors for synaptic GABA release. When two pulses of mCPBG (each 1 μM, 1 min) were given, the response to the second pulse elicited full recovery when the interval between pulses was at least 9 min. Protein kinase A (PKA) activation by 8-Br-cAMP (300 μM) shortened and PKA inhibition by Rp-cAMP (100 μM) prolonged the recovery time. PKA activity did not affect the time course of fast desensitization. Our results suggest that a 5-HT3-specific agonist acts on presynaptic nerve terminals facilitating synaptic GABA release without postsynaptic effects. The facilitation requires calcium influx through presynaptic 5-HT3 receptors. PKA modulates the recovery process from desensitization of presynaptic 5-HT3 receptor-mediated regulation of synaptic GABA release. PMID:11101647

  6. Opioid Receptor-Dependent Sex Differences in Synaptic Plasticity in the Hippocampal Mossy Fiber Pathway of the Adult Rat

    PubMed Central

    Harte-Hargrove, Lauren C.; Varga-Wesson, Ada; Duffy, Aine M.; Milner, Teresa A.

    2015-01-01

    The mossy fiber (MF) pathway is critical to hippocampal function and influenced by gonadal hormones. Physiological data are limited, so we asked whether basal transmission and long-term potentiation (LTP) differed in slices of adult male and female rats. The results showed small sex differences in basal transmission but striking sex differences in opioid receptor sensitivity and LTP. When slices were made from females on proestrous morning, when serum levels of 17β-estradiol peak, the nonspecific opioid receptor antagonist naloxone (1 μm) enhanced MF transmission but there was no effect in males, suggesting preferential opioid receptor-dependent inhibition in females when 17β-estradiol levels are elevated. The μ-opioid receptor (MOR) antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP; 300 nm) had a similar effect but the δ-opioid receptor (DOR) antagonist naltrindole (NTI; 1 μm) did not, implicating MORs in female MF transmission. The GABAB receptor antagonist saclofen (200 μm) occluded effects of CTOP but the GABAA receptor antagonist bicuculline (10 μm) did not. For LTP, a low-frequency (LF) protocol was used because higher frequencies elicited hyperexcitability in females. Proestrous females exhibited LF-LTP but males did not, suggesting a lower threshold for synaptic plasticity when 17β-estradiol is elevated. NTI blocked LF-LTP in proestrous females, but CTOP did not. Electron microscopy revealed more DOR-labeled spines of pyramidal cells in proestrous females than males. Therefore, we suggest that increased postsynaptic DORs mediate LF-LTP in proestrous females. The results show strong MOR regulation of MF transmission only in females and identify a novel DOR-dependent form of MF LTP specific to proestrus. PMID:25632146

  7. Assemblies of glutamate receptor subunits with post-synaptic density proteins and their alterations in Parkinson's disease.

    PubMed

    Gardoni, Fabrizio; Ghiglieri, Veronica; Di Luca, Monica; Calabresi, Paolo

    2010-01-01

    N-methyl-D-aspartate (NMDA) receptors have been implicated as a mediator of neuronal injury associated with many neurological disorders including ischemia, epilepsy, brain trauma, dementia and neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease. To this, non-selective NMDA receptor antagonists have been tried and have been shown to be effective in many experimental animal models of disease, and some of these compounds have moved into clinical trials. However, the initial enthusiasm for this approach has waned, because the therapeutic index for most NMDA antagonists is quite poor, with significant adverse effects at clinically effective doses, thus limiting their utility. More recently, the concept that the exact pathways downstream NMDA receptor activation could represent a key variable element among neurological disorders has been put forward. In particular, variations in NMDA receptor subunit composition could be important in different disorders, both in the pathophysiological mechanisms of cell death and in the application of specific symptomatic therapies. As to PD, NMDA receptor complex has been shown to be altered in experimental models of parkinsonism and in PD in humans. Further, it has become increasingly evident that the NMDA receptor complex is intimately involved in the regulation of corticostriatal long-term potentiation, which is altered in experimental parkinsonism. The following sections will examine the modifications of specific NMDA receptor subunits as well as post-synaptic associated signalling complex including kinases and scaffolding proteins in experimental parkinsonism. These findings may allow the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for PD.

  8. Activation of kappa opioid receptors decreases synaptic transmission and inhibits long-term potentiation in the basolateral amygdala of the mouse.

    PubMed

    Huge, Volker; Rammes, Gerhard; Beyer, Antje; Zieglgänsberger, Walter; Azad, Shahnaz C

    2009-02-01

    The amygdala plays an important role in the processing of chronic pain and pain memory formation. Particularly, it is involved in the emotional and affective components of the pain circuitry. The role of kappa opioid receptors in these pain conditions is only partly known. The present study investigates the effect of kappa receptor activation on synaptic transmission and synaptic plasticity in the amygdala. Electrophysiological in vitro experiments were carried out in brain slices of male C57BL/6JOlaHsd mice. The effect of the kappa opioid receptor agonist U50,488H (5 microM) and the selective kappa opioid receptor antagonist nor-BNI (3 microM) on field potential (FP) amplitude and the induction of long-term potentiation (LTP) in the basolateral amygdala (BLA) was examined. High frequency stimulation (HFS) of afferents in the lateral amygdala with two trains of 100 pulses at 50 Hz increased the FP amplitudes to 119+/-2% (mean+/-SEM; n=6) in the BLA. U50,488H decreased synaptic transmission (baseline: 100+/-0.5%; U50,488H: 86.3+/-2.4%; n=6) and blocked the induction of LTP (U50,488H: 100+/-4.1%; HFS: 102.6+/-7%; n=6). The effect on synaptic transmission and on LTP was completely reversed or prevented by application of nor-BNI, which itself had no effect on synaptic transmission or the induction of LTP. Kappa opioid receptor activation decreases synaptic transmission and inhibits the induction of LTP in the BLA of the mouse. These findings may be associated with the effects of kappa opioid agonists in chronic pain and pain memory formation.

  9. Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression.

    PubMed

    Ryan, Ben; Musazzi, Laura; Mallei, Alessandra; Tardito, Daniela; Gruber, Suzanne H M; El Khoury, Aram; Anwyl, Roger; Racagni, Giorgio; Mathé, Aleksander A; Rowan, Michael J; Popoli, Maurizio

    2009-05-01

    An animal model of depression combining genetic vulnerability and early-life stress (ELS) was prepared by submitting the Flinders Sensitive Line (FSL) rats to a standard paradigm of maternal separation. We analysed hippocampal synaptic transmission and plasticity in vivo and ionotropic receptors for glutamate in FSL rats, in their controls Flinders Resistant Line (FRL) rats, and in both lines subjected to ELS. A strong inhibition of long-term potentiation (LTP) and lower synaptic expression of NR1 subunit of the NMDA receptor were found in FSL rats. Remarkably, ELS induced a remodelling of synaptic plasticity only in FSL rats, reducing inhibition of LTP; this was accompanied by marked increase of synaptic NR1 subunit and GluR2/3 subunits of AMPA receptors. Chronic treatment with escitalopram inhibited LTP in FRL rats, but this effect was attenuated by prior ELS. The present results suggest that early gene-environment interactions cause lifelong synaptic changes affecting functional and molecular aspects of plasticity, partly reversed by antidepressant treatments.

  10. Long-term depression-inducing stimuli promote cleavage of the synaptic adhesion molecule NGL-3 through NMDA receptors, matrix metalloproteinases and presenilin/γ-secretase

    PubMed Central

    Lee, Hyejin; Lee, Eun-Jae; Song, Yoo Sung; Kim, Eunjoon

    2014-01-01

    Long-term depression (LTD) reduces the functional strength of excitatory synapses through mechanisms that include the removal of AMPA glutamate receptors from the postsynaptic membrane. LTD induction is also known to result in structural changes at excitatory synapses, including the shrinkage of dendritic spines. Synaptic adhesion molecules are thought to contribute to the development, function and plasticity of neuronal synapses largely through their trans-synaptic adhesions. However, little is known about how synaptic adhesion molecules are altered during LTD. We report here that NGL-3 (netrin-G ligand-3), a postsynaptic adhesion molecule that trans-synaptically interacts with the LAR family of receptor tyrosine phosphatases and intracellularly with the postsynaptic scaffolding protein PSD-95, undergoes a proteolytic cleavage process. NGL-3 cleavage is induced by NMDA treatment in cultured neurons and low-frequency stimulation in brain slices and requires the activities of NMDA glutamate receptors, matrix metalloproteinases (MMPs) and presenilin/γ-secretase. These results suggest that NGL-3 is a novel substrate of MMPs and γ-secretase and that NGL-3 cleavage may regulate synaptic adhesion during LTD. PMID:24298159

  11. Unlocking the secrets of the δ2 glutamate receptor: A gatekeeper for synaptic plasticity in the cerebellum.

    PubMed

    Kohda, Kazuhisa; Kakegawa, Wataru; Yuzaki, Michisuke

    2013-11-01

    Long-term changes in synaptic transmission in the central nervous system, such as long-term potentiation and long-term depression (LTD), are believed to underlie learning and memory in vivo. Despite intensive research, the precise molecular mechanisms underlying these phenomena have remained unclear. LTD is most commonly caused by the endocytosis of postsynaptic AMPA-type glutamate receptors, triggered by activity-induced serine phosphorylation of the GluA2 subunit. Interestingly, cerebellar LTD, which occurs at synapses between parallel fibers (PFs; axons of granule cells) and Purkinje cells, is unique in requiring an additional type of glutamate receptor, the δ2 receptor (GluD2). Cbln1 was recently identified as a GluD2 ligand that regulates PF synapse formation and maintenance. However, how GluD2 induces downstream signaling in Purkinje cells to regulate LTD induction is unknown. We here present evidence that GluD2 reduces the tyrosine phosphorylation level of the GluA2 subunit via PTPMEG, a protein tyrosine phosphatase that binds to GluD2's C-terminus. We also found that the serine phosphorylation of GluA2, a crucial step for AMPA-receptor endocytosis, requires prior tyrosine dephosphorylation. Thus, GluD2 may serve as a gatekeeper for LTD induction by coordinating interactions between GluA2's 2 phosphorylation sites.

  12. Unique ionotropic receptors for D-aspartate are a target for serotonin-induced synaptic plasticity in Aplysia californica.

    PubMed

    Carlson, Stephen L; Fieber, Lynne A

    2012-01-01

    The non-L-glutamate (L-Glu) receptor component of D-aspartate (D-Asp) currents in Aplysia californica buccal S cluster (BSC) neurons was studied with whole cell voltage clamp to differentiate it from receptors activated by other well-known agonists of the Aplysia nervous system and investigate modulatory mechanisms of D-Asp currents associated with synaptic plasticity. Acetylcholine (ACh) and serotonin (5-HT) activated whole cell excitatory currents with similar current voltage relationships to D-Asp. These currents, however, were pharmacologically distinct from D-Asp. ACh currents were blocked by hexamethonium (C6) and tubocurarine (D-TC), while D-Asp currents were unaffected. 5-HT currents were blocked by granisetron and methysergide (MES), while D-Asp currents were unaffected. Conversely, while (2S,3R)-1-(Phenanthren-2-carbonyl)piperazine-2,3-dicarboxylic acid(PPDA) blocked D-Asp currents, it had no effect on ACh or 5-HT currents. Comparison of the charge area described by currents induced by ACh or 5-HT separately from, or with, D-Asp suggests activation of distinct receptors by all 3 agonists. Charge area comparisons with L-Glu, however, suggested some overlap between L-Glu and D-Asp receptors. Ten minute exposure to 5-HT induced facilitation of D-Asp-evoked responses in BSC neurons. This effect was mimicked by phorbol ester, suggesting that protein kinase C (PKC) was involved.

  13. Loss of D2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area.

    PubMed

    Madhavan, Anuradha; Argilli, Emanuela; Bonci, Antonello; Whistler, Jennifer L

    2013-07-24

    Potentiation of glutamate responses is a critical synaptic response to cocaine exposure in ventral tegmental area (VTA) neurons. However, the mechanism by which cocaine exposure promotes potentiation of NMDA receptors (NMDARs) and subsequently AMPA receptors (AMPARs) is not fully understood. In this study we demonstrate that repeated cocaine treatment causes loss of D2 dopamine receptor functional responses via interaction with lysosome-targeting G-protein-associated sorting protein1 (GASP1). We also show that the absence of D2 downregulation in GASP1-KO mice prevents cocaine-induced potentiation of NMDAR currents, elevation of the AMPA/NMDA ratio, and redistribution of NMDAR and AMPAR subunits to the membrane. As a pharmacological parallel, coadministration of the high-affinity D2 agonist, aripiprazole, reduces not only functional downregulation of D2s in response to cocaine but also potentiation of NMDAR and AMPAR responses in wild-type mice. Together these data suggest that functional loss of D2 receptors is a critical mechanism mediating cocaine-induced glutamate plasticity in VTA neurons.

  14. Chaotic itinerancy in coupled dynamical recognizers.

    PubMed

    Ikegami, Takashi; Morimoto, Gentaro

    2003-09-01

    We argue that chaotic itinerancy in interaction between humans originates in the fluctuation of predictions provided by the nonconvergent nature of learning dynamics. A simple simulation model called the coupled dynamical recognizer is proposed to study this phenomenon. Daily cognitive phenomena provide many examples of chaotic itinerancy, such as turn taking in conversation. It is therefore an interesting problem to bridge two chaotic itinerant phenomena. A clue to solving this is the fluctuation of prediction, which can be translated as "hot prediction" in the context of cognitive theory. Hot prediction is simply defined as a prediction based on an unstable model. If this approach is correct, the present simulation will reveal some dynamic characteristics of cognitive interactions.

  15. 47 CFR 90.138 - Applications for itinerant frequencies.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SERVICES PRIVATE LAND MOBILE RADIO SERVICES Applications and Authorizations § 90.138 Applications for itinerant frequencies. An application for authority to conduct an itinerant operation in the Industrial... 47 Telecommunication 5 2011-10-01 2011-10-01 false Applications for itinerant frequencies....

  16. 47 CFR 90.138 - Applications for itinerant frequencies.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... SERVICES PRIVATE LAND MOBILE RADIO SERVICES Applications and Authorizations § 90.138 Applications for itinerant frequencies. An application for authority to conduct an itinerant operation in the Industrial... 47 Telecommunication 5 2010-10-01 2010-10-01 false Applications for itinerant frequencies. 90.138...

  17. 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

  18. Rescuing the Corticostriatal Synaptic Disconnection in the R6/2 Mouse Model of Huntington's Disease: Exercise, Adenosine Receptors and Ampakines.

    PubMed

    Cepeda, Carlos; Cummings, Damian M; Hickey, Miriam A; Kleiman-Weiner, Max; Chen, Jane Y; Watson, Joseph B; Levine, Michael S

    2010-09-20

    In the R6/2 mouse model of Huntington's disease (HD) we examined the effects of a number of behavioral and pharmacological manipulations aimed at rescuing the progressive loss of synaptic communication between cerebral cortex and striatum. Two cohorts of transgenic mice with ~110 and 210 CAG repeats were utilized. Exercise prevented the reduction in striatal medium-sized spiny neuron membrane capacitance but did not reestablish synaptic communication. Activation of adenosine A2A type receptors renormalized postsynaptic activity to some extent. Finally, the ampakine Cx614, which has been shown to prevent α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor desensitization, slow deactivation, and facilitate glutamate release, induced significant increases in synaptic activity, albeit the effect was somewhat reduced in fully symptomatic, compared to control mice. With some limitations, each of these strategies can be used to delay and partially rescue phenotypic progression of HD in this model.

  19. PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission.

    PubMed

    Ko, Ji Seung; Pramanik, Gopal; Um, Ji Won; Shim, Ji Seon; Lee, Dongmin; Kim, Kee Hun; Chung, Gug-Young; Condomitti, Giuseppe; Kim, Ho Min; Kim, Hyun; de Wit, Joris; Park, Kang-Sik; Tabuchi, Katsuhiko; Ko, Jaewon

    2015-02-10

    Leukocyte common antigen-related receptor protein tyrosine phosphatases--comprising LAR, PTPδ, and PTPσ--are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPσ. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPσ. PTPσ bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPσ, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPσ KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPσ, but not by a HS-binding-defective PTPσ mutant. Our results collectively suggest that presynaptic PTPσ, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.

  20. Chronic blockade of extrasynaptic NMDA receptors ameliorates synaptic dysfunction and pro-death signaling in Huntington disease transgenic mice.

    PubMed

    Dau, Alejandro; Gladding, Clare M; Sepers, Marja D; Raymond, Lynn A

    2014-02-01

    In the YAC128 mouse model of Huntington disease (HD), elevated extrasynaptic NMDA receptor (Ex-NMDAR) expression contributes to the onset of striatal dysfunction and atrophy. A shift in the balance of synaptic-extrasynaptic NMDAR signaling and localization is paralleled by early stage dysregulation of intracellular calcium signaling pathways, including calpain and p38 MAPK activation, that couple to pro-death cascades. However, whether aberrant calcium signaling is a consequence of elevated Ex-NMDAR expression in HD is unknown. Here, we aimed to identify calcium-dependent pathways downstream of Ex-NMDARs in HD. Chronic (2-month) treatment of YAC128 and WT mice with memantine (1 and 10mg/kg/day), which at a low dose selectively blocks Ex-NMDARs, reduced striatal Ex-NMDAR expression and current in 4-month old YAC128 mice without altering synaptic NMDAR levels. In contrast, calpain activity was not affected by memantine treatment, and was elevated in untreated YAC128 mice at 1.5months but not 4months of age. In YAC128 mice, memantine at 1mg/kg/day rescued CREB shut-off, while both doses suppressed p38 MAPK activation to WT levels. Taken together, our results indicate that Ex-NMDAR activity perpetuates increased extrasynaptic NMDAR expression and drives dysregulated p38 MAPK and CREB signaling in YAC128 mice. Elucidation of the pathways downstream of Ex-NMDARs in HD could help provide novel therapeutic targets for this disease.

  1. GABAB receptor-mediated, layer-specific synaptic plasticity reorganizes gamma-frequency neocortical response to stimulation

    PubMed Central

    Ainsworth, Matthew; Lee, Shane; Kaiser, Marcus; Simonotto, Jennifer; Kopell, Nancy J.

    2016-01-01

    Repeated presentations of sensory stimuli generate transient gamma-frequency (30–80 Hz) responses in neocortex that show plasticity in a task-dependent manner. Complex relationships between individual neuronal outputs and the mean, local field potential (population activity) accompany these changes, but little is known about the underlying mechanisms responsible. Here we show that transient stimulation of input layer 4 sufficient to generate gamma oscillations induced two different, lamina-specific plastic processes that correlated with lamina-specific changes in responses to further, repeated stimulation: Unit rates and recruitment showed overall enhancement in supragranular layers and suppression in infragranular layers associated with excitatory or inhibitory synaptic potentiation onto principal cells, respectively. Both synaptic processes were critically dependent on activation of GABAB receptors and, together, appeared to temporally segregate the cortical representation. These data suggest that adaptation to repetitive sensory input dramatically alters the spatiotemporal properties of the neocortical response in a manner that may both refine and minimize cortical output simultaneously. PMID:27118845

  2. Recruitment of resting vesicles into recycling pools supports NMDA receptor-dependent synaptic potentiation in cultured hippocampal neurons

    PubMed Central

    Ratnayaka, Arjuna; Marra, Vincenzo; Bush, Daniel; Burden, Jemima J; Branco, Tiago; Staras, Kevin

    2012-01-01

    Most presynaptic terminals in the central nervous system are characterized by two functionally distinct vesicle populations: a recycling pool, which supports action potential-driven neurotransmitter release via vesicle exocytosis, and a resting pool. The relative proportions of these two pools are highly variable between individual synapses, prompting speculation on their specific relationship, and on the possible functions of the resting pool. Using fluorescence imaging of FM-styryl dyes and synaptophysinI-pHluorin (sypHy) as well as correlative electron microscopy approaches, we show here that Hebbian plasticity-dependent changes in synaptic strength in rat hippocampal neurons can increase the recycling pool fraction at the expense of the resting pool in individual synaptic terminals. This recruitment process depends on NMDA-receptor activation, nitric oxide signalling and calcineurin and is accompanied by an increase in the probability of neurotransmitter release at individual terminals. Blockade of actin-mediated intersynaptic vesicle exchange does not prevent recycling pool expansion demonstrating that vesicle recruitment is intrasynaptic. We propose that the conversion of resting pool vesicles to the functionally recycling pool provides a rapid mechanism to implement long-lasting changes in presynaptic efficacy. PMID:22271866

  3. The Metabotropic Glutamate Receptor Subtype 1 Mediates Experience-Dependent Maintenance of Mature Synaptic Connectivity in the Visual Thalamus.

    PubMed

    Narushima, Madoka; Uchigashima, Motokazu; Yagasaki, Yuki; Harada, Takeshi; Nagumo, Yasuyuki; Uesaka, Naofumi; Hashimoto, Kouichi; Aiba, Atsu; Watanabe, Masahiko; Miyata, Mariko; Kano, Masanobu

    2016-09-07

    Neural circuits formed during postnatal development have to be maintained stably thereafter, but their mechanisms remain largely unknown. Here we report that the metabotropic glutamate receptor subtype 1 (mGluR1) is essential for the maintenance of mature synaptic connectivity in the dorsal lateral geniculate nucleus (dLGN). In mGluR1 knockout (mGluR1-KO) mice, strengthening and elimination at retinogeniculate synapses occurred normally until around postnatal day 20 (P20). However, during the subsequent visual-experience-dependent maintenance phase, weak retinogeniculate synapses were newly recruited. These changes were similar to those of wild-type (WT) mice that underwent visual deprivation or inactivation of mGluR1 in the dLGN from P21. Importantly, visual deprivation was ineffective in mGluR1-KO mice, and the changes induced by visual deprivation in WT mice were rescued by pharmacological activation of mGluR1 in the dLGN. These results demonstrate that mGluR1 is crucial for the visual-experience-dependent maintenance of mature synaptic connectivity in the dLGN.

  4. Activation of synaptic and extrasynaptic glycine receptors by taurine in preoptic hypothalamic neurons.

    PubMed

    Bhattarai, Janardhan Prasad; Park, Soo Joung; Chun, Sang Woo; Cho, Dong Hyu; Han, Seong Kyu

    2015-11-03

    Taurine is an essential amino-sulfonic acid having a fundamental function in the brain, participating in both cell volume regulation and neurotransmission. Using a whole cell voltage patch clamp technique, the taurine-activated neurotransmitter receptors in the preoptic hypothalamic area (PHA) neurons were investigated. In the first set of experiments, different concentrations of taurine were applied on PHA neurons. Taurine-induced responses were concentration-dependent. Taurine-induced currents were action potential-independent and sensitive to strychnine, suggesting the involvement of glycine receptors. In addition, taurine activated not only α-homomeric, but also αβ-heteromeric glycine receptors in PHA neurons. Interestingly, a low concentration of taurine (0.5mM) activated glycine receptors, whereas a higher concentration (3mM) activated both glycine and gamma-aminobutyric acid A (GABAA) receptors in PHA neurons. These results suggest that PHA neurons are influenced by taurine and respond via glycine and GABAA receptors.

  5. Toll Receptors Instruct Axon and Dendrite Targeting and Participate in Synaptic Partner Matching in a Drosophila Olfactory Circuit

    PubMed Central

    Ward, Alex; Hong, Weizhe; Favaloro, Vincenzo; Luo, Liqun

    2015-01-01

    SUMMARY Our understanding of the mechanisms that establish wiring specificity of complex neural circuits is far from complete. During Drosophila olfactory circuit assembly, axons of 50 olfactory receptor neuron (ORN) classes and dendrites of 50 projection neuron (PN) classes precisely target to 50 discrete glomeruli, forming parallel information-processing pathways. Here we show that Toll-6 and Toll-7, members of the Toll receptor family best known for functions in innate immunity and embryonic patterning, cell-autonomously instruct the targeting of specific classes of PN dendrites and ORN axons, respectively. The canonical ligands and downstream partners of Toll receptors in embryonic patterning and innate immunity are not required for the function of Toll-6/Toll-7 in wiring specificity, nor are their cytoplasmic domains. Interestingly, both Toll-6 and Toll-7 participate in synaptic partner matching between ORN axons and PN dendrites. Our investigations reveal that olfactory circuit assembly involves dynamic and long-range interactions between PN dendrites and ORN axons. PMID:25741726

  6. Toll receptors instruct axon and dendrite targeting and participate in synaptic partner matching in a Drosophila olfactory circuit.

    PubMed

    Ward, Alex; Hong, Weizhe; Favaloro, Vincenzo; Luo, Liqun

    2015-03-04

    Our understanding of the mechanisms that establish wiring specificity of complex neural circuits is far from complete. During Drosophila olfactory circuit assembly, axons of 50 olfactory receptor neuron (ORN) classes and dendrites of 50 projection neuron (PN) classes precisely target to 50 discrete glomeruli, forming parallel information-processing pathways. Here we show that Toll-6 and Toll-7, members of the Toll receptor family best known for functions in innate immunity and embryonic patterning, cell autonomously instruct the targeting of specific classes of PN dendrites and ORN axons, respectively. The canonical ligands and downstream partners of Toll receptors in embryonic patterning and innate immunity are not required for the function of Toll-6/Toll-7 in wiring specificity, nor are their cytoplasmic domains. Interestingly, both Toll-6 and Toll-7 participate in synaptic partner matching between ORN axons and PN dendrites. Our investigations reveal that olfactory circuit assembly involves dynamic and long-range interactions between PN dendrites and ORN axons. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Activity-induced synaptic delivery of the GluN2A-containing NMDA receptor is dependent on endoplasmic reticulum chaperone Bip and involved in fear memory

    PubMed Central

    Zhang, Xiao-min; Yan, Xun-yi; Zhang, Bin; Yang, Qian; Ye, Mao; Cao, Wei; Qiang, Wen-bin; Zhu, Li-jun; Du, Yong-lan; Xu, Xing-xing; Wang, Jia-sheng; Xu, Fei; Lu, Wei; Qiu, Shuang; Yang, Wei; Luo, Jian-hong

    2015-01-01

    The N-methyl-D-aspartate receptor (NMDAR) in adult forebrain is a heterotetramer mainly composed of two GluN1 subunits and two GluN2A and/or GluN2B subunits. The synaptic expression and relative numbers of GluN2A- and GluN2B-containing NMDARs play critical roles in controlling Ca2+-dependent signaling and synaptic plasticity. Previous studies have suggested that the synaptic trafficking of NMDAR subtypes is differentially regulated, but the precise molecular mechanism is not yet clear. In this study, we demonstrated that Bip, an endoplasmic reticulum (ER) chaperone, selectively interacted with GluN2A and mediated the neuronal activity-induced assembly and synaptic incorporation of the GluN2A-containing NMDAR from dendritic ER. Furthermore, the GluN2A-specific synaptic trafficking was effectively disrupted by peptides interrupting the interaction between Bip and GluN2A. Interestingly, fear conditioning in mice was disrupted by intraperitoneal injection of the interfering peptide before training. In summary, we have uncovered a novel mechanism for the activity-dependent supply of synaptic GluN2A-containing NMDARs, and demonstrated its relevance to memory formation. PMID:26088419

  8. Blocking Synaptic Removal of GluA2-Containing AMPA Receptors Prevents the Natural Forgetting of Long-Term Memories.

    PubMed

    Migues, Paola Virginia; Liu, Lidong; Archbold, Georgina E B; Einarsson, Einar Ö; Wong, Jacinda; Bonasia, Kyra; Ko, Seung Hyun; Wang, Yu Tian; Hardt, Oliver

    2016-03-23

    The neurobiological processes underpinning the natural forgetting of long-term memories are poorly understood. Based on the critical role of GluA2-containing AMPA receptors (GluA2/AMPARs) in long-term memory persistence, we tested in rats whether their synaptic removal underpins time-dependent memory loss. We found that blocking GluA2/AMPAR removal with the interference peptides GluA23Y or G2CT in the dorsal hippocampus during a memory retention interval prevented the normal forgetting of established, long-term object location memories, but did not affect their acquisition. The same intervention also preserved associative memories of food-reward conditioned place preference that would otherwise be lost over time. We then explored whether this forgetting process could play a part in behavioral phenomena involving time-dependent memory change. We found that infusing GluA23Y into the dorsal hippocampus during a 2 week retention interval blocked generalization of contextual fear expression, whereas infusing it into the infralimbic cortex after extinction of auditory fear prevented spontaneous recovery of the conditioned response. Exploring possible physiological mechanisms that could be involved in this form of memory decay, we found that bath application of GluA23Y prevented depotentiation, but not induction of long-term potentiation, in a hippocampal slice preparation. Together, these findings suggest that a decay-like forgetting process that involves the synaptic removal of GluA2/AMPARs erases consolidated long-term memories in the hippocampus and other brain structures over time. This well regulated forgetting process may critically contribute to establishing adaptive behavior, whereas its dysregulation could promote the decline of memory and cognition in neuropathological disorders. The neurobiological mechanisms involved in the natural forgetting of long-term memory and its possible functions are not fully understood. Based on our previous work describing the

  9. Abnormalities in α/β-CaMKII and related mechanisms suggest synaptic dysfunction in hippocampus of LPA1 receptor knockout mice.

    PubMed

    Musazzi, Laura; Di Daniel, Elena; Maycox, Peter; Racagni, Giorgio; Popoli, Maurizio

    2011-08-01

    Lysophosphatidic acid (LPA) is a natural lysophospholipid that regulates neuronal maturation. In mice, the deletion of the LPA1 receptor causes some phenotypic defects partly overlapping with those found in schizophrenia. In this study, we identified molecular abnormalities in hippocampal synaptic mechanisms involved in glutamatergic neurotransmission, which allow further characterization of synaptic aberrations in LPA1 knockout (KO) mice. At the synaptic level, we found dysregulation of Ca2+/calmodulin (CaM)-dependent kinase II (CaMKII) activity and phosphorylation, with markedly higher Ca2+-dependent kinase activity, probably related to increased expression levels of the β isoform of CaMKII. Conversely, although the synaptic Ca2+-independent activity of the enzyme was unchanged, autophosphorylation levels of both α and β isoforms were significantly increased in LPA1 KO mice. Moreover, in LPA1 KO mice the α/β isoform ratio of CaMKII, which plays a key role in neuronal maturation during development, was markedly decreased, as found previously in schizophrenia patients. At post-synaptic level, LPA1 KO mice showed changes in expression, phosphorylation and interactions of NMDA and AMPA receptor subunits that are consistent with basal strengthening of glutamatergic synapses. However, we measured a reduction of nuclear cAMP responsive element-binding protein phosphorylation, suggesting that activation of the NMDA receptor does not occur at the intracellular signalling level. At the presynaptic level, in line with previous evidence from schizophrenia patients and animal models of pathology, LPA1 KO mice showed accumulation of SNARE protein complexes. This study shows that CaMKII and related synaptic mechanisms at glutamatergic synapses are strongly dysregulated in LPA1 KO mice.

  10. Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons: distinctive sufficiency for hippocampus-dependent and amygdala-dependent synaptic and behavioral functions.

    PubMed

    Ruehle, Sabine; Remmers, Floor; Romo-Parra, Hector; Massa, Federico; Wickert, Melanie; Wörtge, Simone; Häring, Martin; Kaiser, Nadine; Marsicano, Giovanni; Pape, Hans-Christian; Lutz, Beat

    2013-06-19

    A major goal in current neuroscience is to understand the causal links connecting protein functions, neural activity, and behavior. The cannabinoid CB1 receptor is expressed in different neuronal subpopulations, and is engaged in fine-tuning excitatory and inhibitory neurotransmission. Studies using conditional knock-out mice revealed necessary roles of CB1 receptor expressed in dorsal telencephalic glutamatergic neurons in synaptic plasticity and behavior, but whether this expression is also sufficient for brain functions is still to be determined. We applied a genetic strategy to reconstitute full wild-type CB1 receptor functions exclusively in dorsal telencephalic glutamatergic neurons and investigated endocannabinoid-dependent synaptic processes and behavior. Using this approach, we partly restored the phenotype of global CB1 receptor deletion in anxiety-like behaviors and fully restored hippocampus-dependent neuroprotection from chemically induced epileptiform seizures. These features coincided with a rescued hippocampal depolarization-induced suppression of excitation (DSE), a CB1 receptor-dependent form of synaptic plasticity at glutamatergic neurons. By comparison, the rescue of the CB1 receptor on dorsal telencephalic glutamatergic neurons prolonged the time course of DSE in the amygdala, and impaired fear extinction in auditory fear conditioning. These data reveal that CB1 receptor in dorsal telencephalic glutamatergic neurons plays a sufficient role to control neuronal functions that are in large part hippocampus-dependent, while it is insufficient for proper amygdala functions, suggesting an unexpectedly complex circuit regulation by endocannabinoid signaling in the amygdala. Our data pave the way to a better understanding of neuronal networks in the context of behavior, by fine-tuned interference with synaptic transmission processes.

  11. Synaptic fusion pore structure and AMPA receptor activation according to Brownian simulation of glutamate diffusion.

    PubMed

    Ventriglia, Francesco; Maio, Vito Di

    2003-03-01

    The rising phase of fast, AMPA-mediated Excitatory Post Synaptic Currents (EPSCs) has a primary role in the computational ability of neurons. The structure and radial expansion velocity of the fusion pore between the vesicle and the presynaptic membrane could be important factors in determining the time course of the EPSC. We have used a Brownian simulation model for glutamate neurotransmitter diffusion to test two hypotheses on the fusion pore structure, namely, the proteinaceous pore and the purely lipidic pore. Three more hypotheses on the radial expansion velocity were also tested. The rising phases of the EPSC, computed under various conditions, were compared with experimental data from the literature. Our present results show that a proteinaceous fusion pore should produce a more marked foot at the beginning of the rising phase of the EPSC. They also confirm the hypothesis that the structure of the fusion pore and its radial expansion velocity play significant roles in shaping the fast EPSC time course.

  12. Seizure induced synaptic plasticity alteration in hippocampus is mediated by IL-1β receptor through PI3K/Akt pathway

    PubMed Central

    Han, Tao; Qin, Yanyu; Mou, Chenzhi; Wang, Min; Jiang, Meng; Liu, Bin

    2016-01-01

    Seizures, which result from synchronized aberrant firing of neuronal populations, can cause long-term sequelae, such as epilepsy, cognitive and behavioral issues, in which the synaptic plasticity alteration may play an important role. Long-term potentiation (LTP) is a persistent increase in synaptic strength and is essential for learning and memory. In the present study, we first examined the alteration of cognitive impairments and synaptic plasticity in mice with seizures, then explored the underlying mechanism involving pro-inflammatory factors and PI3K/Akt pathway. The results demonstrated that: (1) PTZ-induced seizure impairs learning and memory in mice, indicated by Morris water maze test; (2) PTZ-induced seizure decreased LTP; (3) the mRNA expression of IL-1β, IL-6 and TNF-α in the hippocampus were increased in mice with seizures; (4) LTP was increased by IL-1β receptor antagonist anakinra, but not inhibitors of IL-6 or TNF-α receptor; (5) Antagonist of IL-1β receptor rescues deficits in learning and memory of mice with seizures through PI3K/Akt pathway. It is concluded that the IL-1β induced by PTZ-induced seizures may impair the synaptic plasticity alteration in hippocampus as well as learning and memory ability by PI3K/Akt signaling pathway. PMID:27830035

  13. Synaptic-type α1β2γ2L GABAA receptors produce large persistent currents in the presence of ambient GABA and anesthetic drugs.

    PubMed

    Li, Ping; Akk, Gustav

    2015-05-01

    Synaptic GABAA receptors respond to synaptically released GABA and are considered to be unaffected by the low levels of ambient transmitter in the brain. We show that synaptic-type α1β2γ2L GABAA receptors expressed in HEK293 cells respond with large steady-state currents to combinations of a low concentration (0.5 μM) of GABA and clinically used GABAergic modulators propofol, etomidate, or pentobarbital or the steroid alphaxalone. At a maximally effective concentration of modulator, the current levels at the end of 2-minute applications of drug combinations were >10% of the peak response to saturating GABA. In the absence of modulators, 0.5 μM GABA generated a steady-state response of 1% of the peak response to saturating GABA. The concentration-response curves for enhancement of steady-state currents by propofol, etomidate, pentobarbital, or alphaxalone were at similar or lower drug concentrations compared with concentration-response relationships for enhancement of peak responses. We propose that modulation of tonically activated synaptic-type GABAA receptors contributes to the clinical actions of sedative drugs.

  14. 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

  15. Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine-binding site of N-methyl-D-aspartate receptor.

    PubMed

    Moriguchi, Shigeki; Tanaka, Tomoya; Narahashi, Toshio; Fukunaga, Kohji

    2013-10-01

    Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine-binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of α-amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase Cα (PKCα). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKCα (Ser-657) and Src family (Tyr-416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKCα (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high

  16. 'TRPing' synaptic ribbon function in the rat pineal gland: neuroendocrine regulation involves the capsaicin receptor TRPV1.

    PubMed

    Reuss, Stefan; Disque-Kaiser, Ursula; Binzen, Uta; Greffrath, Wolfgang; Peschke, Elmar

    2010-01-01

    Synaptic ribbons (SRs) are presynaptic structures thought to regulate and facilitate multivesicular release. In the pineal gland, they display a circadian rhythm with higher levels at night paralleling melatonin synthesis. To gain more insight into the processes involved and the possible functions of these structures, a series of experiments were conducted in rodents. We studied the regional distribution of a molecular marker of pineal SRs, the kinesin motor KIF3A in the gland. Respective immunoreactivity was abundant in central regions of the gland where sympathetic fibers were less dense, and vice versa, revealing that intercellular communication between adjacent pinealocytes is enhanced under low sympathetic influence. KIF3A was found to be colocalized to the transient receptor potential channel of the vanilloid receptor family, subtype 1 (TRPV1). The TRPV1 agonist capsaicin increased melatonin secretion from perifused pineals in a dose-dependent manner that was blocked by the competitive TRPV1 antagonist capsazepine. No change in free intracellular calcium was observed in response to TRPV1 ligands applied to pinealocytes responding to norepinephrine, bradykinin and/or depolarization. These data clearly indicate that TRPV1 actively regulates pineal gland function.

  17. Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines

    PubMed Central

    Afroz, Sonia; Parato, Julie; Shen, Hui; Smith, Sheryl Sue

    2016-01-01

    Adolescent synaptic pruning is thought to enable optimal cognition because it is disrupted in certain neuropathologies, yet the initiator of this process is unknown. One factor not yet considered is the α4βδ GABAA receptor (GABAR), an extrasynaptic inhibitory receptor which first emerges on dendritic spines at puberty in female mice. Here we show that α4βδ GABARs trigger adolescent pruning. Spine density of CA1 hippocampal pyramidal cells decreased by half post-pubertally in female wild-type but not α4 KO mice. This effect was associated with decreased expression of kalirin-7 (Kal7), a spine protein which controls actin cytoskeleton remodeling. Kal7 decreased at puberty as a result of reduced NMDAR activation due to α4βδ-mediated inhibition. In the absence of this inhibition, Kal7 expression was unchanged at puberty. In the unpruned condition, spatial re-learning was impaired. These data suggest that pubertal pruning requires α4βδ GABARs. In their absence, pruning is prevented and cognition is not optimal. DOI: http://dx.doi.org/10.7554/eLife.15106.001 PMID:27136678

  18. Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2

    PubMed Central

    Gingrich, Jeffrey R.; Pelkey, Kenneth A.; Fam, Sami R.; Huang, Yueqiao; Petralia, Ronald S.; Wenthold, Robert J.; Salter, Michael W.

    2004-01-01

    Src is the prototypic protein tyrosine kinase and is critical for controlling diverse cellular functions. Regions in Src define structural and functional domains conserved in many cell signaling proteins. Src also contains a region of low sequence conservation termed the unique domain, the function of which has until now remained enigmatic. Here, we show that the unique domain of Src is a protein–protein interaction region and we identify NADH dehydrogenase subunit 2 (ND2) as a Src unique domain-interacting protein. ND2 is a subunit of complex I in mitochondria, but we find that ND2 interacts with Src outside this organelle at excitatory synapses in the brain. ND2 acts as an adapter protein anchoring Src to the N-methyl-d-aspartate (NMDA) receptor complex, and is crucial for Src regulation of synaptic NMDA receptor activity. By showing an extramitochondrial action for a protein encoded in the mitochondrial genome, we identify a previously unsuspected means by which mitochondria regulate cellular function, suggesting a new paradigm that may be of general relevance for control of Src signaling. PMID:15069201

  19. Calmodulin binding proteins of the cholinergic electromotor synapse: synaptosomes, synaptic vesicles, receptor-enriched membranes, and cytoskeleton.

    PubMed

    Walker, J H; Stadler, H; Witzemann, V

    1984-02-01

    Calmodulin binding proteins (CBPs) have been identified using a gel overlay technique for fractions isolated from Torpedo electromotor nerve endings. Different fractions possessed characteristic patterns of CBPs. Synaptosomes showed five major CBPs--Mr 220,000, 160,000, 125,000, 55,000, and 51,000. Polypeptides of Mr 55,000 and 51,000 were found in the cytoplasm and the others are membrane-associated. The Triton X-100-insoluble cytoskeleton of synaptosomes was isolated in the presence or absence of calcium. The major CBPs had Mr of 19,000, 18,000, and 16,000. In the presence of calcium, no other CBPs were seen. In the absence of calcium, an Mr 160,000 polypeptide was present in the Triton cytoskeleton. Synaptic vesicles showed CBPs of Mr 160,000, 25,000, and 20,000. Membrane fragments enriched in acetylcholine receptors contained two major CBPs, Mr 160,000 and 125,000, together with a less prominent protein at Mr 26,000. A protein of Mr similar to that of fodrin was present in synaptosomes and acetylcholine receptor membrane fragments, but only in small amounts relative to the other polypeptides observed. The heavy and light chains of clathrin-coated vesicles from pig brain did not bind calmodulin, although strong labelling of an Mr 47,000 polypeptide was found. Results showed that calelectrin does not bind calmodulin. The possible identity of the calmodulin binding proteins is discussed.

  20. Synaptic relationship between somatostatin- and neurokinin-1 receptor-immunoreactive neurons in the pre-Bötzinger complex of rats.

    PubMed

    Wei, Xiao-Yan; Zhao, Yu; Wong-Riley, Margaret T T; Ju, Gong; Liu, Ying-Ying

    2012-09-01

    The pre-Bötzinger complex (pre-BötC) in the ventrolateral medulla oblongata is critical for the generation of respiratory rhythm in mammals. Somatostatin (SST) and neurokinin 1 receptor (NK1R) immunoreactivity have been used as markers of the pre-BötC. SST immunoreactivity almost completely overlaps with small fusiform NK1R-immunoreactive (ir) neurons, the presumed rhythmogenic neurons, but not with large multipolar NK1R-ir neurons. Understanding the neurochemical characteristics, especially the synaptic relationship of SST/NK1R-ir neurons within the pre-BötC network is essential in providing cellular and structural bases for understanding their physiological significance. This work has not been documented so far. We found that SST immunoreactivity was highly expressed in terminals, somas, and primary dendrites in the pre-BötC. Besides the small fusiform neurons, a small population of medium-sized NK1R-ir neurons also colocalized with SST. Large NK1R-ir neurons were not SST-ir, but received somatostatinergic inputs. SST-ir terminals were glutamatergic or GABAergic, and synapsed with NK1R-ir neurons. Most of synapses between them were of the symmetric type, indicating their inhibitory nature. Asymmetric synapses were evident between SST-ir terminals and NK1R-ir dendrites, strongly suggesting an excitatory innervation from the presumed rhythmogenic neurons as these neurons are glutamatergic. We speculate that SST-mediated excitatory and inhibitory synaptic transmission onto NK1R-ir rhythmogenic and follower neurons synchronizes their activity to contribute to respiratory rhythmogenesis and control.

  1. Super-Resolution Microscopy Reveals a Nanoscale Organization of Acetylcholine Receptors for Trans-Synaptic Alignment at Neuromuscular Synapses.

    PubMed

    York, Amanda L; Zheng, James Q

    2017-01-01

    The neuromuscular junction (NMJ) is a chemical synapse formed between motoneurons and skeletal muscle fibers. The vertebrate NMJ uses acetylcholine (ACh) as the neurotransmitter and features numerous invaginations of the postsynaptic muscle membrane termed junctional folds. ACh receptors (AChRs) are believed to be concentrated on the crest of junctional folds but their spatial organization remains to be fully understood. In this study, we utilized super-resolution microscopy to examine the nanoscale organization of AChRs at NMJ. Using Structured Illumination Microscopy, we found that AChRs appear as stripes within the pretzel-shaped mouse NMJs, which however, do not correlate with the size of the crests of junctional folds. By comparing the localization of AChRs with several pre- and postsynaptic markers of distinct compartments of NMJs, we found that AChRs are not distributed evenly across the crest of junctional folds as previously thought. Instead, AChR stripes are more closely aligned with the openings of junctional folds as well as with the presynaptic active zone. Using Stochastic Optical Reconstruction Microscopy (STORM) for increased resolution, we found that each AChR stripe contains an AChR-poor slit at the center that is equivalent to the size of the opening of junctional folds. Together, these findings indicate that AChRs are largely localized to the edges of crests surrounding the opening of folds to align with the presynaptic active zones. Such a nanoscale organization of AChRs potentially enables trans-synaptic alignment for effective synaptic transmission of NMJs.

  2. Cross-talk between P2X4 and gamma-aminobutyric acid, type A receptors determines synaptic efficacy at a central synapse.

    PubMed

    Jo, Young-Hwan; Donier, Emmanuelle; Martinez, Audrey; Garret, Maurice; Toulmé, Estelle; Boué-Grabot, Eric

    2011-06-03

    The essence of neuronal function is to generate outputs in response to synaptic potentials. Synaptic integration at postsynaptic sites determines neuronal outputs in the CNS. Using immunohistochemical and electrophysiological approaches, we first reveal that steroidogenic factor 1 (SF-1) green fluorescent protein (GFP)-positive neurons in the ventromedial nucleus of the hypothalamus express P2X4 subunits that are activated by exogenous ATP. Increased membrane expression of P2X4 channels by using a peptide competing with P2X4 intracellular endocytosis motif enhances neuronal excitability of SF-1 GFP-positive neurons. This increased excitability is inhibited by a P2X receptor antagonist. Furthermore, increased surface P2X4 receptor expression significantly decreases the frequency and the amplitude of GABAergic postsynaptic currents of SF-1 GFP-positive neurons. Co-immunopurification and pulldown assays reveal that P2X4 receptors complex with aminobutyric acid, type A (GABA(A)) receptors and demonstrate that two amino acids in the carboxyl tail of the P2X4 subunit are crucial for its physical association with GABA(A) receptors. Mutation of these two residues prevents the physical association, thereby blocking cross-inhibition between P2X4 and GABA(A) receptors. Moreover, disruption of the physical coupling using competitive peptides containing the identified motif abolishes current inhibition between P2X4 and GABA(A) receptors in recombinant system and P2X4 receptor-mediated GABAergic depression in SF-1 GFP-positive neurons. Our present work thus provides evidence for cross-talk between excitatory and inhibitory receptors that appears to be crucial in determining GABAergic synaptic strength at a central synapse.

  3. Cross-talk between P2X4 and γ-Aminobutyric Acid, Type A Receptors Determines Synaptic Efficacy at a Central Synapse*

    PubMed Central

    Jo, Young-Hwan; Donier, Emmanuelle; Martinez, Audrey; Garret, Maurice; Toulmé, Estelle; Boué-Grabot, Eric

    2011-01-01

    The essence of neuronal function is to generate outputs in response to synaptic potentials. Synaptic integration at postsynaptic sites determines neuronal outputs in the CNS. Using immunohistochemical and electrophysiological approaches, we first reveal that steroidogenic factor 1 (SF-1) green fluorescent protein (GFP)-positive neurons in the ventromedial nucleus of the hypothalamus express P2X4 subunits that are activated by exogenous ATP. Increased membrane expression of P2X4 channels by using a peptide competing with P2X4 intracellular endocytosis motif enhances neuronal excitability of SF-1 GFP-positive neurons. This increased excitability is inhibited by a P2X receptor antagonist. Furthermore, increased surface P2X4 receptor expression significantly decreases the frequency and the amplitude of GABAergic postsynaptic currents of SF-1 GFP-positive neurons. Co-immunopurification and pulldown assays reveal that P2X4 receptors complex with aminobutyric acid, type A (GABAA) receptors and demonstrate that two amino acids in the carboxyl tail of the P2X4 subunit are crucial for its physical association with GABAA receptors. Mutation of these two residues prevents the physical association, thereby blocking cross-inhibition between P2X4 and GABAA receptors. Moreover, disruption of the physical coupling using competitive peptides containing the identified motif abolishes current inhibition between P2X4 and GABAA receptors in recombinant system and P2X4 receptor-mediated GABAergic depression in SF-1 GFP-positive neurons. Our present work thus provides evidence for cross-talk between excitatory and inhibitory receptors that appears to be crucial in determining GABAergic synaptic strength at a central synapse. PMID:21482824

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. Dopamine D1/D5 receptor signaling regulates synaptic cooperation and competition in hippocampal CA1 pyramidal neurons via sustained ERK1/2 activation.

    PubMed

    Shivarama Shetty, Mahesh; Gopinadhan, Suma; Sajikumar, Sreedharan

    2016-02-01

    Synaptic cooperation and competition are important components of synaptic plasticity that tune synapses for the formation of associative long-term plasticity, a cellular correlate of associative long-term memory. We have recently reported that coincidental activation of weak synapses within the vicinity of potentiated synapses will alter the cooperative state of synapses to a competitive state thus leading to the slow decay of long-term plasticity, but the molecular mechanism underlying this is still unknown. Here, using acute hippocampal slices of rats, we have examined how increasing extracellular dopamine concentrations interact and/or affect electrically induced long-term potentiation (LTP) in the neighboring synapses. We demonstrate that D1/D5-receptor-mediated potentiation at the CA1 Schaffer collateral synapses differentially regulates synaptic co-operation and competition. Further investigating the molecular players involved, we reveal an important role for extracellular signal-regulated kinases-1 and 2 (ERK1/2) as signal integrators and dose-sensors. Interestingly, a sustained activation of ERK1/2 pathway seems to be involved in the differential regulation of synaptic associativity. The concentration-dependent effects of the modulatory transmitter, as demonstrated for dopaminergic signaling in the present study, might offer additional computational power by fine tuning synaptic associativity processes for establishing long-term associative memory in neural networks.

  9. A role for protein kinase A and protein kinase M zeta in muscarinic acetylcholine receptor-initiated persistent synaptic enhancement in rat hippocampus in vivo.

    PubMed

    Hayes, J; Li, S; Anwyl, R; Rowan, M J

    2008-01-24

    Antagonists at presynaptic muscarinic autoreceptors increase endogenous acetylcholine (ACh) release and enhance cognition but little is known regarding their actions on plasticity at glutamatergic synapses. Here the mechanisms of the persistent enhancement of hippocampal excitatory transmission induced by the M2/M4 muscarinic ACh receptor antagonist methoctramine were investigated in vivo. The persistent facilitatory effect of i.c.v. methoctramine in the CA1 region of urethane-anesthetized rats was mimicked by gallamine, an M2 receptor antagonist, supporting a role for this receptor subtype. Neither the N-methyl-D-aspartate (NMDA) receptor antagonists D-(-)-2-amino phosphonopentanoic acid (d-AP5) and memantine, nor the metabotropic glutamate receptor subtype 1a antagonist (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) significantly affected the methoctramine-induced persistent synaptic enhancement, indicating a lack of requirement for these glutamate receptors. The selective kinase inhibitors Rp-adenosine-3', 5'-cyclic monophosphorothioate (Rp-cAMPS) and the myrostylated pseudosubstrate peptide, Myr-Ser-Ile-Tyr-Arg-Arg-Gly-Ala-Arg-Arg-Trp-Arg-Lys-Leu-OH (ZIP), were used to investigate the roles of protein kinase A (PKA) and the atypical protein kinase C, protein kinase Mzeta (PKM zeta), respectively. Remarkably, pretreatment with either agent prevented the induction of the persistent synaptic enhancement by methoctramine and post-methoctramine treatment with Rp-cAMPS transiently reversed the enhancement. These findings are strong evidence that antagonism of M2 muscarinic ACh receptors in vivo induces an NMDA receptor-independent persistent synaptic enhancement that requires activation of both PKA and PKM zeta.

  10. 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.

  11. Drebrin depletion alters neurotransmitter receptor levels in protein complexes, dendritic spine morphogenesis and memory-related synaptic plasticity in the mouse hippocampus.

    PubMed

    Jung, Gangsoo; Kim, Eun-Jung; Cicvaric, Ana; Sase, Sunetra; Gröger, Marion; Höger, Harald; Sialana, Fernando Jayson; Berger, Johannes; Monje, Francisco J; Lubec, Gert

    2015-07-01

    Drebrin an actin-bundling key regulator of dendritic spine genesis and morphology, has been recently proposed as a regulator of hippocampal glutamatergic activity which is critical for memory formation and maintenance. Here, we examined the effects of genetic deletion of drebrin on dendritic spine and on the level of complexes containing major brain receptors. To this end, homozygous and heterozygous drebrin knockout mice generated in our laboratory and related wild-type control animals were studied. Level of protein complexes containing dopamine receptor D1/dopamine receptor D2, 5-hydroxytryptamine receptor 1A (5-HT1(A)R), and 5-hydroxytryptamine receptor 7 (5-HT7R) were significantly reduced in hippocampus of drebrin knockout mice whereas no significant changes were detected for GluR1, 2, and 3 and NR1 as examined by native gel-based immunoblotting. Drebrin depletion also altered dendritic spine formation, morphology, and reduced levels of dopamine receptor D1 in dendritic spines as evaluated using immunohistochemistry/confocal microscopy. Electrophysiological studies further showed significant reduction in memory-related hippocampal synaptic plasticity upon drebrin depletion. These findings provide unprecedented experimental support for a role of drebrin in the regulation of memory-related synaptic plasticity and neurotransmitter receptor signaling, offer relevant information regarding the interpretation of previous studies and help in the design of future studies on dendritic spines. © 2015 International Society for Neurochemistry.

  12. Resistivity Minimum in Highly Frustrated Itinerant Magnets

    NASA Astrophysics Data System (ADS)

    Wang, Zhentao; Barros, Kipton; Chern, Gia-Wei; Maslov, Dmitrii L.; Batista, Cristian D.

    2016-11-01

    We study the transport properties of frustrated itinerant magnets comprising localized classical moments, which interact via exchange with the conduction electrons. Strong frustration stabilizes a liquidlike spin state, which extends down to temperatures well below the effective Ruderman-Kittel-Kasuya-Yosida interaction scale. The crossover into this state is characterized by spin structure factor enhancement at wave vectors smaller than twice the Fermi wave vector magnitude. The corresponding enhancement of electron scattering generates a resistivity upturn at decreasing temperatures.

  13. Developmental regulation of hippocampal excitatory synaptic transmission by metabotropic glutamate receptors

    PubMed Central

    Ross, F M; Cassidy, J; Wilson, M; Davies, S N

    2000-01-01

    The aims of this study were, to use agonists selective for the 3 mGlu receptor groups to identify developmental changes in their effects, and to assess the usefulness of proposed selective antagonists as pharmacological tools.Hippocampal slices (400 μm) were prepared from neonate (9–14 days) and young adult (5–7 weeks) Sprague-Dawley rats. Field excitatory postsynaptic potentials (fEPSP) were recorded from CA1.DHPG (100 μM), a group I agonist, produced a slowly developing enhancement of fEPSP slope in slices from adults. In slices from neonates, DHPG (75 μM) depressed fEPSP slope.DCG-IV (500 nM), a group II agonist, did not affect the fEPSP recorded from slices from adults whereas perfusion in neonate slices produced a sustained depression.The group III agonist L-AP4 (50 μM) was ineffective in adult slices but depressed fEPSP slope in slices prepared from neonates.DHPG-induced depression of fEPSP slope was inhibited by 4-CPG (400 μM), a group I antagonist, but was unaffected by MCCG (500 μM) and MAP4 (500 μM), group II and III receptor antagonists respectively. MCCG but not MAP4 antagonized the effects of DCG-IV with 4-CPG producing variable effects. The effect of L-AP4 was unaffected by MCCG, blocked by MAP4, and enhanced by 4-CPG.The results show that the effects of the agonists for all groups of mGlu receptors are developmentally regulated. Furthermore, MCCG and MAP4 behave as effective and selective antagonists for group II and group III mGlu receptors respectively, whereas the usefulness of 4-CPG as a group I antagonist may be limited. PMID:11015295

  14. Numb deficiency in cerebellar Purkinje cells impairs synaptic expression of metabotropic glutamate receptor and motor coordination

    PubMed Central

    Zhou, Liang; Yang, Dong; Wang, De-Juan; Xie, Ya-Jun; Zhou, Jia-Huan; Zhou, Lin; Huang, Hao; Han, Shuo; Shao, Chong-Yu; Li, Hua-Shun; Zhu, J. Julius; Qiu, Meng-Sheng; De Zeeuw, Chris I.; Shen, Ying

    2015-01-01

    Protein Numb, first identified as a cell-fate determinant in Drosophila, has been shown to promote the development of neurites in mammals and to be cotransported with endocytic receptors in clathrin-coated vesicles in vitro. Nevertheless, its function in mature neurons has not yet been elucidated. Here we show that cerebellar Purkinje cells (PCs) express high levels of Numb during adulthood and that conditional deletion of Numb in PCs is sufficient to impair motor coordination despite maintenance of a normal cerebellar cyto-architecture. Numb proved to be critical for internalization and recycling of metabotropic glutamate 1 receptor (mGlu1) in PCs. A significant decrease of mGlu1 and an inhibition of long-term depression at the parallel fiber–PC synapse were observed in conditional Numb knockout mice. Indeed, the trafficking of mGlu1 induced by agonists was inhibited significantly in these mutants, but the expression of ionotropic glutamate receptor subunits and of mGlu1-associated proteins was not affected by the loss of Numb. Moreover, transient and persistent forms of mGlu1 plasticity were robustly induced in mutant PCs, suggesting that they do not require mGlu1 trafficking. Together, our data demonstrate that Numb is a regulator for constitutive expression and dynamic transport of mGlu1. PMID:26621723

  15. Adaptation in sound localization: from GABA(B) receptor-mediated synaptic modulation to perception.

    PubMed

    Stange, Annette; Myoga, Michael H; Lingner, Andrea; Ford, Marc C; Alexandrova, Olga; Felmy, Felix; Pecka, Michael; Siveke, Ida; Grothe, Benedikt

    2013-12-01

    Across all sensory modalities, the effect of context-dependent neural adaptation can be observed at every level, from receptors to perception. Nonetheless, it has long been assumed that the processing of interaural time differences, which is the primary cue for sound localization, is nonadaptive, as its outputs are mapped directly onto a hard-wired representation of space. Here we present evidence derived from in vitro and in vivo experiments in gerbils indicating that the coincidence-detector neurons in the medial superior olive modulate their sensitivity to interaural time differences through a rapid, GABA(B) receptor-mediated feedback mechanism. We show that this mechanism provides a gain control in the form of output normalization, which influences the neuronal population code of auditory space. Furthermore, psychophysical tests showed that the paradigm used to evoke neuronal GABA(B) receptor-mediated adaptation causes the perceptual shift in sound localization in humans that was expected on the basis of our physiological results in gerbils.

  16. EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats.

    PubMed

    Song, Xue-Jun; Zheng, Ji-Hong; Cao, Jun-Li; Liu, Wen-Tao; Song, Xue-Song; Huang, Zhi-Jiang

    2008-09-30

    Bidirectional signaling between ephrins and Eph receptor tyrosine kinases was first found to play important roles during development, but recently has been implicated in synaptic plasticity and pain processing in the matured nervous system. We show that ephrinB-EphB receptor signaling plays a critical role is induction and maintenance of neuropathic pain by regulating neural excitability and synaptic plasticity in the dorsal root ganglion (DRG) and the spinal dorsal horn (DH). Intrathecal application of blocking reagents for EphB-receptors, EphB1-Fc and EphB2-Fc chimeras inhibits the induction and maintenance of nerve injury-induced thermal hyperalgesia and mechanical allodynia. These blockers also prevent and suppress the nerve injury-induced hyperexcitability of nociceptive small DRG neurons, sensitization of DH neurons and long-term potentiation (LTP) of synapses between C fibers and DH neurons. In naïve, uninjured animals intrathecal administration of EphB-receptor activators ephrinB1-Fc and ephrinB2-Fc, respectively, induces thermal hypersensitivity and lowers the threshold for LTP, while EphB1-Fc prevents induction of the LTP. Western Blot analysis shows that nerve injury triggers an upregulation of the ephrinB1 and EphB1 receptor proteins in DRG and the spinal cord. These results indicate that, by regulating excitability of nociceptive-related neurons in DRG and DH and the synaptic plasticity at the spinal level, ephrinB-EphB receptor signaling contributes to neuropathic pain. This novel role for ephrinB-EphB receptor signaling suggests that these molecules may be useful therapeutic targets for treating pain after nerve injury.

  17. Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory.

    PubMed

    Moosmang, Sven; Haider, Nicole; Klugbauer, Norbert; Adelsberger, Helmuth; Langwieser, Nicolas; Müller, Jochen; Stiess, Michael; Marais, Else; Schulla, Verena; Lacinova, Lubica; Goebbels, Sandra; Nave, Klaus-Armin; Storm, Daniel R; Hofmann, Franz; Kleppisch, Thomas

    2005-10-26

    Current knowledge about the molecular mechanisms of NMDA receptor (NMDAR)-independent long-term potentiation (LTP) in the hippocampus and its function for memory formation in the behaving animal is limited. NMDAR-independent LTP in the CA1 region is thought to require activity of postsynaptic L-type voltage-dependent Ca2+ channels (Cav1.x), but the underlying channel isoform remains unknown. We evaluated the function of the Cav1.2 L-type Ca2+ channel for spatial learning, synaptic plasticity, and triggering of learning-associated biochemical processes using a mouse line with an inactivation of the CACNA1C (Cav1.2) gene in the hippocampus and neocortex (Cav1.2(HCKO)). This model shows (1) a selective loss of protein synthesis-dependent NMDAR-independent Schaffer collateral/CA1 late-phase LTP (L-LTP), (2) a severe impairment of hippocampus-dependent spatial memory, and (3) decreased activation of the mitogen-activated protein kinase (MAPK) pathway and reduced cAMP response element (CRE)-dependent transcription in CA1 pyramidal neurons. Our results provide strong evidence for a role of L-type Ca2+ channel-dependent, NMDAR-independent hippocampal L-LTP in the formation of spatial memory in the behaving animal and for a function of the MAPK/CREB (CRE-binding protein) signaling cascade in linking Cav1.2 channel-mediated Ca2+ influx to either process.

  18. Implication of a multisubunit Ets-related transcription factor in synaptic expression of the nicotinic acetylcholine receptor.

    PubMed Central

    Schaeffer, L; Duclert, N; Huchet-Dymanus, M; Changeux, J P

    1998-01-01

    In adult muscle, transcription of the nicotinic acetylcholine receptor (AChR) is restricted to the nuclei located at the neuromuscular junction. The N-box, a new promoter element, was identified recently and shown to contribute to this compartmentalized synaptic expression of the AChR delta- and epsilon-subunits. We demonstrate that the N-box mediates transcriptional activation in cultured myotubes and identify the transcription factor that binds to the N-box as a heterooligomer in myotubes and adult muscle. The GABP (GA-binding protein) alpha-subunit belongs to the Ets family of transcription factors, whereas the beta-subunit shares homology with IkappaB and Drosophila Notch protein. GABP binding specificity to mutated N-box in vitro strictly parallels the sequence requirement for beta-galactosidase targeting to the endplate in vivo. In situ hybridization studies reveal that the mRNAs of both GABP subunits are abundant in mouse diaphragm, with preferential expression of the alpha-subunit at motor endplates. In addition, heregulin increases GABPalpha protein levels and regulates phosphorylation of both subunits in cultured chick myotubes. Finally, dominant-negative mutants of either GABPalpha or GABPbeta block heregulin-elicited transcriptional activation of the AChR delta and epsilon genes. These findings establish the expected connection with a presynaptic trophic factor whose release contributes to the accumulation of AChR subunit mRNAs at the motor endplate. PMID:9606190

  19. Regulation of synaptic MAPK/ERK phosphorylation in the rat striatum and medial prefrontal cortex by dopamine and muscarinic acetylcholine receptors.

    PubMed

    Xue, Bing; Mao, Li-Min; Jin, Dao-Zhong; Wang, John Q

    2015-10-01

    Dopamine and acetylcholine are two principal transmitters in the striatum and are usually balanced to modulate local neural activity and to maintain striatal homeostasis. This study investigates the role of dopamine and muscarinic acetylcholine receptors in the regulation of a central signaling protein, i.e., the mitogen-activated protein kinase (MAPK). We focus on the synaptic pool of MAPKs because of the fact that these kinases reside in peripheral synaptic structures in addition to their somatic locations. We show that a systemic injection of dopamine D1 receptor (D1R) agonist SKF81297 enhances phosphorylation of extracellular signal-regulated kinases (ERKs), a prototypic subclass of MAPKs, in the adult rat striatum. Similar results were observed in another dopamine-responsive region, the medial prefrontal cortex (mPFC). The dopamine D2 receptor agonist quinpirole had no such effects. Pretreatment with a positive allosteric modulator (PAM) of muscarinic acetylcholine M4 receptors (M4Rs), VU0152100, attenuated the D1R agonist-stimulated ERK phosphorylation in the two regions, whereas the PAM itself did not alter basal ERK phosphorylation. All drug treatments had no effect on phosphorylation of c-Jun N-terminal kinases (JNKs), another MAPK subclass, in the striatum and mPFC. These results demonstrate that dopamine and acetylcholine are integrated to control synaptic ERK but not JNK activation in striatal and mPFC neurons in vivo. Activation of M4Rs exerts an inhibitory effect on the D1R-mediated upregulation of synaptic ERK phosphorylation.

  20. Major Impairments of Glutamatergic Transmission and Long-Term Synaptic Plasticity in the Hippocampus of Mice Lacking the Melanin-Concentrating Hormone Receptor-1

    PubMed Central

    Pachoud, Bastien; Adamantidis, Antoine; Ravassard, Pascal; Luppi, Pierre-Hervé; Grisar, Thierry; Lakaye, Bernard

    2010-01-01

    The hypothalamic neuropeptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis, anxiety, and sleep regulation. Since the MCH receptor-1 (MCH-R1), the only functional receptor that mediates MCH functions in rodents, facilitates behavioral performance in hippocampus-dependent learning tasks, we investigated whether glutamatergic transmission in CA1 pyramidal cells could be modulated in mice lacking the MCH-R1 gene (MCH-R1−/−). We found that both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor-mediated transmissions were diminished in the mutant mice compared with their controls. This deficit was explained, at least in part, by a postsynaptic down-regulation of these receptors since the amplitude of miniature excitatory postsynaptic currents and the NMDA/AMPA ratio were decreased. Long-term synaptic potentiation (LTP) was also impaired in MCH-R1−/− mice. This was due to an altered induction, rather than an impaired, expression because repeating the induction stimulus restored LTP to a normal magnitude. In addition, long-term synaptic depression was strongly diminished in MCH-R1−/− mice. These results suggest that MCH exerts a facilitatory effect on CA1 glutamatergic synaptic transmission and long-term synaptic plasticity. Recently, it has been shown that MCH neurons fire exclusively during sleep and mainly during rapid eye movement sleep. Thus these findings provide a mechanism by which sleep might facilitate memory consolidation. PMID:20592115

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

    PubMed Central

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

    2016-01-01

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

  2. Signaling Cascades for δ-Opioid Receptor-Mediated Inhibition of GABA Synaptic Transmission and Behavioral Antinociception

    PubMed Central

    Zhang, Zhi

    2012-01-01

    Membrane trafficking of the δ-opioid receptor (DOR) from intracellular compartments to plasma membrane in central neurons, induced by various pathological conditions such as long-term opioid exposure, represents unique receptor plasticity involved in the mechanisms of long-term opioid effects in opioid addiction and opioid treatment of chronic pain. However, the signaling pathways coupled to the newly emerged functional DOR in central neurons are largely unknown at present. In this study, we investigated the signaling cascades of long-term morphine-induced DOR for its cellular and behavioral effects in neurons of the rat brainstem nucleus raphe magnus (NRM), a key supraspinal site for opioid analgesia. We found that, among the three phospholipase A2 (PLA2)-regulated arachidonic acid (AA) metabolic pathways of lipoxygenase, cyclooxygenase, and epoxygenase, 12-lipoxygenase of the lipoxygenase pathway primarily mediated DOR inhibition of GABA synaptic transmission, because inhibitors of 12-lipoxygenase as well as lipoxygenases and PLA2 largely blocked the DOR- or AA-induced GABA inhibition in NRM neurons in brainstem slices in vitro. Blockade of the epoxygenase pathway was ineffective, whereas blocking either 5-lipoxygenase of the lipoxygenase pathway or the cyclooxygenase pathway enhanced the DOR-mediated GABA inhibition. Behaviorally in rats in vivo, NRM infusion of 12-lipoxygenase inhibitors significantly reduced DOR-induced antinociceptive effect whereas inhibitors of 5-lipoxygenase and cyclooxygenase augmented the DOR antinociception. These findings suggest the PLA2-AA-12-lipoxygenase pathway as a primary signaling cascade for DOR-mediated analgesia through inhibition of GABA neurotransmission and indicate potential therapeutic benefits of combining 5-lipoxygenase and cyclooxygenase inhibitors for maximal pain inhibition. PMID:22144670

  3. 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

  4. 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

  5. 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.

  6. Cholinergic receptor activation induces a relative facilitation of synaptic responses in the entorhinal cortex during theta- and gamma-frequency stimulation of parasubicular inputs.

    PubMed

    Sparks, D W; Chapman, C A

    2013-01-29

    The parasubiculum sends its single major output to layer II of the entorhinal cortex, and it may therefore interact with inputs to the entorhinal cortex from other cortical areas, and help to shape the activity of layer II entorhinal cells that project to the hippocampal formation. Cholinergic inputs are thought to contribute to the generation of theta- and gamma-frequency activities in the parasubiculum and entorhinal cortex, and the present study assessed how cholinergic receptor activation affects synaptic responses of the entorhinal cortex to theta- and gamma-frequency stimulation. Depth profiles of field excitatory postsynaptic potentials (fEPSPs) in acute brain slices showed a short-latency negative fEPSP in layer II, consistent with the activation of excitatory synaptic inputs to layer II. Application of the cholinergic agonist carbachol (CCh) suppressed synaptic responses and enhanced paired-pulse facilitation. CCh also resulted in a marked relative facilitation of synaptic responses evoked during short 5-pulse trains of stimulation at both theta- and gamma-frequencies. Application of the M(1) antagonist pirenzepine, but not the M(2) antagonist methoctramine, blocked the facilitation of responses. Inhibition of the M-current or block of GABA(B) receptors had no effect, but the facilitation effect was partially blocked by the N-methyl-d-aspartate (NMDA) antagonist APV, indicating that NMDA receptors play a role. Application of ZD7288, a selective inhibitor of the hyperpolarization-activated cationic current I(h), almost completely blocked the relative facilitation of responses, and the less potent I(h)-blocker Cs(+) also resulted in a partial block. The relative facilitation of synaptic responses induced by CCh is therefore likely mediated by multiple mechanisms including the cholinergic suppression of transmitter release that enhances transmitter availability during repetitive stimulation, NMDA receptor-mediated effects on pre- or postsynaptic function, and

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

    PubMed

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

    2015-06-01

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

  8. Potentiation of convergent synaptic inputs onto pyramidal neurons in somatosensory cortex: dependence on brain wave frequencies and NMDA receptor subunit composition.

    PubMed

    Pilli, J; Kumar, S S

    2014-07-11

    N-methyl-d-aspartate receptors (NMDARs) at layer (L)1/primary whisker motor cortex synaptic inputs are distinct from thalamic/striatal (Str) synaptic inputs onto L5 pyramidal neurons in the rat somatosensory cortex. However, the consequences of differential expression of putative GluN3A-containing triheteromeric NMDARs at L1 inputs and GluN2A-containing diheteromeric NMDARs at Str inputs on plasticity of the underlying synapses at the respective inputs remain unknown. Here we demonstrate that L1, but not Str, synapses are potentiated following delta burst stimulation (dBS). This potentiation is blocked by d-serine and/or intracellular 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) suggesting that it is subunit-specific and dependent on elevations in intracellular Ca(2+). Interestingly, ifenprodil, the GluN2B-preferring antagonist, suppresses baseline L1 responses but does not prevent induction of dBS-evoked potentiation. Unlike L1, Str synapses are maximally potentiated following theta burst stimulation (tBS) and this potentiation is blocked with BAPTA and/or the GluN2A-preferring antagonist NVP-AAM077. We show further that while dBS is both necessary and sufficient to potentiate L1 synapses, tBS is most effective in potentiating Str synapses. Our data suggest distinct potentiating paradigms for the two convergent inputs onto pyramidal neurons in the somatosensory cortex and co-dependence of synaptic potentiation on brain wave-tuned frequencies of burst stimulation and subunit composition of underlying NMDARs. A model for predicting the likelihood of enhancing synaptic efficacy is proposed based on Ca(2+) influx through these receptors and integration of EPSPs at these inputs. Together, these findings raise the possibility of input-specific enhancements of synaptic efficacy in neurons as a function of the animal's behavioral state and/or arousal in vivo.

  9. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors.

    PubMed

    Ohkawa, Toshika; Fukata, Yuko; Yamasaki, Miwako; Miyazaki, Taisuke; Yokoi, Norihiko; Takashima, Hiroshi; Watanabe, Masahiko; Watanabe, Osamu; Fukata, Masaki

    2013-11-13

    More than 30 mutations in LGI1, a secreted neuronal protein, have been reported with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although LGI1 haploinsufficiency is thought to cause ADLTE, the underlying molecular mechanism that results in abnormal brain excitability remains mysterious. Here, we focused on a mode of action of LGI1 autoantibodies associated with limbic encephalitis (LE), which is one of acquired epileptic disorders characterized by subacute onset of amnesia and seizures. We comprehensively screened human sera from patients with immune-mediated neurological disorders for LGI1 autoantibodies, which also uncovered novel autoantibodies against six cell surface antigens including DCC, DPP10, and ADAM23. Our developed ELISA arrays revealed a specific role for LGI1 antibodies in LE and concomitant involvement of multiple antibodies, including LGI1 antibodies in neuromyotonia, a peripheral nerve disorder. LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23 by targeting the EPTP repeat domain of LGI1 and reversibly reduced synaptic AMPA receptor clusters in rat hippocampal neurons. Furthermore, we found that disruption of LGI1-ADAM22 interaction by soluble extracellular domain of ADAM22 was sufficient to reduce synaptic AMPA receptors in rat hippocampal neurons and that levels of AMPA receptor were greatly reduced in the hippocampal dentate gyrus in the epileptic LGI1 knock-out mouse. Therefore, either genetic or acquired loss of the LGI1-ADAM22 interaction reduces the AMPA receptor function, causing epileptic disorders. These results suggest that by finely regulating the synaptic AMPA receptors, the LGI1-ADAM22 interaction maintains physiological brain excitability throughout life.

  10. Autoantibodies to Epilepsy-Related LGI1 in Limbic Encephalitis Neutralize LGI1-ADAM22 Interaction and Reduce Synaptic AMPA Receptors

    PubMed Central

    Ohkawa, Toshika; Fukata, Yuko; Yamasaki, Miwako; Miyazaki, Taisuke; Yokoi, Norihiko; Takashima, Hiroshi; Watanabe, Masahiko; Watanabe, Osamu

    2013-01-01

    More than 30 mutations in LGI1, a secreted neuronal protein, have been reported with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although LGI1 haploinsufficiency is thought to cause ADLTE, the underlying molecular mechanism that results in abnormal brain excitability remains mysterious. Here, we focused on a mode of action of LGI1 autoantibodies associated with limbic encephalitis (LE), which is one of acquired epileptic disorders characterized by subacute onset of amnesia and seizures. We comprehensively screened human sera from patients with immune-mediated neurological disorders for LGI1 autoantibodies, which also uncovered novel autoantibodies against six cell surface antigens including DCC, DPP10, and ADAM23. Our developed ELISA arrays revealed a specific role for LGI1 antibodies in LE and concomitant involvement of multiple antibodies, including LGI1 antibodies in neuromyotonia, a peripheral nerve disorder. LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23 by targeting the EPTP repeat domain of LGI1 and reversibly reduced synaptic AMPA receptor clusters in rat hippocampal neurons. Furthermore, we found that disruption of LGI1-ADAM22 interaction by soluble extracellular domain of ADAM22 was sufficient to reduce synaptic AMPA receptors in rat hippocampal neurons and that levels of AMPA receptor were greatly reduced in the hippocampal dentate gyrus in the epileptic LGI1 knock-out mouse. Therefore, either genetic or acquired loss of the LGI1-ADAM22 interaction reduces the AMPA receptor function, causing epileptic disorders. These results suggest that by finely regulating the synaptic AMPA receptors, the LGI1-ADAM22 interaction maintains physiological brain excitability throughout life. PMID:24227725

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

    PubMed

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

    2013-03-01

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

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

    PubMed Central

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

    2013-01-01

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

  14. Long-lasting effects of neonatal dexamethasone treatment on spatial learning and hippocampal synaptic plasticity: involvement of the NMDA receptor complex.

    PubMed

    Kamphuis, Patrick J G H; Gardoni, Fabrizio; Kamal, Amer; Croiset, Gerda; Bakker, Joost M; Cattabeni, Flaminio; Gispen, Willem Hendrik; van Bel, Frank; Di Luca, Monica; Wiegant, Victor M

    2003-05-01

    The effects of neonatal dexamethasone (DEX) treatment on spatial learning and hippocampal synaptic plasticity were investigated in adult rats. Spatial learning in reference and working memory versions of the Morris maze was impaired in DEX-treated rats. In hippocampal slices of DEX rats, long-term depression was facilitated and potentiation was impaired. Paired-pulse facilitation was normal, suggesting a postsynaptic defect as cause of the learning and plasticity deficits. Western blot analysis of hippocampal postsynaptic densities (PSD) revealed a reduction in NR2B subunit protein, whereas the abundance of the other major N-methyl-D-aspartate (NMDA) receptor subunits (NR1, NR2A), AMPA receptor subunits (GluR2/3), scaffolding proteins, and Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII) were unaltered. This selective reduction in NR2B likely resulted from altered receptor assembly rather than subunit expression, because the abundance of NR2B in the homogenate and crude synaptosomal fractions was unaltered. In addition, the activity of alphaCaMKII, an NMDA receptor complex associated protein kinase, was increased in PSD of DEX rats. The results indicate that neonatal treatment with DEX causes alterations in composition and function of the hippocampal NMDA receptor complex that persist into adulthood. These alterations likely explain the deficits in hippocampal synaptic plasticity and spatial learning induced by neonatal DEX treatment.

  15. Lanthanum-mediated modification of GABAA receptor deactivation, desensitization and inhibitory synaptic currents in rat cerebellar neurons.

    PubMed

    Zhu, W J; Wang, J F; Corsi, L; Vicini, S

    1998-09-15

    1. We investigated La3+ effects on recombinant and native gamma-aminobutyric acid A (GABAA) receptors using rapid agonist applications and on inhibitory synaptic currents (IPSCs) in granule and stellate neurons of rat cerebellar slices. 2. Rapid desensitization of currents elicited by 200 ms pulses of 1 mM GABA to small lifted cells transfected with alpha1beta3gamma2 cDNAs was greatly decreased by the coapplication of 100 microM LaCl3. 3. GABA responses were unaffected when coapplication lasted only 2 ms. In contrast, with LaCl3 pre-perfusion, a significant slowing of deactivation in response to 2 ms applications was observed. LaCl3 pre-perfusion also prolonged the duration of responses to 20 mM taurine. 4. Outside-out patches excised from cells transfected with alpha1beta3gamma2 subunit cDNAs were briefly exposed to a saturating concentration of GABA, eliciting a transient activation of single channel currents with a main conductance of 30 pS. Opening and burst durations increased by pre-equilibration of patches with LaCl3. 5. LaCl3 depressed the peak amplitude without affecting the slow deactivation and desensitization of GABA responses in cells transfected with alpha6beta3gamma2 and alpha6beta3delta cDNAs. No significant difference in La3+ modulation of GABA-gated currents was observed between alpha1beta3gamma2 and alpha1beta3delta receptors. 6. The effects of LaCl3 on deactivation and desensitization of GABA responses observed in nucleated patches excised from rat cerebellar granule and stellate neurons were comparable to those in the cells transfected with alpha1beta3gamma2 cDNAs. In addition, La3+ clearly prolonged the spontaneous IPSC time course without changing the amplitude. 7. Our results indicate that La3+ has a dual action on GABA-gated currents: it decreases desensitization and increases channel opening duration. These actions depend on receptor subunit composition and contribute to the prolongation of IPSCs.

  16. 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.

  17. Muscarinic cholinergic receptors modulate inhibitory synaptic rhythms in hippocampus and neocortex

    PubMed Central

    Alger, Bradley E.; Nagode, Daniel A.; Tang, Ai-Hui

    2014-01-01

    Activation of muscarinic acetylcholine (ACh) receptors (mAChRs) powerfully affects many neuronal properties as well as numerous cognitive behaviors. Small neuronal circuits constitute an intermediate level of organization between neurons and behaviors, and mAChRs affect interactions among cells that compose these circuits. Circuit activity is often assessed by extracellular recordings of the local field potentials (LFPs), which are analogous to in vivo EEGs, generated by coordinated neuronal interactions. Coherent forms of physiologically relevant circuit activity manifest themselves as rhythmic oscillations in the LFPs. Frequencies of rhythmic oscillations that are most closely associated with animal behavior are in the range of 4–80 Hz, which is subdivided into theta (4–14 Hz), beta (15–29 Hz) and gamma (30–80 Hz) bands. Activation of mAChRs triggers rhythmic oscillations in these bands in the hippocampus and neocortex. Inhibitory responses mediated by GABAergic interneurons constitute a prominent feature of these oscillations, and indeed, appear to be their major underlying factor in many cases. An important issue is which interneurons are involved in rhythm generation. Besides affecting cellular and network properties directly, mAChRs can cause the mobilization of endogenous cannabinoids (endocannabinoids, eCBs) that, by acting on the principal cannabinoid receptor of the brain, CB1R, regulate the release of certain neurotransmitters, including GABA. CB1Rs are heavily expressed on only a subset of interneurons and, at lower density, on glutamatergic neurons. Exogenous cannabinoids typically disrupt oscillations in the theta (θ) and gamma (γ) ranges, which probably contributes to the behavioral effects of these drugs. It is important to understand how neuronal circuit activity is affected by mAChR-driven eCBs, as this information will provide deeper insight into the actions of ACh itself, as well as into the effects of eCBs and exogenous cannabinoids

  18. Neuromuscular synaptic patterning requires the function of skeletal muscle dihydropyridine receptors

    PubMed Central

    Chen, Fujun; Liu, Yun; Sugiura, Yoshie; Allen, Paul D.; Gregg, Ronald G.; Lin, Weichun

    2011-01-01

    Developing skeletal myofibers in vertebrates are intrinsically “pre-patterned” for motor nerve innervation. However, the intrinsic factors that regulate muscle pre-patterning remain unknown. Here we show that a functional skeletal muscle dihydropyridine receptor (DHPR, the L-type Ca2+ channel in muscle) is required for muscle pre-patterning during the development of the neuromuscular junction (NMJ). Targeted deletion of the β1 subunit of DHPR (Cacnb1) in mice leads to muscle pre-patterning defects, aberrant innervation and precocious maturation of the NMJ. Reintroducing the Cacnb1 gene into Cacnb1−/− muscles reverses the pre-patterning defects and restores normal development of the NMJ. The mechanism by which DHPRs govern muscle pre-patterning is independent of their role in excitation-contraction coupling (E-C coupling), but requires Ca2+ influx through the L-type Ca2+ channel. Our findings demonstrate that the skeletal muscle DHPR retrogradely regulates the patterning and formation of the NMJ. PMID:21441923

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

    PubMed Central

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

    2017-01-01

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

  20. Non-fibrillar beta-amyloid abates spike-timing-dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors.

    PubMed

    Shemer, Isaac; Holmgren, Carl; Min, Rogier; Fülöp, Livia; Zilberter, Misha; Sousa, Kyle M; Farkas, Tamás; Härtig, Wolfgang; Penke, Botond; Burnashev, Nail; Tanila, Heikki; Zilberter, Yuri; Harkany, Tibor

    2006-04-01

    Cognitive decline in Alzheimer's disease (AD) stems from the progressive dysfunction of synaptic connections within cortical neuronal microcircuits. Recently, soluble amyloid beta protein oligomers (Abeta(ol)s) have been identified as critical triggers for early synaptic disorganization. However, it remains unknown whether a deficit of Hebbian-related synaptic plasticity occurs during the early phase of AD. Therefore, we studied whether age-dependent Abeta accumulation affects the induction of spike-timing-dependent synaptic potentiation at excitatory synapses on neocortical layer 2/3 (L2/3) pyramidal cells in the APPswe/PS1dE9 transgenic mouse model of AD. Synaptic potentiation at excitatory synapses onto L2/3 pyramidal cells was significantly reduced at the onset of Abeta pathology and was virtually absent in mice with advanced Abeta burden. A decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/N-methyl-D-aspartate (NMDA) receptor-mediated current ratio implicated postsynaptic mechanisms underlying Abeta synaptotoxicity. The integral role of Abeta(ol)s in these processes was verified by showing that pretreatment of cortical slices with Abeta((25-35)ol)s disrupted spike-timing-dependent synaptic potentiation at unitary connections between L2/3 pyramidal cells, and reduced the amplitude of miniature excitatory postsynaptic currents therein. A robust decrement of AMPA, but not NMDA, receptor-mediated currents in nucleated patches from L2/3 pyramidal cells confirmed that Abeta(ol)s perturb basal glutamatergic synaptic transmission by affecting postsynaptic AMPA receptors. Inhibition of AMPA receptor desensitization by cyclothiazide significantly increased the amplitude of excitatory postsynaptic potentials evoked by afferent stimulation, and rescued synaptic plasticity even in mice with pronounced Abeta pathology. We propose that soluble Abeta(ol)s trigger the diminution of synaptic plasticity in neocortical pyramidal cell networks during early

  1. Differential Synaptic and Extrasynaptic Glutamate-Receptor Alterations in Striatal Medium-Sized Spiny Neurons of Aged YAC128 Huntington's Disease Mice.

    PubMed

    Botelho, Eliã P; Wang, Elizabeth; Chen, Jane Y; Holley, Sandra; Andre, Veronique; Cepeda, Carlos; Levine, Michael S

    2014-05-01

    Huntington's disease (HD) is a late-onset, slowly progressing neurodegenerative disorder caused by an expansion of glutamine repeats. The YAC128 mouse model has been widely used to study the progression of HD symptoms, but little is known about synaptic alterations in very old animals. The present experiments examined synaptic properties of striatal medium-sized spiny neurons (MSNs) in 16 month-old YAC128 mice. These mice were crossed with mice expressing enhanced green fluorescent protein (EGFP) under the control of either D1 or D2 dopamine receptor promoters to identify MSNs originating the direct and indirect pathways, respectively. The input-output curves of evoked excitatory postsynaptic currents mediated by activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-D-aspartate (NMDA) receptors were reduced in MSNs in both pathways. In the presence of DL-threo-β-Benzyloxyaspartic acid (DL-TBOA), a glutamate transporter blocker used to increase activation of extrasynaptic receptors, NMDA receptor-mediated currents displayed altered amplitudes, longer decay times, and greater charge (response areas) in both direct and indirect pathway MSNs in YAC128 mice compared to wildtype controls. Amplitudes were significantly increased, primarily in direct pathway MSNs while normalized areas were significantly increased only in indirect pathway MSNs, suggesting that the two types of MSNs are affected in different ways. It may be that indirect pathway neurons are more susceptible to changes in glutamate transport. Taken together, the present findings demonstrate differential alterations in synaptic versus extrasynaptic NMDA receptors in both direct and indirect pathway MSNs in late HD, which may contribute to the dysfunction and degeneration in both pathways.

  2. 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

  3. A Rapid Ethnography of Itinerant Teachers of the Deaf

    ERIC Educational Resources Information Center

    Kluwin, Thomas N.; Morris, C. S.; Clifford, Jesteene

    2004-01-01

    A rapid ethnograhic study of 10 itinerant teachers in two school districts and 21 other professionals working with the itinerants was conducted. Rapid ethnography starts with the same assumptions about culture as conventional ethnography. However, it is not constrained by the assumption of cultural ignorance on the investigator's part. Thus, it…

  4. A Guide to Itinerant Early Childhood Special Education Services

    ERIC Educational Resources Information Center

    Dinnebeil, Laurie A.; McInerney, William F.

    2011-01-01

    Itinerant special educators can be much more than "tutors" for young children with special needs. They can transform whole classrooms and help inclusion flourish--if they have the clear guidelines and best practices they need to make the most of their critical roles. This is the book that every itinerant early childhood special educator has been…

  5. The Rural Itinerant Special Physical Education Service Delivery Model.

    ERIC Educational Resources Information Center

    Lavay, Barry

    1990-01-01

    Describes the multiple roles and special challenges experienced by rural itinerant teachers delivering special physical education services. Provides a breakdown of time spent in various job functions by two itinerant special physical educators (ISPEs) studied in north central Kansas. Suggests strategies for successful delivery using the ISPE…

  6. Alpha-Synuclein Produces Early Behavioral Alterations via Striatal Cholinergic Synaptic Dysfunction by Interacting With GluN2D N-Methyl-D-Aspartate Receptor Subunit.

    PubMed

    Tozzi, Alessandro; de Iure, Antonio; Bagetta, Vincenza; Tantucci, Michela; Durante, Valentina; Quiroga-Varela, Ana; Costa, Cinzia; Di Filippo, Massimiliano; Ghiglieri, Veronica; Latagliata, Emanuele Claudio; Wegrzynowicz, Michal; Decressac, Mickael; Giampà, Carmela; Dalley, Jeffrey W; Xia, Jing; Gardoni, Fabrizio; Mellone, Manuela; El-Agnaf, Omar Mukhtar; Ardah, Mustafa Taleb; Puglisi-Allegra, Stefano; Björklund, Anders; Spillantini, Maria Grazia; Picconi, Barbara; Calabresi, Paolo

    2016-03-01

    Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overexpression of nigral α-syn are still a matter of debate. We performed behavioral, molecular, and immunohistochemical analyses in two transgenic models of PD, mice transgenic for truncated human α-synuclein 1-120 and rats injected with the adeno-associated viral vector carrying wild-type human α-synuclein. We also investigated striatal synaptic plasticity by electrophysiological recordings from spiny projection neurons and cholinergic interneurons. We found that overexpression of truncated or wild-type human α-syn causes partial reduction of striatal dopamine levels and selectively blocks the induction of long-term potentiation in striatal cholinergic interneurons, producing early memory and motor alterations. These effects were dependent on α-syn modulation of the GluN2D-expressing N-methyl-D-aspartate receptors in cholinergic interneurons. Acute in vitro application of human α-syn oligomers mimicked the synaptic effects observed ex vivo in PD models. We suggest that striatal cholinergic dysfunction, induced by a direct interaction between α-syn and GluN2D-expressing N-methyl-D-aspartate receptors, represents a precocious biological marker of the disease. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  7. NMDA Receptor Hypofunction Induces Dysfunctions of Energy Metabolism And Semaphorin Signaling in Rats: A Synaptic Proteome Study

    PubMed Central

    Zhou, Kejun; Yang, Yifeng; Gao, Linghan; He, Guang; Li, Weidong; Tang, Kefu; Ji, Baohu; Zhang, Ming; Li, Yang; Yang, Jinglei; Sun, Liya; Zhang, Zhao; Zhu, Hui; Wan, Chunling

    2012-01-01

    There is considerable evidence to suggest that aberrations of synapse connectivity contribute to the pathophysiology of schizophrenia and that N-methyl-d-aspartate (NMDA) receptor–mediated glutamate transmission is especially important. Administration of MK-801 ([+]-5-methyl-10, 11-dihydro-5H-dibenzo-[a, d]-cycloheptene-5, 10-iminehydrogenmaleate) induces hypofunction of NMDA receptors in rats, which are widely used as a model for schizophrenia. We investigated synaptosomal proteome expression profiling of the cerebral cortex of MK-801–treated Sprague-Dawley rats using the 2-dimensional difference gel electrophoresis method, and 49 differentially expression proteins were successfully identified using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight/Time-of-Flight mass spectrometry. We carried out a literature search for further confirmation of subsynaptic locations and to explore the relevance to the diseases of differentially expressed proteins. Ingenuity Pathways Analysis (IPA) was used to further examine the underlying relationship between the changed proteins. The network encompassing “cell morphology, cell-to-cell signaling and interaction, nervous system development and function” was found to be significantly altered in the MK-801–treated rats. “Energy metabolism” and “semaphorin signaling in neurons” are the most significant IPA canonical pathways to be affected by MK-801 treatment. Using western blots, we confirmed the differential expression of Camk2a, Crmp2, Crmp5, Dnm1, and Ndufs3 in both synaptosome proteins and total proteins in the cerebral cortex of the rats. Our study identified the change and/or response of the central nervous transmission system under the stress of NMDA hypofunction, underlining the importance of the synaptic function in schizophrenia. PMID:21084551

  8. Muscarinic Receptor Subtypes Differentially Control Synaptic Input and Excitability of Cerebellum-Projecting Medial Vestibular Nucleus Neurons

    PubMed Central

    Zhu, Yun; Chen, Shao-Rui; Pan, Hui-Lin

    2016-01-01

    Neurons in the vestibular nuclei have a vital function in balance maintenance, gaze stabilization, and posture. Although muscarinic acetylcholine receptors (mAChRs) are expressed and involved in regulating vestibular function, it is unclear how individual mAChR subtypes regulate vestibular neuronal activity. In this study, we determined which specific subtypes of mAChRs control synaptic input and excitability of medial vestibular nucleus (MVN) neurons that project to the cerebellum. Cerebellum-projecting MVN neurons were labeled by a fluorescent retrograde tracer and then identified in rat brainstem slices. Quantitative PCR analysis suggested that M2 and M3 were the possible major mAChR subtypes expressed in the MVN. The mAChR agonist oxotremorine-M significantly reduced the amplitude of glutamatergic excitatory postsynaptic currents evoked by stimulation of vestibular primary afferents, and this effect was abolished by the M2-preferring antagonist AF-DX 116. However, oxotremorine-M had no effect on GABA-mediated spontaneous inhibitory postsynaptic currents of labeled MVN neurons. Furthermore, oxotremorine-M significantly increased the firing activity of labeled MVN neurons, and this effect was blocked by the M3-preferring antagonist J104129 in most neurons tested. In addition, AF-DX 116 reduced the onset latency and prolonged the excitatory effect of oxotremorine-M on the firing activity of labeled MVN neurons. Our findings suggest that M3 is the predominant postsynaptic mAChR involved in muscarinic excitation of cerebellum-projecting MVN neurons. Presynaptic M2 mAChR regulates excitatory glutamatergic input from vestibular primary afferents, which in turn influences the excitability of cerebellum-projecting MVN neurons. This new information has important therapeutic implications for treating vestibular disorders with mAChR subtype-selective agents. PMID:26823384

  9. Large variability in synaptic N-methyl-D-aspartate receptor density on interneurons and a comparison with pyramidal-cell spines in the rat hippocampus.

    PubMed

    Nyíri, G; Stephenson, F A; Freund, T F; Somogyi, P

    2003-01-01

    Pyramidal cells receive input from several types of GABA-releasing interneurons and innervate them reciprocally. Glutamatergic activation of interneurons involves both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) type glutamate receptors expressed in type I synapses, mostly on their dendritic shafts. On average, the synaptic AMPA receptor content is several times higher on interneurons than in the spines of pyramidal cells. To compare the NMDA receptor content of synapses, we used a quantitative postembedding immunogold technique on serial electron microscopic sections, and analysed the synapses on interneuron dendrites and pyramidal cell spines in the CA1 area. Because all NMDA receptors contain the obligatory NR1 subunit, receptor localisation was carried out using antibodies recognising all splice variants of the NR1 subunit. Four populations of synapse were examined: i). on spines of pyramidal cells in stratum (str.) radiatum and str. oriens; ii). on parvalbumin-positive interneuronal dendritic shafts in str. radiatum; iii). on randomly found dendritic shafts in str. oriens and iv). on somatostatin-positive interneuronal dendritic shafts and somata in str. oriens. On average, the size of the synapses on spines was about half of those on interneurons. The four populations of synapse significantly differed in labelling for the NR1 subunit. The median density of NR1 subunit labelling was highest on pyramidal cell spines. It was lowest in the synapses on parvalbumin-positive dendrites in str. radiatum, where more than half of these synapses were immunonegative. In str. oriens, synapses on interneurons had a high variability of receptor content; some dendrites were similar to those in str. radiatum, including the proximal synapses of somatostatin-positive cells, whereas others had immunoreactivity for the NR1 subunit similar to or higher than synapses on pyramidal cell spines. These results show that synaptic NMDA

  10. Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors

    PubMed Central

    Viana da Silva, Silvia; Haberl, Matthias Georg; Zhang, Pei; Bethge, Philipp; Lemos, Cristina; Gonçalves, Nélio; Gorlewicz, Adam; Malezieux, Meryl; Gonçalves, Francisco Q.; Grosjean, Noëlle; Blanchet, Christophe; Frick, Andreas; Nägerl, U Valentin; Cunha, Rodrigo A.; Mulle, Christophe

    2016-01-01

    Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. Impaired episodic memory is an early manifestation of cognitive deficits in Alzheimer's disease (AD). In the APP/PS1 mouse model of AD amyloidosis, we show that associative long-term synaptic potentiation (LTP) is abolished in CA3 pyramidal cells at an early stage. This is caused by activation of upregulated neuronal adenosine A2A receptors (A2AR) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A2AR by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A2AR antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A2AR antagonists in early AD patients. PMID:27312972

  11. How Ca2+-permeable AMPA receptors, the kinase PKA, and the phosphatase PP2B are intertwined in synaptic LTP and LTD.

    PubMed

    Hell, Johannes W

    2016-04-26

    Both synaptic long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical for memory formation. Dell'Acqua and co-workers now demonstrate that transient postsynaptic incorporation of Ca(2+)-permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is required for LTD in the exemplary hippocampal CA1 region in 2-week-old mice. Mechanistically, LTD depends on AKAP150-anchored protein kinase A (PKA) to promote the initial functional recruitment of CP-AMPARs during LTD induction and on AKAP150-anchored protein phosphatase 2B (PP2B) to trigger their subsequent removal as part of the lasting depression of synaptic transmission. Copyright © 2016, American Association for the Advancement of Science.

  12. Lack of GSK3β activation and modulation of synaptic plasticity by dopamine in 5-HT1A-receptor KO mice.

    PubMed

    Meunier, C N J; Cancela, J-M; Fossier, P

    2017-02-01

    Psychiatric disorders are associated with excitation-inhibition (E-I) balance impairment in the prefrontal cortex. However, how the E-I balance is regulated is poorly known. The E-I balance of neuronal networks is linked to the action of numerous neuromodulators such as dopamine and 5-HT. We investigated the role of D2-receptors in tuning the E-I balance in a mouse model of anxiety, the 5-HT1A-receptor KO mice. We focused on synaptic plasticity of excitation and inhibition on layer 5 pyramidal neurons. We show that D2-receptor activation decreases the excitation and favors HFS-induced LTD of excitatory synapses via the activation of GSK3β. This effect is absent in 5-HT1A-receptor KO mice. Our data show that the fine control of excitatory transmission by GSK3β requires recruitment of D2-receptors and depends on the presence of 5-HT1A-receptors. In psychiatric disorders in which the number of 5-HT1A-receptors decreased, therapies should reconsider how serotonin and dopamine receptors interact and control neuronal network activity.

  13. The AMPA receptor positive allosteric modulator S 47445 rescues in vivo CA3-CA1 long-term potentiation and structural synaptic changes in old mice.

    PubMed

    Giralt, Albert; Gómez-Climent, María Ángeles; Alcalá, Rafael; Bretin, Sylvie; Bertrand, Daniel; María Delgado-García, José; Pérez-Navarro, Esther; Alberch, Jordi; Gruart, Agnès

    2017-09-01

    Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are small molecules that decrease deactivation of AMPARs via an allosteric site. These molecules keep the receptor in an active state. Interestingly, this type of modulator has been proposed for treating cognitive decline in ageing, dementias, and Alzheimer's disease (AD). S 47445 (8-cyclopropyl-3-[2-(3-fluorophenyl)ethyl]-7,8-dihydro-3H-[1,3]oxazino[6,5-g][1,2,3]benzotriazine-4,9-dione) is a novel AMPAR positive allosteric modulator (AMPA-PAM). Here, the mechanisms by which S 47445 could improve synaptic strength and connectivity were studied and compared between young and old mice. A single oral administration of S 47445 at 10 mg/kg significantly increased long-term potentiation (LTP) in CA3-CA1 hippocampal synapses in alert young mice in comparison to control mice. Moreover, chronic treatment with S 47445 at 10 mg/kg in old alert animals significantly counteracted the deficit of LTP due to age. Accordingly, chronic treatment with S 47445 at 10 mg/kg seems to preserve synaptic cytoarchitecture in old mice as compared with young control mice. It was shown that the significant decreases in number and size of pre-synaptic buttons stained for VGlut1, and post-synaptic dendritic spines stained for spinophilin, observed in old mice were significantly prevented after chronic treatment with 10 mg/kg of S 47445. Altogether, by its different effects on LTP, VGlut1-positive particles, and spinophilin, S 47445 is able to modulate both the structure and function of hippocampal excitatory synapses known to be involved in learning and memory processes. These results open a new window for the treatment of specific age-dependent cognitive decline and dementias such as AD. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. 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

  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. mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo

    PubMed Central

    Hu, Neng-Wei; Nicoll, Andrew J.; Zhang, Dainan; Mably, Alexandra J.; O’Malley, Tiernan; Purro, Silvia A.; Terry, Cassandra; Collinge, John; Walsh, Dominic M.; Rowan, Michael J.

    2014-01-01

    NMDA-type glutamate receptors (NMDARs) are currently regarded as paramount in the potent and selective disruption of synaptic plasticity by Alzheimer’s disease amyloid β-protein (Aβ). Non-NMDAR mechanisms remain relatively unexplored. Here we describe how Aβ facilitates NMDAR-independent long-term depression of synaptic transmission in the hippocampus in vivo. Synthetic Aβ and Aβ in soluble extracts of Alzheimer’s disease brain usurp endogenous acetylcholine muscarinic receptor-dependent long-term depression, to enable long-term depression that required metabotropic glutamate-5 receptors (mGlu5Rs). We also find that mGlu5Rs are essential for Aβ-mediated inhibition of NMDAR-dependent long-term potentiation in vivo. Blocking Aβ binding to cellular prion protein with antibodies prevents the facilitation of long-term depression. Our findings uncover an overarching role for Aβ-PrPC-mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary. PMID:24594908

  17. NMDA receptor-dependent long-term potentiation comprises a family of temporally overlapping forms of synaptic plasticity that are induced by different patterns of stimulation

    PubMed Central

    Park, Pojeong; Volianskis, Arturas; Sanderson, Thomas M.; Bortolotto, Zuner A.; Jane, David E.; Zhuo, Min; Kaang, Bong-Kiun; Collingridge, Graham L.

    2014-01-01

    N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studied since it is believed to use the same molecular mechanisms that are required for many forms of learning and memory. Unfortunately, many controversies exist, not least the seemingly simple issue concerning the locus of expression of LTP. Here, we review our recent work and some of the extensive literature on this topic and present new data that collectively suggest that LTP can be explained, during its first few hours, by the coexistence of at least three mechanistically distinct processes that are all triggered by the synaptic activation of NMDARs. PMID:24298134

  18. Physiological and pathophysiological control of synaptic GluN2B-NMDA receptors by the C-terminal domain of amyloid precursor protein.

    PubMed

    Pousinha, Paula A; Mouska, Xavier; Raymond, Elisabeth F; Gwizdek, Carole; Dhib, Gihen; Poupon, Gwenola; Zaragosi, Laure-Emmanuelle; Giudici, Camilla; Bethus, Ingrid; Pacary, Emilie; Willem, Michael; Marie, Hélène

    2017-07-06

    The amyloid precursor protein (APP) harbors physiological roles at synapses and is central to Alzheimer's disease (AD) pathogenesis. Evidence suggests that APP intracellular domain (AICD) could regulate synapse function, but the underlying molecular mechanisms remain unknown. We addressed AICD actions at synapses, per se, combining in vivo AICD expression, ex vivo AICD delivery or APP knock-down by in utero electroporation of shRNAs with whole-cell electrophysiology. We report a critical physiological role of AICD in controlling GluN2B-containing NMDA receptors (NMDARs) at immature excitatory synapses, via a transcription-dependent mechanism. We further show that AICD increase in mature neurons, as reported in AD, alters synaptic NMDAR composition to an immature-like GluN2B-rich profile. This disrupts synaptic signal integration, via over-activation of SK channels, and synapse plasticity, phenotypes rescued by GluN2B antagonism. We provide a new physiological role for AICD, which becomes pathological upon AICD increase in mature neurons. Thus, AICD could contribute to AD synaptic failure.

  19. Lack of IL-1R8 in neurons causes hyperactivation of IL-1 receptor pathway and induces MECP2-dependent synaptic defects

    PubMed Central

    Tomasoni, Romana; Morini, Raffaella; Lopez-Atalaya, Jose P; Corradini, Irene; Canzi, Alice; Rasile, Marco; Mantovani, Cristina; Pozzi, Davide; Garlanda, Cecilia; Mantovani, Alberto; Menna, Elisabetta; Barco, Angel; Matteoli, Michela

    2017-01-01

    Inflammation modifies risk and/or severity of a variety of brain diseases through still elusive molecular mechanisms. Here we show that hyperactivation of the interleukin 1 pathway, through either ablation of the interleukin 1 receptor 8 (IL-1R8, also known as SIGIRR or Tir8) or activation of IL-1R, leads to up-regulation of the mTOR pathway and increased levels of the epigenetic regulator MeCP2, bringing to disruption of dendritic spine morphology, synaptic plasticity and plasticity-related gene expression. Genetic correction of MeCP2 levels in IL-1R8 KO neurons rescues the synaptic defects. Pharmacological inhibition of IL-1R activation by Anakinra corrects transcriptional changes, restores MeCP2 levels and spine plasticity and ameliorates cognitive defects in IL-1R8 KO mice. By linking for the first time neuronal MeCP2, a key player in brain development, to immune activation and demonstrating that synaptic defects can be pharmacologically reversed, these data open the possibility for novel treatments of neurological diseases through the immune system modulation. DOI: http://dx.doi.org/10.7554/eLife.21735.001 PMID:28347403

  20. Lack of IL-1R8 in neurons causes hyperactivation of IL-1 receptor pathway and induces MECP2-dependent synaptic defects.

    PubMed

    Tomasoni, Romana; Morini, Raffaella; Lopez-Atalaya, Jose P; Corradini, Irene; Canzi, Alice; Rasile, Marco; Mantovani, Cristina; Pozzi, Davide; Garlanda, Cecilia; Mantovani, Alberto; Menna, Elisabetta; Barco, Angel; Matteoli, Michela

    2017-03-28

    Inflammation modifies risk and/or severity of a variety of brain diseases through still elusive molecular mechanisms. Here we show that hyperactivation of the interleukin 1 pathway, through either ablation of the interleukin 1 receptor 8 (IL-1R8, also known as SIGIRR or Tir8) or activation of IL-1R, leads to up-regulation of the mTOR pathway and increased levels of the epigenetic regulator MeCP2, bringing to disruption of dendritic spine morphology, synaptic plasticity and plasticity-related gene expression. Genetic correction of MeCP2 levels in IL-1R8 KO neurons rescues the synaptic defects. Pharmacological inhibition of IL-1R activation by Anakinra corrects transcriptional changes, restores MeCP2 levels and spine plasticity and ameliorates cognitive defects in IL-1R8 KO mice. By linking for the first time neuronal MeCP2, a key player in brain development, to immune activation and demonstrating that synaptic defects can be pharmacologically reversed, these data open the possibility for novel treatments of neurological diseases through the immune system modulation.

  1. Traumatic Brain Injury Impairs Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor Complex Formation and Alters Synaptic Vesicle Distribution in the Hippocampus

    PubMed Central

    Carlson, Shaun W.; Yan, Hong; Ma, Michelle; Li, Youming; Henchir, Jeremy

    2016-01-01

    Abstract Traumatic brain injury (TBI) impairs neuronal function and can culminate in lasting cognitive impairment. While impaired neurotransmitter release has been well established after experimental TBI, little is understood about the mechanisms underlying this consequence. In the synapse, vesicular docking and neurotransmitter release requires the formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Impairments in vesicle docking, and alterations in SNARE complex formation are associated with impaired neurotransmitter release. We hypothesized that TBI reduces SNARE complex formation and disrupts synaptic vesicle distribution in the hippocampus. To examine the effect of TBI on the SNARE complex, rats were subjected to controlled cortical impact (CCI) or sham injury, and the brains were assessed at 6 h, 1 d, one week, two weeks, or four weeks post-injury. Immunoblotting of hippocampal homogenates revealed significantly reduced SNARE complex formation at one week and two weeks post-injury. To assess synaptic vesicles distribution, rats received CCI or sham injury and the brains were processed for transmission electron microscopy at one week post-injury. Synapses in the hippocampus were imaged at 100k magnification, and vesicle distribution was assessed in pre-synaptic terminals at the active zone. CCI resulted in a significant reduction in vesicle number within 150 nm of the active zone. These findings provide the first evidence of TBI-induced impairments in synaptic vesicle docking, and suggest that reductions in the pool of readily releasable vesicles and impaired SNARE complex formation are two novel mechanisms contributing to impaired neurotransmission after TBI. PMID:25923735

  2. P2X-mediated AMPA receptor internalization and synaptic depression is controlled by two CaMKII phosphorylation sites on GluA1 in hippocampal neurons

    PubMed Central

    Pougnet, Johan-Till; Compans, Benjamin; Martinez, Audrey; Choquet, Daniel; Hosy, Eric; Boué-Grabot, Eric

    2016-01-01

    Plasticity at excitatory synapses can be induced either by synaptic release of glutamate or the release of gliotransmitters such as ATP. Recently, we showed that postsynaptic P2X2 receptors activated by ATP released from astrocytes downregulate synaptic AMPAR, providing a novel mechanism by which glial cells modulate synaptic activity. ATP- and lNMDA-induced depression in the CA1 region of the hippocampus are additive, suggesting distinct molecular pathways. AMPARs are homo-or hetero-tetramers composed of GluA1-A4. Here, we first show that P2X2-mediated AMPAR inhibition is dependent on the subunit composition of AMPAR. GluA3 homomers are insensitive and their presence in heteromers alters P2X-mediated inhibition. Using a mutational approach, we demonstrate that the two CaMKII phosphorylation sites S567 and S831 located in the cytoplasmic Loop1 and C-terminal tail of GluA1 subunits, respectively, are critical for P2X2-mediated AMPAR inhibition recorded from co-expressing Xenopus oocytes and removal of surface AMPAR at synapses of hippocampal neurons imaged by the super-resolution dSTORM technique. Finally, using phosphorylation site-specific antibodies, we show that P2X-induced depression in hippocampal slices produces a dephosphorylation of the GluA1 subunit at S567, contrary to NMDAR-mediated LTD. These findings indicate that GluA1 phosphorylation of S567 and S831 is critical for P2X2-mediated AMPAR internalization and ATP-driven synaptic depression. PMID:27624155

  3. Itinerant Antiferromagnetism in RuO2

    DOE PAGES

    Berlijn, Tom; Snijders, Paul C.; Delaire, Oliver A.; ...

    2017-02-15

    Bulk rutile RuO2 has long been considered a Pauli paramagnet. Here, in this article, we report that RuO2 exhibits a hitherto undetected lattice distortion below approximately 900 K. The distortion is accompanied by antiferromagnetic order up to at least 300 K with a small room temperature magnetic moment of approximately 0.05μB as evidenced by polarized neutron diffraction. Density functional theory plus U(DFT+U) calculations indicate that antiferromagnetism is favored even for small values of the Hubbard U of the order of 1 eV. The antiferromagnetism may be traced to a Fermi surface instability, lifting the band degeneracy imposed by the rutilemore » crystal field. The combination of high Néel temperature and small itinerant moments make RuO2 unique among ruthenate compounds and among oxide materials in general.« less

  4. Itinerant Antiferromagnetism in RuO2

    NASA Astrophysics Data System (ADS)

    Berlijn, T.; Snijders, P. C.; Delaire, O.; Zhou, H.-D.; Maier, T. A.; Cao, H.-B.; Chi, S.-X.; Matsuda, M.; Wang, Y.; Koehler, M. R.; Kent, P. R. C.; Weitering, H. H.

    2017-02-01

    Bulk rutile RuO2 has long been considered a Pauli paramagnet. Here we report that RuO2 exhibits a hitherto undetected lattice distortion below approximately 900 K. The distortion is accompanied by antiferromagnetic order up to at least 300 K with a small room temperature magnetic moment of approximately 0.05 μB as evidenced by polarized neutron diffraction. Density functional theory plus U (DFT +U ) calculations indicate that antiferromagnetism is favored even for small values of the Hubbard U of the order of 1 eV. The antiferromagnetism may be traced to a Fermi surface instability, lifting the band degeneracy imposed by the rutile crystal field. The combination of high Néel temperature and small itinerant moments make RuO2 unique among ruthenate compounds and among oxide materials in general.

  5. Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors.

    PubMed

    Fischell, Jonathan; Van Dyke, Adam M; Kvarta, Mark D; LeGates, Tara A; Thompson, Scott M

    2015-10-01

    Selective serotonin reuptake inhibitors (SSRIs) are the primary pharmacological treatment for depression, but SSRIs are effective in only half of the patients and typically take several weeks to relieve symptoms. The NMDA receptor antagonist ketamine exerts a rapid antidepressant action, but has troubling side effects. We hypothesized that negative allosteric modulators of GABAA receptors would exert similar effects on brain activity as ketamine, but would not exert as many side effects if targeted only to GABAA receptors containing α5 subunits, which are enriched in the hippocampus and prefrontal cortex. Here, we show that the α5-selective negative modulator L-655,708 reversed the alterations in hedonic behavior in the sucrose preference and social interaction tests produced by two different chronic stress paradigms in rats within 24 h of systemic administration. Similar effects were observed with another α5-selective negative modulator, MRK-016. L-655,708 had no effect on hedonic or open-field behavior in unstressed animals. Within 24 h, L-655,708 injection also restored the strength of pathologically weakened excitatory synaptic transmission at the stress-sensitive temporoammonic-CA1 synapse, measured electrophysiologically, and increased levels of the GluA1 subunit of the AMPA receptor, measured with western blotting. We suggest that the ability of L-655,708 to restore excitatory synaptic strength rapidly may underlie its ability to restore stress-induced behavioral alterations rapidly, supporting evidence that dysfunction of multiple excitatory synapses in cortico-mesolimbic reward pathways contributes, in part, to the genesis of depression. Negative allosteric modulators of α5 subunit-containing GABAA receptors represent a promising novel class of fast-acting and clinically viable antidepressant compounds.

  6. 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.

  7. Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning.

    PubMed

    Hagena, Hardy; Manahan-Vaughan, Denise

    2016-01-01

    Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an

  8. Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning

    PubMed Central

    Hagena, Hardy; Manahan-Vaughan, Denise

    2016-01-01

    Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an

  9. Depressed GABA and glutamate synaptic signaling by 5-HT1A receptors in the nucleus tractus solitarii and their role in cardiorespiratory function

    PubMed Central

    Ostrowski, Tim D.; Ostrowski, Daniela; Hasser, Eileen M.

    2014-01-01

    Serotonin (5-HT), and its 5-HT1A receptor (5-HT1AR) subtype, is a powerful modulator of the cardiorespiratory system and its sensory reflexes. The nucleus tractus solitarii (nTS) serves as the first central station for visceral afferent integration and is critical for cardiorespiratory reflex responses. However, the physiological and synaptic role of 5-HT1ARs in the nTS is relatively unknown. In the present study, we examined the distribution and modulation of 5-HT1ARs on cardiorespiratory and synaptic parameters in the nTS. 5-HT1ARs were widely distributed to cell bodies within the nTS but not synaptic terminals. In anesthetized rats, activation of 5-HT1ARs by microinjection of the 5-HT1AR agonist 8-OH-DPAT into the caudal nTS decreased minute phrenic neural activity via a reduction in phrenic amplitude. In brain stem slices, 8-OH-DPAT decreased the amplitude of glutamatergic tractus solitarii-evoked excitatory postsynaptic currents, and reduced overall spontaneous excitatory nTS network activity. These effects persisted in the presence of GABAA receptor blockade and were antagonized by coapplication of 5-HT1AR blocker WAY-100135. 5-HT1AR blockade alone had no effect on tractus solitarii-evoked excitatory postsynaptic currents, but increased excitatory network activity. On the other hand, GABAergic nTS-evoked inhibitory postsynaptic currents did not change by activation of the 5-HT1ARs, but spontaneous inhibitory nTS network activity decreased. Blocking 5-HT1ARs tended to increase nTS-evoked inhibitory postsynaptic currents and inhibitory network activity. Taken together, 5-HT1ARs in the caudal nTS decrease breathing, likely via attenuation of afferent transmission, as well as overall nTS network activity. PMID:24671532

  10. Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction.

    PubMed

    Origlia, Nicola; Righi, Massimo; Capsoni, Simona; Cattaneo, Antonino; Fang, Fang; Stern, David M; Chen, John Xi; Schmidt, Ann Marie; Arancio, Ottavio; Yan, Shi Du; Domenici, Luciano

    2008-03-26

    Soluble amyloid-beta (Abeta) peptide is likely to play a key role during early stages of Alzheimer's disease (AD) by perturbing synaptic function and cognitive processes. Receptor for advanced glycation end products (RAGE) has been identified as a receptor involved in Abeta-induced neuronal dysfunction. We investigated the role of neuronal RAGE in Abeta-induced synaptic dysfunction in the entorhinal cortex, an area of the brain important in memory processes that is affected early in AD. We found that soluble oligomeric Abeta peptide (Abeta42) blocked long-term potentiation (LTP), but did not affect long-term depression, paired-pulse facilitation, or basal synaptic transmission. In contrast, Abeta did not inhibit LTP in slices from RAGE-null mutant mice or in slices from wild-type mice treated with anti-RAGE IgG. Similarly, transgenic mice expressing a dominant-negative form of RAGE targeted to neurons showed normal LTP in the presence of Abeta, suggesting that neuronal RAGE functions as a signal transducer for Abeta-mediated LTP impairment. To investigate intracellular pathway transducing RAGE activation by Abeta, we used inhibitors of stress activated kinases. We found that inhibiting p38 mitogen-activated protein kinase (p38 MAPK), but not blocking c-Jun N-terminal kinase activation, was capable of maintaining LTP in Abeta-treated slices. Moreover, Abeta-mediated enhancement of p38 MAPK phosphorylation in cortical neurons was reduced by blocking antibodies to RAGE. Together, our results indicate that Abeta impairs LTP in the entorhinal cortex through neuronal RAGE-mediated activation of p38 MAPK.

  11. Effect of short-term exposure to dichlorvos on synaptic plasticity of rat hippocampal slices: Involvement of acylpeptide hydrolase and {alpha}{sub 7} nicotinic receptors

    SciTech Connect

    Olmos, Cristina; Sandoval, Rodrigo; Rozas, Carlos; Navarro, Sebastian; Wyneken, Ursula; Zeise, Marc; Morales, Bernardo; Pancetti, Floria

    2009-07-01

    Dichlorvos is the active molecule of the pro-drug metrifonate used to revert the cognitive deficits associated with Alzheimer's disease. A few years ago it was reported that dichlorvos inhibits the enzyme acylpeptide hydrolase at lower doses than those necessary to inhibit acetylcholinesterase to the same extent. Therefore, the aim of our investigation was to test the hypothesis that dichlorvos can enhance synaptic efficacy through a mechanism that involves acylpeptide hydrolase instead of acetylcholinesterase inhibition. We used long-term potentiation induced in rat hippocampal slices as a model of synaptic plasticity. Our results indicate that short-term exposures (20 min) to 50 {mu}M dichlorvos enhance long-term potentiation in about 200% compared to the control condition. This effect is correlated with approximately 60% inhibition of acylpeptide hydrolase activity, whereas acetylcholinesterase activity remains unaffected. Paired-pulse facilitation and inhibition experiments indicate that dichlorvos does not have any presynaptic effect in the CA3 {yields} CA1 pathway nor affect gabaergic interneurons. Interestingly, the application of 100 nM methyllicaconitine, an {alpha}{sub 7} nicotinic receptor antagonist, blocked the enhancing effect of dichlorvos on long-term potentiation. These results indicate that under the exposure conditions described above, dichlorvos enhances long-term potentiation through a postsynaptic mechanism that involves (a) the inhibition of the enzyme acylpeptide hydrolase and (b) the modulation of {alpha}{sub 7} nicotinic receptors.

  12. Cognitive impairments associated with alterations in synaptic proteins induced by the genetic loss of adenosine A2A receptors in mice.

    PubMed

    Moscoso-Castro, Maria; López-Cano, Marc; Gracia-Rubio, Irene; Ciruela, Francisco; Valverde, Olga

    2017-11-01

    The study of psychiatric disorders usually focuses on emotional symptoms assessment. However, cognitive deficiencies frequently constitute the core symptoms, are often poorly controlled and handicap individual's quality of life. Adenosine receptors, through the control of both dopamine and glutamate systems, have been implicated in the pathophysiology of several psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder. Indeed, clinical data indicate that poorly responsive schizophrenia patients treated with adenosine adjuvants show improved treatment outcomes. The A2A adenosine receptor subtype (A2AR) is highly expressed in brain areas controlling cognition and motivational responses including the striatum, hippocampus and cerebral cortex. Accordingly, we study the role of A2AR in the regulation of cognitive processes based on a complete cognitive behavioural analysis coupled with the assessment of neurogenesis and sub-synaptic protein expression in adult and middle-aged A2AR constitutional knockout mice and wild-type littermates. Our results show overall cognitive impairments in A2AR knockout mice associated with a decrease in new-born hippocampal neuron proliferation and concomitant changes in synaptic protein expression, in both the prefrontal cortex and the hippocampus. These results suggest a deficient adenosine signalling in cognitive processes, thus providing new opportunities for the therapeutic management of cognitive deficits associated with psychiatric disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Role of adenosine A(2A) receptors in modulating synaptic functions and brain levels of BDNF: a possible key mechanism in the pathophysiology of Huntington's disease.

    PubMed

    Tebano, Maria Teresa; Martire, Alberto; Chiodi, Valentina; Ferrante, Antonella; Popoli, Patrizia

    2010-09-01

    In the last few years, accumulating evidence has shown the existence of an important cross-talk between adenosine A(2A) receptors (A(2A)Rs) and brain-derived neurotrophic factor (BDNF). Not only are A(2A)Rs involved in the mechanism of transactivation of BDNF receptor TrkB, they also modulate the effect of BDNF on synaptic transmission, playing a facilitatory and permissive role. The cAMP-PKA pathway, the main transduction system operated by A(2A)Rs, is involved in such effects. Furthermore, a basal tonus of A(2A)Rs is required to allow the regulation of BDNF physiological levels in the brain, as demonstrated by the reduced protein levels measured in A(2A)Rs KO mice. The crucial role of adenosine A(2A)Rs in the maintenance of synaptic functions and BDNF levels will be reviewed here and discussed in the light of possible implications for Huntington's disease therapy, in which a joint impairment of BDNF and A(2A)Rs seems to play a pathogenetic role.

  14. Requirement of rapid Ca2+ entry and synaptic activation of metabotropic glutamate receptors for the induction of long-term depression in adult rat hippocampus

    PubMed Central

    Otani, Satoru; Connor, John A

    1998-01-01

    During block of γ-aminobutyric acid-A-mediated inhibition, low-frequency stimulation (2 Hz, 900 pulses) to Schaffer collateral-CA1 neuron synapses of adult rat hippocampus induced an N-methyl-D-aspartate receptor-independent, postsynaptic Ca2+-dependent depression of synaptic strength (long-term depression; LTD). Ratio imaging with fura-2 revealed moderate dendritic [Ca2+] increases (≈500 nM) during only the initial ≈30 s of the 7.5 min stimulation period. Conditioning for 30 s was, however, insufficient to induce LTD. The [Ca2+] changes were insensitive to the metabotropic glutamate receptor (mGluR) antagonist (+)-α-methyl-4-carboxyphenylglycine (MCPG). MCPG, however, completely blocked LTD when present during conditioning. The [Ca2+] changes were abolished by postsynaptic hyperpolarization (-110 mV at the soma). Hyperpolarizing neurons to -110 mV during conditioning significantly attenuated LTD induction. LTD induction was also blocked by the postsynaptic presence of the protein kinase C inhibitor peptide PKC(19-36). These results suggest that LTD induction in adult hippocampus by prolonged low-frequency stimulation depends on both a rapid Ca2+ influx through voltage-sensitive channels and synaptic stimulation of mGluRs which may be coupled to phospholipase C. PMID:9714858

  15. Phosphorylation of Ser1166 on GluN2B by PKA Is Critical to Synaptic NMDA Receptor Function and Ca2+ Signaling in Spines

    PubMed Central

    Murphy, Jessica A.; Stein, Ivar S.; Lau, C. Geoffrey; Peixoto, Rui T.; Aman, Teresa K.; Kaneko, Naoki; Aromolaran, Kelly; Saulnier, Jessica L.; Popescu, Gabriela K.

    2014-01-01

    The NMDA-type glutamate receptor (NMDAR) is essential for synaptogenesis, synaptic plasticity, and higher cognitive function. Emerging evidence indicates that NMDAR Ca2+ permeability is under the control of cAMP/protein kinase A (PKA) signaling. Whereas the functional impact of PKA on NMDAR-dependent Ca2+ signaling is well established, the molecular target remains unknown. Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca2+ permeation and Ca2+ signaling in spines. Activation of β-adrenergic and D1/D5-dopamine receptors induces Ser1166 phosphorylation. Loss of this single phosphorylation site abolishes PKA-dependent potentiation of NMDAR Ca2+ permeation, synaptic currents, and Ca2+ rises in dendritic spines. We further show that adverse experience in the form of forced swim, but not exposure to fox urine, elicits striking phosphorylation of Ser1166 in vivo, indicating differential impact of different forms of stress. Our data identify a novel molecular and functional target of PKA essential to NMDAR-mediated Ca2+ signaling at synapses and regulated by the emotional response to stress. PMID:24431445

  16. α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors.

    PubMed

    Wei, Mengping; Zhang, Jian; Jia, Moye; Yang, Chaojuan; Pan, Yunlong; Li, Shuaiqi; Luo, Yiwen; Zheng, Junyuan; Ji, Jianguo; Chen, Jianguo; Hu, Xinli; Xiong, Jingwei; Shi, Yun; Zhang, Chen

    2016-05-10

    In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/β-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6.

  17. Control of neural chaos by synaptic noise.

    PubMed

    Cortes, J M; Torres, J J; Marro, J

    2007-02-01

    We study neural automata - or neurobiologically inspired cellular automata - which exhibits chaotic itinerancy among the different stored patterns or memories. This is a consequence of activity-dependent synaptic fluctuations, which continuously destabilize the attractor and induce irregular hopping to other possible attractors. The nature of these irregularities depends on the dynamic details, namely, on the intensity of the synaptic noise and the number of sites of the network, which are synchronously updated at each time step. Varying these factors, different regimes occur, ranging from regular to chaotic dynamics. As a result, and in absence of external agents, the chaotic behavior may turn regular after tuning the noise intensity. It is argued that a similar mechanism might be on the basis of self-controlling chaos in natural systems.

  18. Sensitivity of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials and synaptic plasticity to TCN 201 and TCN 213 in rat hippocampal slices.

    PubMed

    Izumi, Yukitoshi; Zorumski, Charles F

    2015-02-01

    Whereas ifenprodil has been used as a selective GluN1/GluN2B (NR1/NR2B, B-type) receptor antagonist to distinguish between GluN2B (NR2B) and GluN2A (NR2A)-containing N-methyl-d-aspartate receptors (NMDARs), TCN 201 (3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide) and TCN 213 [N-(cyclohexylmethyl)-2-[{5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio]acetamide] have been found to be selective GluN1/GluN2A (NR1/NR2A, A-type) antagonists. Based on the premise that A- and B-types are major synaptic NMDARs, we examined whether inhibition of NMDAR excitatory postsynaptic potentials (EPSPs) by the TCN compounds and ifenprodil are complementary. Contrary to this prediction, inhibition of NMDAR EPSPs by the TCN compounds and ifenprodil were largely overlapping in the CA1 region of hippocampal slices from 30-day-old rats. After partial inhibition by ifenprodil, TCN compounds produced little further suppression of NMDAR EPSPs. Similarly, after partial inhibition by TCN compounds ifenprodil failed to further suppress NMDAR EPSPs. However, low micromolar d-2-amino-5-phosphonovalerate, a competitive NMDAR antagonist, which alone only partially inhibits NMDAR EPSPs, markedly suppresses residual NMDAR responses in the presence of ifenprodil or the TCNs, suggesting that low 2-amino-5-phosphonovalerate antagonizes both ifenprodil- and TCN-insensitive synaptic NMDARs. These observations can be most readily interpreted if ifenprodil and TCNs act on a similar population of synaptic NMDARs. Recent lines of evidence suggest that the majority of hippocampal synaptic NMDARs are triheteromers. If so, modulation of GluN2A, and not just GluN2B NMDARs, could dampen long-term depression (LTD). Indeed, both TCNs, like ifenprodil, blocked LTD, suggesting the involvement of ifenprodil- and TCN-sensitive NMDARs in LTD induction. However, the TCNs plus ifenprodil failed to inhibit long-term potentiation (LTP), suggesting that neither ifenprodil- nor TCN

  19. [Memory and synaptic plasticity].

    PubMed

    Maitre, M

    1996-01-01

    Short term memory traces are probably induced by a sustained and specific functional activation of some sensory and/or motor circuits in brain. These modifications, which could concern a large proportion of the brain but especially the limbic areas, are constituted primarily by ionic mechanisms and second messengers cascades induced by the activation of glutamatergic receptors (namely NMDA). In the invertebrate (Drosophilia melanogaster, aplysia), the role of serotonergic receptors seems to be more important. The activated cAMP-dependent and calcium dependent protein kinases target several proteins which are reversibly phosphorylated modifying the synaptic functions which in turn induce potentiated (PLT) or depressed (DLT) post-synaptic responses. These phenomena are at the basis of specific protein neosynthesis which is initiated by several early genes or trancription factor (cfos, zif 268, jun, CREB). Specific mRNA migrate to the potentiated synapse or dendritic spine where activated polyribosomes synthesize trophic factor, adhesion molecules and synaptic constituents. The building of new synaptic contacts and/or the plastic evolution of existing synapses could explain long-term LTP and long-term memory traces.

  20. Changes in mGlu5 receptor-dependent synaptic plasticity and coupling to homer proteins in the hippocampus of Ube3A hemizygous mice modeling angelman syndrome.

    PubMed

    Pignatelli, Marco; Piccinin, Sonia; Molinaro, Gemma; Di Menna, Luisa; Riozzi, Barbara; Cannella, Milena; Motolese, Marta; Vetere, Gisella; Catania, Maria Vincenza; Battaglia, Giuseppe; Nicoletti, Ferdinando; Nisticò, Robert; Bruno, Valeria

    2014-03-26

    Angelman syndrome (AS) is caused by the loss of Ube3A, an ubiquitin ligase that commits specific proteins to proteasomal degradation. How this defect causes autism and other pathological phenotypes associated with AS is unknown. Long-term depression (LTD) of excitatory synaptic transmission mediated by type 5 metabotropic glutamate (mGlu5) receptors was enhanced in hippocampal slices of Ube3A(m-/p+) mice, which model AS. No changes were found in NMDA-dependent LTD induced by low-frequency stimulation. mGlu5 receptor-dependent LTD in AS mice was sensitive to the protein synthesis inhibitor anisomycin, and relied on the same signaling pathways as in wild-type mice, e.g., the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycine pathway, and protein tyrosine phosphatase. Neither the stimulation of MAPK and PI3K nor the increase in Arc (activity-regulated cytoskeleton-associated protein) levels in response to mGlu5 receptor activation were abnormal in hippocampal slices from AS mice compared with wild-type mice. mGlu5 receptor expression and mGlu1/5 receptor-mediated polyphosphoinositide hydrolysis were also unchanged in the hippocampus of AS mice. In contrast, AS mice showed a reduced expression of the short Homer protein isoform Homer 1a, and an increased coupling of mGlu5 receptors to Homer 1b/c proteins in the hippocampus. These findings support the link between Homer proteins and monogenic autism, and lay the groundwork for the use of mGlu5 receptor antagonists in AS.

  1. Cocaine-induced synaptic structural modification is differentially regulated by dopamine D1 and D3 receptors-mediated signaling pathways.

    PubMed

    Zhang, Lei; Huang, Lu; Lu, Kangrong; Liu, Yutong; Tu, Genghong; Zhu, Mengjuan; Ying, Li; Zhao, Jinlan; Liu, N; Guo, Fukun; Zhang, Lin; Zhang, Lu

    2016-10-12

    Synaptic plasticity plays a critical role in cocaine addiction. The dopamine D1 and D3 receptors differentially regulate the cocaine-induced gene expression, structural remodeling and behavioral response. However, how these two receptors coordinately mediate the ultra-structural changes of synapses after cocaine exposure and whether these changes are behaviorally relevant are still not clear. Here, using quantitative electron microscopy, we show that D1 and D3 receptors have distinct roles in regulating cocaine-induced ultra-structural changes of synapses in the nucleus accumbens and caudoputamen. Pre-treatment of cocaine-treated mice with D3 receptor antagonist NGB2904 resulted in an increase in the ratio of total and asymmetric synapse to neuron and in the length of postsynaptic densities, compared with cocaine treatment alone. In contrast, pre-treatment of cocaine-treated mice with D1 receptor antagonist SCH23390 caused a reduction in synapse-to-neuron ratio and in postsynaptic densities length. Similarly, NGB2904 and SCH23390 showed opposite/differential effects on cocaine-induced structural plasticity, conditioned place preference and locomotor activity and signaling activation, including the activation of ERK, CREB and NR1 and the expression of c-fos and Cdk5. Therefore, we provide direct electron microscopy evidence that dopamine D1 and D3 receptors reciprocally regulate the ultra-structural changes of synapses following chronic exposure to cocaine. In addition, our data suggest that D1 and D3 receptors may regulate cocaine-induced ultra-structural changes and behavior responses by impact on structural plasticity and signaling transduction. © 2016 Society for the Study of Addiction.

  2. A Model of Synaptic Reconsolidation

    PubMed Central

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

    2016-01-01

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

  3. D2-like dopamine receptors promote interactions between calcium and chloride channels that diminish rod synaptic transfer in the salamander retina

    PubMed Central

    THORESON, WALLACE B.; STELLA, SALVATORE L.; BRYSON, ERIC J.; CLEMENTS, JOHN; WITKOVSKY, PAUL

    2017-01-01

    Activation of D2-like dopamine receptors in rods with quinpirole stimulates L-type calcium currents (ICa). This result appears inconsistent with studies showing that D2-like dopamine receptor activation diminishes rod signals in second-order retinal neurons. Since small reductions in [Cl−]i can inhibit photoreceptor ICa, we tested the hypothesis that enhancement of ICa with the D2/D4 receptor agonist, quinpirole, increases calcium-activated chloride currents (ICl(Ca)) causing an efflux of Cl− from rods that would provide a negative feedback inhibition of ICa. In agreement with studies from Xenopus, quinpirole reduced rod input to second-order neurons of tiger salamander retina without significantly altering rod voltage responses. Quinpirole also diminished the amplitude of depolarization-evoked increases in [Ca2+]i measured with Fura-2 in rods, a finding consistent with inhibition of synaptic transmission from rods. Electrophysiological and Cl−-imaging experiments indicated ECl in rods is ~ −220 mV. Quinpirole enhanced ICl(Ca) and elicited an efflux of Cl− at the resting potential. A similar Cl− efflux was produced by extracellular replacement of 24 mM Cl− with CH3SO4− and this low Cl− solution inhibited Ca2+ responses to a similar degree as quinpirole did. When ICl(Ca) was inhibited with niflumic acid, quinpirole enhanced both ICa and depolarization-evoked increases in [Ca2+]i. Furthermore, with niflumic acid, quinpirole no longer inhibited rod inputs into horizontal and bipolar cells. These results suggest an initial enhancement of ICa by quinpirole is followed by a stimulation of Cl− currents, including ICl(Ca). The net result is a Cl− efflux that inhibits depolarization-evoked increases in [Ca2+]i and synaptic transmission from rods. PMID:12392173

  4. Presynaptic angiotensin II AT1 receptors enhance inhibitory and excitatory synaptic neurotransmission to motoneurons and other ventral horn neurons in neonatal rat spinal cord.

    PubMed

    Oz, Murat; Yang, Keun-Hang; O'donovan, Michael J; Renaud, Leo P

    2005-08-01

    In neonatal spinal cord, we previously reported that exogenous angiotensin II (ANG II) acts at postsynaptic AT1 receptors to depolarize neonatal rat spinal ventral horn neurons in vitro. This study evaluated an associated increase in synaptic activity. Patch clamp recordings revealed that 38/81 thoracolumbar (T7-L5) motoneurons responded to bath applied ANG II (0.3-1 microM; 30 s) with a prolonged (5-10 min) and reversible increase in spontaneous postsynaptic activity, selectively blockable with Losartan (n = 5) but not PD123319 (n = 5). ANG-II-induced events included both spontaneous inhibitory (IPSCs; n = 6) and excitatory postsynaptic currents (EPSCs; n = 5). While most ANG induced events were tetrodotoxin-sensitive, ANG induced a significant tetrodotoxin-resistant increase in frequency but not amplitude of miniature IPSCs (n = 7/13 cells) and EPSCs (n = 2/7 cells). In 35/77 unidentified neurons, ANG II also induced a tetrodotoxin-sensitive and prolonged increase in their spontaneous synaptic activity that featured both IPSCs (n = 5) and EPSCs (n = 4) when tested in the presence of selective amino acid receptor antagonists. When tested in the presence of tetrodotoxin, ANG II was noted to induce a significant increase in the frequency but not the amplitude of mIPSCs (n = 9) and mEPSCs (n = 8). ANG also increased spontaneous motor activity from isolated mouse lumbar ventral rootlets. Collectively, these observations support the existence of a wide pre- and postsynaptic distribution of ANG II AT1 receptors in neonatal ventral spinal cord that are capable of influencing both inhibitory and excitatory neurotransmission.

  5. Choline induces opposite changes in pyramidal neuron excitability and synaptic transmission through a nicotinic receptor-independent process in hippocampal slices.

    PubMed

    Albiñana, E; Luengo, J G; Baraibar, A M; Muñoz, M D; Gandía, L; Solís, J M; Hernández-Guijo, J M

    2017-06-01

    Choline is present at cholinergic synapses as a product of acetylcholine degradation. In addition, it is considered a selective agonist for α5 and α7 nicotinic acetylcholine receptors (nAChRs). In this study, we determined how choline affects action potentials and excitatory synaptic transmission using extracellular and intracellular recording techniques in CA1 area of hippocampal slices obtained from both mice and rats. Choline caused a reversible depression of evoked field excitatory postsynaptic potentials (fEPSPs) in a concentration-dependent manner that was not affected by α7 nAChR antagonists. Moreover, this choline-induced effect was not mimicked by either selective agonists or allosteric modulators of α7 nAChRs. Additionally, this choline-mediated effect was not prevented by either selective antagonists of GABA receptors or hemicholinium, a choline uptake inhibitor. The paired pulse facilitation paradigm, which detects whether a substance affects presynaptic release of glutamate, was not modified by choline. On the other hand, choline induced a robust increase of population spike evoked by orthodromic stimulation but did not modify that evoked by antidromic stimulation. We also found that choline impaired recurrent inhibition recorded in the pyramidal cell layer through a mechanism independent of α7 nAChR activation. These choline-mediated effects on fEPSP and population spike observed in rat slices were completely reproduced in slices obtained from α7 nAChR knockout mice, which reinforces our conclusion that choline modulates synaptic transmission and neuronal excitability by a mechanism independent of nicotinic receptor activation.

  6. A study of the oligomeric state of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-preferring glutamate receptors in the synaptic junctions of porcine brain.

    PubMed Central

    Wu, T Y; Liu, C I; Chang, Y C

    1996-01-01

    The number of the subunits in an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring L-glutamate receptor in the synaptic junctions of porcine brain was investigated in this study. Upon incubation of the synaptic junctions with three cross-linking regents, dimethyl adipimidate (DMA), dimethyl suberimidate (DMS) and N-succinimidyl-(4-azidophenyl)-1,3'-dithiopropionate (SADP), AMPA receptor subunits in higher-molecular-mass aggregates were detected by immunoblotting. These aggregates migrated as proteins of approx. 200, 300 and 400 kDa. The number and identity of the subunits in a solubilized AMPA receptor were also investigated here. Two samples, W1 and W2, enriched in AMPA receptors were prepared from synaptic junctions by a combination of detergent-solubilization, anion-exchange chromatography and wheatgerm agglutinin affinity chromatography. Hydrodynamic behaviour analyses revealed that the majority of the AMPA receptors in either one of these samples were asymmetrical detergent-surrounded particles with a protein mass around 350 kDa. SDS/PAGE analysis revealed that the majority of AMPA receptors in the W1 sample were comprised of dimers of 106 kDa subunits which were covalently linked by disulphide bonds. Cross-linking these receptors with SADP yielded a new band of approx. 400 kDa. The results obtained here, either from the studies of AMPA receptors embedding in synaptic junctions or from those of detergent-solubilized and partially purified receptors, suggest that AMPA receptors contain a basic core structure comprising of four 106 kDa subunits. PMID:8920974

  7. Long-term depression of inhibitory synaptic transmission induced by spike-timing dependent plasticity requires coactivation of endocannabinoid and muscarinic receptors.

    PubMed

    Ahumada, Juan; Fernández de Sevilla, David; Couve, Alejandro; Buño, Washington; Fuenzalida, Marco

    2013-12-01

    The precise timing of pre-postsynaptic activity is vital for the induction of long-term potentiation (LTP) or depression (LTD) at many central synapses. We show in synapses of rat CA1 pyramidal neurons in vitro that spike timing dependent plasticity (STDP) protocols that induce LTP at glutamatergic synapses can evoke LTD of inhibitory postsynaptic currents or STDP-iLTD. The STDP-iLTD requires a postsynaptic Ca(2+) increase, a release of endocannabinoids (eCBs), the activation of type-1 endocananabinoid receptors and presynaptic muscarinic receptors that mediate a decreased probability of GABA release. In contrast, the STDP-iLTD is independent of the activation of nicotinic receptors, GABAB Rs and G protein-coupled postsynaptic receptors at pyramidal neurons. We determine that the downregulation of presynaptic Cyclic adenosine monophosphate/protein Kinase A pathways is essential for the induction of STDP-iLTD. These results suggest a novel mechanism by which the activation of cholinergic neurons and retrograde signaling by eCBs can modulate the efficacy of GABAergic synaptic transmission in ways that may contribute to information processing and storage in the hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

  8. Human Freud-2/CC2D1B: a novel repressor of post-synaptic 5-HT1A receptor expression

    PubMed Central

    Hadjighassem, Mahmoud R.; Austin, Mark C.; Szewczyk, Bernadeta; Daigle, Mireille; Stockmeier, Craig A.; Albert, Paul R.

    2014-01-01

    Background Altered expression of serotonin-1A (5-HT1A) receptors, both presynaptic in the raphe nuclei and in limbic and cortical target areas, has been implicated in mood disorders such as major depression and anxiety. Within the 5-HT1A receptor gene (HTR1A), a powerful dual repressor element (DRE) is regulated by two protein complexes: Freud-1/CC2D1A and a second, unknown repressor. Here we identify human Freud-2/CC2D1B, a Freud-1 homologue, as the second repressor. Methods Freud-2 distribution was examined using Northern and Western blot, RT-PCR, immunohistochemistry/immunofluorescence; Freud-2 function was examined by electrophoretic mobility shift, reporter assay and Western blot. Results Freud-2 RNA was widely distributed in brain and peripheral tissues. Freud-2 protein was enriched in the nuclear fraction of human prefrontal cortex and hippocampus, but was weakly expressed in the dorsal raphe nucleus. Freud-2 immunostaining was co-localized with 5-HT1A receptors, neuronal and glial markers. In prefrontal cortex, Freud-2 was expressed at similar levels in control and depressed male subjects. Recombinant hFreud-2 protein bound specifically to 5′ or 3′ human DRE adjacent to the Freud-1 site. Human Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter in human HEK293 5-HT1A-negative cells and neuronal SK-N-SH cells, a model of post-synaptic 5-HT1A receptor-positive cells. Furthermore siRNA knockdown of endogenous hFreud-2 expression de-repressed 5-HT1A promoter activity and increased levels of 5-HT1A receptor protein in SK-N-SH cells. Conclusion Human Freud-2 binds to the 5-HT1A DRE and represses the human 5-HT1A receptor gene to regulate its expression in non-serotonergic cells and neurons. PMID:19423080

  9. Differential Responses of Progesterone Receptor Membrane Component-1 (Pgrmc1) and the Classical Progesterone Receptor (Pgr) to 17β-Estradiol and Progesterone in Hippocampal Subregions that Support Synaptic Remodeling and Neurogenesis

    PubMed Central

    Bali, Namrata; Arimoto, Jason M.; Iwata, Nahoko; Lin, Sharon W.; Zhao, Liqin; Brinton, Roberta D.; Morgan, Todd E.

    2012-01-01

    Progesterone (P4) and estradiol (E2) modulate neurogenesis and synaptic remodeling in the hippocampus during the rat estrous cycle and in response to deafferenting lesions, but little is known about the steroidal regulation of hippocampal progesterone receptors associated with these processes. We examined the neuronal expression of progesterone receptor membrane component-1 (Pgrmc1) and the classical progesterone receptor (Pgr), by in situ hybridization and immunohistochemistry. Pgr, a transcription factor, has been associated with synaptic remodeling and other major actions of P4, whereas Pgrmc1 is implicated in P4-dependent proliferation of adult neuroprogenitor cells and with rapid P4 effects on membranes. Ovariectomized adult rats were given E2, P4, or E2+P4 on two schedules: a 4-d model of the rodent estrous cycle and a 30-d model of postmenopausal hormone therapy. Pgr was hormonally responsive only in CA1 pyramidal neurons, and the induction of Pgr by E2 was partly antagonized by P4 only on the 30-d schedule. In CA3 pyramidal and dentate gyrus (DG) neurons, Pgr was largely unresponsive to all hormone treatments. In contrast to Pgr, Pgrmc1 was generally induced by E2 and/or P4 throughout the hippocampus in CA1, CA3, and DG neurons. In neuroprogenitor cells of the DG (immunopositive for bromodeoxyuridine and doublecortin), both Pgrmc1 and Pgr were detected. The differential regulation of hippocampal Pgrmc1 and Pgr by E2 and P4 may guide drug development in hormonal therapy for support of neurogenesis and synaptic regeneration. PMID:22147012

  10. Opposing effects of Toll-like receptors 2 and 4 on synaptic stability in the spinal cord after peripheral nerve injury

    PubMed Central

    2012-01-01

    Background Glial cells are involved in the synaptic elimination process that follows neuronal lesions, and are also responsible for mediating the interaction between the nervous and immune systems. Neurons and glial cells express Toll-like receptors (TLRs), which may affect the plasticity of the central nervous system (CNS). Because TLRs might also have non-immune functions in spinal-cord injury (SCI), we aimed to investigate the influence of TLR2 and TLR4 on synaptic plasticity and glial reactivity after peripheral nerve axotomy. Methods The lumbar spinal cords of C3H/HePas wild-type (WT) mice, C3H/HeJ TLR4-mutant mice, C57BL/6J WT mice, and C57BL/6J TLR2 knockout (KO) mice were studied after unilateral sciatic nerve transection. The mice were killed via intracardiac perfusion, and the spinal cord was processed for immunohistochemistry, transmission electron microscopy (TEM), western blotting, cell culture, and reverse transcriptase PCR. Primary cultures of astrocytes from newborn mice were established to study the astrocyte response in the absence of TLR2 and the deficiency of TLR4 expression. Results The results showed that TLR4 and TLR2 expression in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord. First, TLR4 contributed to synaptic preservation of terminals in apposition to lesioned motor neurons after peripheral injury, regardless of major histocompatibility complex class I (MHC I) expression. In addition, in the presence of TLR4, there was upregulation of glial cell-derived neurotrophic factor and downregulation of interleukin-6, but no morphological differences in glial reactivity were seen. By contrast, TLR2 expression led to greater synaptic loss, correlating with increased astrogliosis and upregulation of pro-inflammatory interleukins. Moreover, the absence of TLR2 resulted in the upregulation of neurotrophic factors and MHC I expression. Conclusion TLR4 and TLR2 in the CNS may have opposite effects on the

  11. Synaptic transmission in nucleus tractus solitarius is depressed by Group II and III but not Group I presynaptic metabotropic glutamate receptors in rats

    PubMed Central

    Chen, Chao-Yin; Ling, Erh-hsin; Horowitz, John M; Bonham, Ann C

    2002-01-01

    Presynaptic metabotropic glutamate receptors (mGluRs) serve as autoreceptors throughout the CNS to inhibit glutamate release and depress glutamatergic transmission. Both presynaptic and postsynaptic mGluRs have been implicated in shaping autonomic signal transmission in the nucleus tractus solitarius (NTS). We sought to test the hypothesis that activation of presynaptic mGluRs depresses neurotransmission between primary autonomic afferent fibres and second-order NTS neurones. In second-order NTS neurones, excitatory postsynaptic currents (EPSCs) synaptically evoked by stimulation of primary sensory afferent fibres in the tractus solitarius (ts) and currents postsynaptically evoked by α-amino-3-hydroxy-4-isoxazoleproprionic acid (AMPA) were studied in the presence and absence of mGluR agonists and antagonists. Real-time quantitative RT-PCR (reverse transcription-polymerase chain reaction) was used to determine whether the genes for the mGluR subtypes were expressed in the cell bodies of the primary autonomic afferent fibres. Agonist activation of Group II and III but not Group I mGluRs reduced the peak amplitude of synaptically (ts) evoked EPSCs in a concentration-dependent manner while having no effect on postsynaptically (AMPA) evoked currents recorded in the same neurones. At the highest concentrations, the Group II agonist, (2S,3S,4S)-CCG/(2S,1′S,2′S)-2-carboxycyclopropyl (l-CCG-I), decreased the amplitude of the ts-evoked EPSCs by 39 % with an EC50 of 21 μm, and the Group III agonist, l(+)-2-amino-4-phosphonobutyric acid (l-AP4), decreased the evoked EPSCs by 71 % with an EC50 of 1 mm. mRNA for all eight mGluR subtypes was detected in the autonomic afferent fibre cell bodies in the nodose and jugular ganglia. Group II and III antagonists ((2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG) and (RS)-α-methylserine-O-phosphate (MSOP)), at concentrations that blocked the respective agonist-induced synaptic depression, attenuated the frequency

  12. Beliefs and practices of itinerant teachers of deaf and hard of hearing children concerning literacy development.

    PubMed

    Reed, Susanne

    2003-01-01

    A qualitative case study examined beliefs and practices of itinerant teachers of deaf and hard of hearing students concerning literacy development, the match between these teachers' beliefs and practices, and the impact of itinerant settings. Five itinerant teachers and 15 students participated. Hearing losses were mild to profound. The research addressed 5 areas: sociocultural aspects of literacy development; effects of hearing loss on literacy development; beliefs about teaching and literacy development; practices used to develop literacy; the impact of itinerant settings on literacy development of deaf and hard of hearing learners. Five themes emerged from the data: Itinerant teachers used a variety of practices to develop literacy; itinerant teachers played a supporting role in developing literacy; most of the teachers' beliefs about literacy development were matched in their practices; the itinerant teachers were lifelong learners; the impact of itinerant settings on literacy development took many forms.

  13. Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors.

    PubMed

    Kochlamazashvili, Gaga; Senkov, Oleg; Grebenyuk, Sergei; Robinson, Catrina; Xiao, Mei-Fang; Stummeyer, Katharina; Gerardy-Schahn, Rita; Engel, Andreas K; Feig, Larry; Semyanov, Alexey; Suppiramaniam, Vishnu; Schachner, Melitta; Dityatev, Alexander

    2010-03-17

    The neural cell adhesion molecule (NCAM) is the predominant carrier of alpha2,8 polysialic acid (PSA) in the mammalian brain. Abnormalities in PSA and NCAM expression are associated with schizophrenia in humans and cause deficits in hippocampal synaptic plasticity and contextual fear conditioning in mice. Here, we show that PSA inhibits opening of recombinant NMDA receptors composed of GluN1/2B (NR1/NR2B) or GluN1/2A/2B (NR1/NR2A/NR2B) but not of GluN1/2A (NR1/NR2A) subunits. Deficits in NCAM/PSA increase GluN2B-mediated transmission and Ca(2+) transients in the CA1 region of the hippocampus. In line with elevation of GluN2B-mediated transmission, defects in long-term potentiation in the CA1 region and contextual fear memory in NCAM/PSA-deficient mice are abrogated by application of a GluN2B-selective antagonist. Furthermore, treatment with the glutamate scavenger glutamic-pyruvic transaminase, ablation of Ras-GRF1 (a mediator of GluN2B signaling to p38 MAPK), or direct inhibition of hyperactive p38 MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38 MAPK signaling pathway. These findings implicate carbohydrates carried by adhesion molecules in modulating NMDA receptor signaling in the brain and demonstrate reversibility of cognitive deficits associated with ablation of a schizophrenia-related adhesion molecule.

  14. Neural Cell Adhesion Molecule-Associated Polysialic Acid Regulates Synaptic Plasticity and Learning by Restraining the Signaling through GluN2B-Containing NMDA Receptors

    PubMed Central

    Kochlamazashvili, Gaga; Senkov, Oleg; Grebenyuk, Sergei; Robinson, Catrina; Xiao, Mei-Fang; Stummeyer, Katharina; Gerardy-Schahn, Rita; Engel, Andreas K.; Feig, Larry; Semyanov, Alexey; Suppiramaniam, Vishnu; Schachner, Melitta; Dityatev, Alexander

    2017-01-01

    The neural cell adhesion molecule (NCAM) is the predominant carrier of α2,8 polysialic acid (PSA) in the mammalian brain. Abnormalities in PSA and NCAM expression are associated with schizophrenia in humans and cause deficits in hippocampal synaptic plasticity and contextual fear conditioning in mice. Here, we show that PSA inhibits opening of recombinant NMDA receptors composed of GluN1/2B (NR1/NR2B) or GluN1/2A/2B (NR1/NR2A/NR2B) but not of GluN1/2A (NR1/NR2A) subunits. Deficits in NCAM/PSA increase GluN2B-mediated transmission and Ca2+ transients in the CA1 region of the hippocampus. In line with elevation of GluN2B-mediated transmission, defects in long-term potentiation in the CA1 region and contextual fear memory in NCAM/PSA-deficient mice are abrogated by application of a GluN2B-selective antagonist. Furthermore, treatment with the glutamate scavenger glutamic-pyruvic transaminase, ablation of Ras-GRF1 (a mediator of GluN2B signaling to p38 MAPK), or direct inhibition of hyperactive p38 MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38 MAPK signaling pathway. These findings implicate carbohydrates carried by adhesion molecules in modulating NMDA receptor signaling in the brain and demonstrate reversibility of cognitive deficits associated with ablation of a schizophrenia-related adhesion molecule. PMID:20237287

  15. Changes in synaptic plasticity and expression of glutamate receptor subunits in the CA1 and CA3 areas of the hippocampus after transient global ischemia.

    PubMed

    Han, Xin-Jia; Shi, Zhong-Shan; Xia, Luo-Xing; Zhu, Li-Hui; Zeng, Ling; Nie, Jun-Hua; Xu, Zao-Cheng; Ruan, Yi-Wen

    2016-07-07

    Excess glutamate release from the presynaptic membrane has been thought to be the major cause of ischemic neuronal death. Although both CA1 and CA3 pyramidal neurons receive presynaptic glutamate input, transient cerebral ischemia induces CA1 neurons to die while CA3 neurons remain relatively intact. This suggests that changes in the properties of pyramidal cells may be the main cause related to ischemic neuronal death. Our previous studies have shown that the densities of dendritic spines and asymmetric synapses in the CA1 area are increased at 12h and 24h after ischemia. In the present study, we investigated changes in synaptic structures in the CA3 area and compared the expression of glutamate receptors in the CA1 and CA3 hippocampal regions of rats after ischemia. Our results demonstrated that the NR2B/NR2A ratio became larger after ischemia although the expression of both the NR2B subunit (activation of apoptotic pathway) and NR2A subunit (activation of survival pathway) decreased in the CA1 area from 6h to 48h after reperfusion. Furthermore, expression of the GluR2 subunit (calcium impermeable) of the AMPA receptor class significantly decreased while the GluR1 subunit (calcium permeable) remained unchanged at the same examined reperfusion times, which subsequently caused an increase in the GluR1/GluR2 ratio. Despite these notable differences in subunit expression, there were no obvious changes in the density of synapses or expression of NMDAR and AMPAR subunits in the CA3 area after ischemia. These results suggest that delayed CA1 neuronal death may be related to the dramatic fluctuation in the synaptic structure and relative upregulation of NR2B and GluR1 subunits induced by transient global ischemia.

  16. 24S-Hydroxycholesterol enhances synaptic vesicle cycling in the mouse neuromuscular junction: Implication of glutamate NMDA receptors and nitric oxide.

    PubMed

    Kasimov, M R; Fatkhrakhmanova, M R; Mukhutdinova, K A; Petrov, A M

    2017-01-31

    24S-hydroxycholesterol (24S-HC) is a brain-derived product of lipid metabolism present in the systemic circulation, where its level can change significantly in response to physiological and pathophysiological conditions. Here, using electrophysiological and optical approaches, we have found a high sensitivity to 24S-HC of the synaptic vesicle cycle at the mouse neuromuscular junctions. Treatment with 24S-HC increased the end plate potential amplitude (EPP) in response to a single stimulus and attenuated the EPP amplitude rundown during high frequency (HF) activity but had no influence on miniature EPP amplitude or frequency. The effects on evoked responses were associated with enhanced FM1-43 dye loading and unloading by endo- and exocytosis. Comparison of electrophysiological and optical data revealed an increase in the rate of vesicular cycling. The impact of 24S-HC was abolished or potentiated by stimulation or inhibition of NMDA-receptors respectively. Moreover, 24S-HC, acting in the same manner as the endothelial NO synthase (eNOS) inhibitor cavtratin, suppressed an increase in NO-sensitive dye fluorescence during HF stimulation, while l-glutamate had the opposite effect. Inhibitors of NOS (l-NAME and cavtratin, but not the neuronal NOS inhibitor TRIM), a scavenger of extracellular NO and a protein kinase G blocker all had stimulatory effects, similar to those of 24S-HC, on exocytosis induced by HF activity and completely masked the effect of 24S-HC. The data suggest that 24S-HC enhances synaptic vesicle cycling due to an attenuation of retrograde NO signaling that depends on eNOS. In this regard, 24S-HC counteracts the effects of NMDA-receptor stimulation at mouse neuromuscular junctions.

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

    PubMed

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

    2015-08-01

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

  18. A Consultative Itinerant Approach to Service Delivery: Considerations for the Early Childhood Community

    ERIC Educational Resources Information Center

    Dinnebeil, Laurie; Pretti-Frontczak, Kristie; McInerney, William

    2009-01-01

    Purpose: This article, written by experts in itinerant early childhood special education, describes and differentiates approaches to itinerant early childhood special education as a primary service delivery option. Consultative itinerant early childhood special education services, in particular, are a means of ensuring that young children with…

  19. FGF acts as a co-transmitter through Adenosine A2A receptor to regulate morphological and physiological synaptic plasticity

    PubMed Central

    Flajolet, Marc; Wang, Zhongfeng; Futter, Marie; Shen, Weixing; Nuangchamnong, Nina; Bendor, Jacob; Palaszewski, Iwona; Nairn, Angus C.; Surmeier, D. James; Greengard, Paul

    2009-01-01

    Summary Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, and depression. Adenosine, by activation of A2A receptors, antagonizes dopamine signaling at D2 receptors and A2A receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We report here a direct physical interaction between the G protein-coupled A2A receptor and the receptor tyrosine kinase FGF receptor. Concomitant activation of these two classes of receptors, but not individual activation of either one alone, causes a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity induced by a novel A2AR/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A2A and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions. PMID:18953346

  20. The location of muscarinic type 2 receptors within the synaptic circuitry of the cat lateral posterior nucleus.

    PubMed

    Carden, W B; Bickford, M E

    1999-12-10

    The ultrastructural distribution of the muscarinic type 2 acetylcholine receptor (M2) was examined in the lateral division of the lateral posterior (LP) nucleus of the cat thalamus, using immunocytochemistry. Postembedding immunocytochemical staining for gamma-aminobutyric acid (GABA) further characterized M2 stained profiles. M2 receptors were predominately found on small caliber (presumably distal) dendritic arbors of thalamocortical cells and interneurons in the lateral LP nucleus. While glomeruli were not abundant in the lateral LP nucleus, occasionally they contained dendritic terminals of interneurons (F2 profiles) stained for M2 receptors. Some GABAergic terminals throughout the neuropil also stained for M2 receptors. The location of M2 receptors correlates well with the cholinergic innervation of the lateral LP nucleus and suggests that muscarinic modulation of visual signals differs in the lateral LP nucleus as compared with the lateral geniculate and pulvinar nuclei.

  1. Chaotic itinerancy and its roles in cognitive neurodynamics.

    PubMed

    Tsuda, Ichiro

    2015-04-01

    Chaotic itinerancy is an autonomously excited trajectory through high-dimensional state space of cortical neural activity that causes the appearance of a temporal sequence of quasi-attractors. A quasi-attractor is a local region of weakly convergent flows that represent ordered activity, yet connected to divergent flows representing disordered, chaotic activity between the regions. In a cognitive neurodynamic aspect, quasi-attractors represent perceptions, thoughts and memories, chaotic trajectories between them with intelligent searches, such as history-dependent trial-and-error via exploration, and itinerancy with history-dependent sequences in thinking, speaking and writing.

  2. Itinerant magnetism in metallic CuFe2Ge2

    DOE PAGES

    Shanavas, K. V.; Singh, David J.; He, Ruihua

    2015-03-25

    Theoretical calculations are performed to understand the electronic structure and magnetic properties of CuFe2Ge2. The band structure reveals large electron density N(EF) at the Fermi level suggesting a strong itinerant character of magnetism. The Fermi surface is dominated by two dimensional sheet like structures, with potentially strong nesting between them. The magnetic ground state appears to be ferromagnetic along a and antiferromagnetic in other directions. The results show that CuFe2Ge2 is an antiferromagnetic metal, with similarities to the Fe-based superconductors; such as magnetism with substantial itinerant character and coupling between magnetic order and electrons at the Fermi energy.

  3. Itinerant magnetism in metallic CuFe2Ge2.

    PubMed

    Shanavas, K V; Singh, David J

    2015-01-01

    Theoretical calculations are performed to understand the electronic structure and magnetic properties of CuFe2Ge2. The band structure reveals large electron density N(EF) at the Fermi level suggesting a strong itinerant character of magnetism. The Fermi surface is dominated by two dimensional sheet like structures, with potentially strong nesting between them. The magnetic ground state appears to be ferromagnetic along a and antiferromagnetic in other directions. These results show that CuFe2Ge2 is an antiferromagnetic metal, with similarities to the Fe-based superconductors; such as magnetism with substantial itinerant character and coupling between magnetic order and electrons at the Fermi energy.

  4. Two populations of neurokinin 1 receptor-expressing projection neurons in lamina I of the rat spinal cord that differ in AMPA receptor subunit composition and density of excitatory synaptic input

    PubMed Central

    Polgár, E.; Al Ghamdi, K.S.; Todd, A.J.

    2010-01-01

    Lamina I of the spinal cord contains many projection neurons that express the neurokinin 1 receptor (NK1r). It has been reported that these cells can undergo long-term potentiation (LTP), which may result from insertion of AMPA-type glutamate receptors (AMPArs) containing GluA1 or GluA4 subunits. We therefore investigated synaptic AMPAr expression on these cells with immunocytochemistry following antigen-retrieval. We also examined their density of glutamatergic input (by analysing AMPAr synaptic puncta and contacts from glutamatergic boutons), and phosphorylation of extracellular signal-regulated kinases (pERKs) following noxious stimulation. Our results indicate that there are two populations of NK1r-expressing projection neurons: large GluA4+/GluA1− cells with a high density of glutamatergic input and small GluA1+/GluA4− cells with a much lower input density. Results from pERK experiments suggested that the two groups may not differ in the types of noxious stimulus that activate them. Glutamatergic synapses on distal dendrites of the large cells were significantly longer than those on proximal dendrites, which presumably compensates for the greater attenuation of distally-generated excitatory postsynaptic currents (EPSCs). Both types of cell received contacts from peptidergic primary afferents, however, on the large cells these appeared to constitute over half of the glutamatergic synapses, and were often associated with elongated AMPAr puncta. This suggests that these afferents, which probably contain substance P, provide a powerful, secure synaptic input to large NK1r-expressing projection neurons. These results demonstrate the importance of GluA4-containing AMPArs in nociceptive transmission and raise the possibility that different forms of LTP in lamina I projection neurons may be related to differential expression of GluA1/GluA4. PMID:20303396

  5. Synaptic muscarinic response types in hippocampal CA1 interneurons depend on different levels of presynaptic activity and different muscarinic receptor subtypes.

    PubMed

    Bell, L Andrew; Bell, Karen A; McQuiston, A Rory

    2013-10-01

    Depolarizing, hyperpolarizing and biphasic muscarinic responses have been described in hippocampal inhibitory interneurons, but the receptor subtypes and activity patterns required to synaptically activate muscarinic responses in interneurons have not been completely characterized. Using optogenetics combined with whole cell patch clamp recordings in acute slices, we measured muscarinic responses produced by endogenously released acetylcholine (ACh) from cholinergic medial septum/diagonal bands of Broca inputs in hippocampal CA1. We found that depolarizing responses required more cholinergic terminal stimulation than hyperpolarizing ones. Furthermore, elevating extracellular ACh with the acetylcholinesterase inhibitor physostigmine had a larger effect on depolarizing versus hyperpolarizing responses. Another subpopulation of interneurons responded biphasically, and periodic release of ACh entrained some of these interneurons to rhythmically burst. M4 receptors mediated hyperpolarizing responses by activating inwardly rectifying K(+) channels, whereas the depolarizing responses were inhibited by the nonselective muscarinic antagonist atropine but were unaffected by M1, M4 or M5 receptor modulators. In addition, activation of M4 receptors significantly altered biphasic interneuron firing patterns. Anatomically, interneuron soma location appeared predictive of muscarinic response types but response types did not correlate with interneuron morphological subclasses. Together these observations suggest that the hippocampal CA1 interneuron network will be differentially affected by cholinergic input activity levels. Low levels of cholinergic activity will preferentially suppress some interneurons via hyperpolarization and increased activity will recruit other interneurons to depolarize, possibly because of elevated extracellular ACh concentrations. These data provide important information for understanding how cholinergic therapies will affect hippocampal network function

  6. Synaptic muscarinic response types in hippocampal CA1 interneurons depend on different levels of presynaptic activity and different muscarinic receptor subtypes

    PubMed Central

    Bell, L. Andrew; Bell, Karen A.; McQuiston, A. Rory

    2013-01-01

    Depolarizing, hyperpolarizing and biphasic muscarinic responses have been described in hippocampal inhibitory interneurons, but the receptor subtypes and activity patterns required to synaptically activate muscarinic responses in interneurons have not been completely characterized. Using optogenetics combined with whole cell patch clamp recordings in acute slices, we measured muscarinic responses produced by endogenously released acetylcholine (ACh) from cholinergic medial septum/diagonal bands of Broca inputs in hippocampal CA1. We found that depolarizing responses required more cholinergic terminal stimulation than hyperpolarizing ones. Furthermore, elevating extracellular ACh with the acetylcholinesterase inhibitor physostigmine had a larger effect on depolarizing versus hyperpolarizing responses. Another subpopulation of interneurons responded biphasically, and periodic release of ACh entrained some of these interneurons to rhythmically burst. M4 receptors mediated hyperpolarizing responses by activating inwardly rectifying K+ channels, whereas the depolarizing responses were inhibited by the nonselective muscarinic antagonist atropine but were unaffected by M1, M4 or M5 receptor modulators. In addition, activation of M4 receptors significantly altered biphasic interneuron firing patterns. Anatomically, interneuron soma location appeared predictive of muscarinic response types but response types did not correlate with interneuron morphological subclasses. Together these observations suggest that the hippocampal CA1 interneuron network will be differentially affected by cholinergic input activity levels. Low levels of cholinergic activity will preferentially suppress some interneurons via hyperpolarization and increased activity will recruit other interneurons to depolarize, possibly because of elevated extracellular ACh concentrations. These data provide important information for understanding how cholinergic therapies will affect hippocampal network function

  7. γ-Aminobutyric Acid Type A (GABAA) Receptor Subunits Play a Direct Structural Role in Synaptic Contact Formation via Their N-terminal Extracellular Domains*

    PubMed Central

    Brown, Laura E.; Nicholson, Martin W.; Arama, Jessica E.; Thomson, Alex M.

    2016-01-01

    The establishment of cell-cell contacts between presynaptic GABAergic neurons and their postsynaptic targets initiates the process of GABAergic synapse formation. GABAA receptors (GABAARs), the main postsynaptic receptors for GABA, have been recently demonstrated to act as synaptogenic proteins that can single-handedly induce the formation and functional maturation of inhibitory synapses. To establish how the subunit composition of GABAARs influences their ability to induce synaptogenesis, a co-culture model system incorporating GABAergic medium spiny neurons and the HEK293 cells, stably expressing different combinations of receptor subunits, was developed. Analyses of HEK293 cell innervation by medium spiny neuron axons using immunocytochemistry, activity-dependent labeling, and electrophysiology have indicated that the γ2 subunit is required for the formation of active synapses and that its effects are influenced by the type of α/β subunits incorporated into the functional receptor. To further characterize this process, the large N-terminal extracellular domains (ECDs) of α1, α2, β2, and γ2 subunits were purified using the baculovirus/Sf9 cell system. When these proteins were applied to the co-cultures of MSNs and α1/β2/γ2-expressing HEK293 cells, the α1, β2, or γ2 ECD each caused a significant reduction in contact formation, in contrast to the α2 ECD, which had no effect. Together, our experiments indicate that the structural role of GABAARs in synaptic contact formation is determined by their subunit composition, with the N-terminal ECDs of each of the subunits directly participating in interactions between the presynaptic and postsynaptic elements, suggesting the these interactions are multivalent and specific. PMID:27129275

  8. Distinct synaptic properties of perisomatic inhibitory cell types and their different modulation by cholinergic receptor activation in the CA3 region of the mouse hippocampus.

    PubMed

    Szabó, Gergely G; Holderith, Noémi; Gulyás, Attila I; Freund, Tamás F; Hájos, Norbert

    2010-06-01

    Perisomatic inhibition originates from three types of GABAergic interneurons in cortical structures, including parvalbumin-containing fast-spiking basket cells (FSBCs) and axo-axonic cells (AACs), as well as cholecystokinin-expressing regular-spiking basket cells (RSBCs). These interneurons may have significant impact in various cognitive processes, and are subjects of cholinergic modulation. However, it is largely unknown how cholinergic receptor activation modulates the function of perisomatic inhibitory cells. Therefore, we performed paired recordings from anatomically identified perisomatic interneurons and pyramidal cells in the CA3 region of the mouse hippocampus. We determined the basic properties of unitary inhibitory postsynaptic currents (uIPSCs) and found that they differed among cell types, e.g. GABA released from axon endings of AACs evoked uIPSCs with the largest amplitude and with the longest decay measured at room temperature. RSBCs could also release GABA asynchronously, the magnitude of the release increasing with the discharge frequency of the presynaptic interneuron. Cholinergic receptor activation by carbachol significantly decreased the uIPSC amplitude in all three types of cell pairs, but to different extents. M2-type muscarinic receptors were responsible for the reduction in uIPSC amplitudes in FSBC- and AAC-pyramidal cell pairs, while an antagonist of CB(1) cannabinoid receptors recovered the suppression in RSBC-pyramidal cell pairs. In addition, carbachol suppressed or even eliminated the short-term depression of uIPSCs in FSBC- and AAC-pyramidal cell pairs in a frequency-dependent manner. These findings suggest that not only are the basic synaptic properties of perisomatic inhibitory cells distinct, but acetylcholine can differentially control the impact of perisomatic inhibition from different sources.

  9. Inhibition of a slow synaptic response by a metabotropic glutamate receptor antagonist in hippocampal CA3 pyramidal cells.

    PubMed

    Gerber, U; Lüthi, A; Gähwiler, B H

    1993-11-22

    The effects of a novel antagonist of metabotropic glutamate receptors were investigated in CA3 pyramidal cells in hippocampal slice cultures of the rat. Earlier experiments showed that selective activation of metabotropic glutamate receptors with low concentrations of an agonist, 1S, 3R-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD), induced an inward current associated with a decrease in membrane conductance and inhibition of the slow calcium-dependent potassium current. These responses were strongly and reversibly reduced by the antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 0.5-1 mM). In the presence of antagonists of ionotropic glutamate receptors, stimulation of the afferent mossy fibres evoked postsynaptic responses in CA3 pyramidal cells which paralleled those observed with exogenously applied metabotropic glutamate receptor agonists, i.e. a slow inward current and a reduction of calcium-dependent potassium current. Both responses were greatly reduced by bath-applied MCPG (1 mM). These results show that MCPG acts as an effective antagonist at metabotropic glutamate receptors coupled to potassium conductances in the hippocampus. Furthermore, they confirm that glutamate release from presynaptic terminals can modulate postsynaptic properties by activation of metabotropic glutamate receptors.

  10. Elementary spin excitations in ultrathin itinerant magnets

    NASA Astrophysics Data System (ADS)

    Zakeri, Khalil

    2014-12-01

    Elementary spin excitations (magnons) play a fundamental role in condensed matter physics, since many phenomena e.g. magnetic ordering, electrical (as well as heat) transport properties, ultrafast magnetization processes, and most importantly electron/spin dynamics can only be understood when these quasi-particles are taken into consideration. In addition to their fundamental importance, magnons may also be used for information processing in modern spintronics. Here the concept of spin excitations in ultrathin itinerant magnets is discussed and reviewed. Starting with a historical introduction, different classes of magnons are introduced. Different theoretical treatments of spin excitations in solids are outlined. Interaction of spin-polarized electrons with a magnetic surface is discussed. It is shown that, based on the quantum mechanical conservation rules, a magnon can only be excited when a minority electron is injected into the system. While the magnon creation process is forbidden by majority electrons, the magnon annihilation process is allowed instead. These fundamental quantum mechanical selection rules, together with the strong interaction of electrons with matter, make the spin-polarized electron spectroscopies as appropriate tools to excite and probe the elementary spin excitations in low-dimensional magnets e.g ultrathin films and nanostructures. The focus is put on the experimental results obtained by spin-polarized electron energy loss spectroscopy and spin-polarized inelastic tunneling spectroscopy. The magnon dispersion relation, lifetime, group and phase velocity measured using these approaches in various ultrathin magnets are discussed in detail. The differences and similarities with respect to the bulk excitations are addressed. The role of the temperature, atomic structure, number of atomic layers, lattice strain, electronic complexes and hybridization at the interfaces are outlined. A possibility of simultaneous probing of magnons and phonons

  11. Episodic sucrose intake during food restriction increases synaptic abundance of AMPA receptors in nucleus accumbens and augments intake of sucrose following restoration of ad libitum feeding.

    PubMed

    Peng, X-X; Lister, A; Rabinowitsch, A; Kolaric, R; Cabeza de Vaca, S; Ziff, E B; Carr, K D

    2015-06-04

    Weight-loss dieting often leads to loss of control, rebound weight gain, and is a risk factor for binge pathology. Based on findings that food restriction (FR) upregulates sucrose-induced trafficking of glutamatergic AMPA receptors to the nucleus accumbens (NAc) postsynaptic density (PSD), this study was an initial test of the hypothesis that episodic "breakthrough" intake of forbidden food during dieting interacts with upregulated mechanisms of synaptic plasticity to increase reward-driven feeding. Ad libitum (AL) fed and FR subjects consumed a limited amount of 10% sucrose, or had access to water, every other day for 10 occasions. Beginning three weeks after return of FR rats to AL feeding, when 24-h chow intake and rate of body weight gain had normalized, subjects with a history of sucrose intake during FR consumed more sucrose during a four week intermittent access protocol than the two AL groups and the group that had access to water during FR. In an experiment that substituted noncontingent administration of d-amphetamine for sucrose, FR subjects displayed an enhanced locomotor response during active FR but a blunted response, relative to AL subjects, during recovery from FR. This result suggests that the enduring increase in sucrose consumption is unlikely to be explained by residual enhancing effects of FR on dopamine signaling. In a biochemical experiment which paralleled the sucrose behavioral experiment, rats with a history of sucrose intake during FR displayed increased abundance of pSer845-GluA1, GluA2, and GluA3 in the NAc PSD relative to rats with a history of FR without sucrose access and rats that had been AL throughout, whether they had a history of episodic sucrose intake or not. A history of FR, with or without a history of sucrose intake, was associated with increased abundance of GluA1. A terminal 15-min bout of sucrose intake produced a further increase in pSer845-GluA1 and GluA2 in subjects with a history of sucrose intake during FR

  12. Episodic Sucrose Intake During Food Restriction Increases Synaptic Abundance of AMPA Receptors in Nucleus Accumbens and Augments Intake of Sucrose Following Restoration of Ad Libitum Feeding

    PubMed Central

    Peng, Xing-Xiang; Lister, Amanda; Rabinowitsch, Ariana; Kolaric, Rhonda; de Vaca, Soledad Cabeza; Ziff, Edward B.; Carr, Kenneth D.

    2015-01-01

    Weight-loss dieting often leads to loss of control, rebound weight gain, and is a risk factor for binge pathology. Based on findings that food restriction (FR) upregulates sucrose-induced trafficking of glutamatergic AMPA receptors to the nucleus accumbens (NAc) postsynaptic density (PSD), this study was an initial test of the hypothesis that episodic “breakthrough” intake of forbidden food during dieting interacts with upregulated mechanisms of synaptic plasticity to increase reward-driven feeding. Ad libitum (AL) fed and FR subjects consumed a limited amount of 10% sucrose, or had access to water, every other day for ten occasions. Beginning three weeks after return of FR rats to AL feeding, when 24-hour chow intake and rate of body weight gain had normalized, subjects with a history of sucrose intake during FR consumed more sucrose during a four week intermittent access protocol than the two AL groups and the group that had access to water during FR. In an experiment that substituted noncontingent administration of d-amphetamine for sucrose, FR subjects displayed an enhanced locomotor response during active FR but a blunted response, relative to AL subjects, during recovery from FR. This result suggests that the enduring increase in sucrose consumption is unlikely to be explained by residual enhancing effects of FR on dopamine signaling. In a biochemical experiment which paralleled the sucrose behavioral experiment, rats with a history of sucrose intake during FR displayed increased abundance of pSer845-GluA1, GluA2, and GluA3 in the NAc PSD relative to rats with a history of FR without sucrose access and rats that had been AL throughout, whether they had a history of episodic sucrose intake or not. A history of FR, with or without a history of sucrose intake, was associated with increased abundance of GluA1. A terminal 15-min bout of sucrose intake produced a further increase in pSer845-GluA1 and GluA2 in subjects with a history of sucrose intake during FR

  13. 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

  14. GluN2B-containing NMDA receptors blockade rescues bidirectional synaptic plasticity in the bed nucleus of the stria terminalis of cocaine self-administering rats.

    PubMed

    deBacker, Julian; Hawken, Emily R; Normandeau, Catherine P; Jones, Andrea A; Di Prospero, Cynthia; Mechefske, Elysia; Gardner Gregory, James; Hayton, Scott J; Dumont, Éric C

    2015-01-01

    Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) and after withdrawal. The sucrose rats also displayed a decrease in NMDA current decay time with continued self-administration (maintenance), which normalized after withdrawal. Cocaine self-administering rats exhibited impairment in NMDA-dependent long-term depression (LTD) that could be rescued by GluN2B-containing NMDA receptor blockade. Sucrose self-administering rats demonstrated no impairment in NMDA-dependent LTD. During the maintenance period of self-administration, in vivo (daily intraperitoneally for 5 days) pharmacologic blockade of GluN2B-containing NMDA receptors did not reduce lever pressing for cocaine. However, in vivo GluN2B blockade did normalize A:N ratios in cocaine self-administrating rats, and dissociated the magnitude of ovBNST A:N ratios from drug-seeking behavior after protracted withdrawal. Altogether, our data demonstrate when and how bidirectional plasticity at ovBNST excitatory synapses becomes dysfunctional with cocaine self-administration and that NMDA

  15. Selective 5-HT7 Receptor Activation May Enhance Synaptic Plasticity Through N-methyl-D-aspartate (NMDA) Receptor Activity in the Visual Cortex.

    PubMed

    Xiang, Kangjian; Zhao, Xuefei; Li, Youjun; Zheng, Liang; Wang, Jue; Li, Yan-Hai

    2016-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that modulates N-methyl-D-aspartate (NMDA) receptor activity by binding to several different 5-HT receptor subtypes. In the present study, we used whole-cell patch-clamp recordings in transverse slice preparations to test the role of 5-HT receptors in modulating the NMDA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex. We found that the NMDA receptor-mediated component of mEPSCs could be potentiated by exogenously applied 5-HT. Similar results were obtained by exogenously applied 5-CT or 8-OH-DPAT (the 5-HT1A and 5-HT7 receptor agonist). A specific antagonist for the 5-HT7 receptor, SB-269970, completely blocked the increase in NMDA receptor-mediated component of mEPSCs by 5-CT or 8- OH-DPAT. Moreover, the selective 5-HT1A receptor antagonist, WAY-100135, displayed no influence on the enhancement in NMDA receptor-mediated component of mEPSCs by 5-CT or 8-OHDPAT. These results indicated that the increase in NMDA receptor-mediated component of mEPSCs by 5-HT in layer II/III pyramidal neurons of the young rat visual cortex requires activation of 5-HT7 receptors, but not 5-HT1A receptors. These observations might be clinically relevant to schizophrenia and Alzheimer's disease (AD), where enhancing NMDA receptor-mediated neurotransmission is considered to be a promising strategy for treatment of these diseases.

  16. Astrocyte-derived adenosine and A1 receptor activity contribute to sleep loss-induced deficits in hippocampal synaptic plasticity and memory in mice.

    PubMed

    Florian, Cédrick; Vecsey, Christopher G; Halassa, Michael M; Haydon, Philip G; Abel, Ted

    2011-05-11

    Sleep deprivation (SD) can have a negative impact on cognitive function, but the mechanism(s) by which SD modulates memory remains unclear. We have previously shown that astrocyte-derived adenosine is a candidate molecule involved in the cognitive deficits following a brief period of SD (Halassa et al., 2009). In this study, we examined whether genetic disruption of soluble N-ethylmaleimide-sensitive factor attached protein (SNARE)-dependent exocytosis in astrocytes (dnSNARE mice) or pharmacological blockade of A1 receptor signaling using an adenosine A1 receptor (A1R) antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT), could prevent the negative effects of 6 h of SD on hippocampal late-phase long-term potentiation (L-LTP) and hippocampus-dependent spatial object recognition memory. We found that SD impaired L-LTP in wild-type mice but not in dnSNARE mice. Similarly, this deficit in L-LTP resulting from SD was prevented by a chronic infusion of CPT. Consistent with these results, we found that hippocampus-dependent memory deficits produced by SD were rescued in dnSNARE mice and CPT-treated mice. These data provide the first evidence that astrocytic ATP and adenosine A1R activity contribute to the effects of SD on hippocampal synaptic plasticity and hippocampus-dependent memory, and suggest a new therapeutic target to reverse the hippocampus-related cognitive deficits induced by sleep loss.

  17. Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors.

    PubMed

    Li, Wei; Xu, Xin; Pozzo-Miller, Lucas

    2016-03-15

    Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naïve excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders.

  18. Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors

    PubMed Central

    Li, Wei; Xu, Xin

    2016-01-01

    Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naïve excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders. PMID:26929363

  19. Astrocyte-derived Adenosine and A1 Receptor Activity Contribute to Sleep Loss-Induced Deficits in Hippocampal Synaptic Plasticity and Memory in Mice

    PubMed Central

    Florian, Cédrick; Vecsey, Christopher G.; Halassa, Michael M.; Haydon, Philip G.; Abel, Ted

    2011-01-01

    Sleep deprivation (SD) can have a negative impact on cognitive function, but the mechanism(s) by which SD modulates memory remain unclear. We have previously shown that astrocyte-derived adenosine is a candidate molecule involved in the cognitive deficits following a brief period of SD (Halassa et al., 2009). In this study, we examined whether genetic disruption of SNARE-dependent exocytosis in astrocytes (dnSNARE mice) or pharmacological blockade of A1 receptor signaling using an adenosine A1 receptor (A1R) antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) could prevent the negative effects of 6 hours of SD on hippocampal late-phase long-term potentiation (L-LTP) and hippocampus-dependent spatial object recognition memory. We found that SD impaired L-LTP in wild-type mice but not in dnSNARE mice. Similarly, this deficit in L-LTP resulting from SD was prevented by a chronic infusion of CPT. Consistent with these results, we found that hippocampus-dependent memory deficits produced by SD were rescued in dnSNARE mice and CPT-treated mice. These data provide the first evidence that astrocytic ATP and adenosine A1R activity contribute to the effects of SD on hippocampal synaptic plasticity and hippocampus-dependent memory, and suggest a new therapeutic target to reverse the hippocampus-related cognitive deficits induced by sleep loss. PMID:21562257

  20. 5-HT(2C) serotonin receptor blockade prevents tau protein hyperphosphorylation and corrects the defect in hippocampal synaptic plasticity caused by a combination of environmental stressors in mice.

    PubMed

    Busceti, Carla Letizia; Di Pietro, Paola; Riozzi, Barbara; Traficante, Anna; Biagioni, Francesca; Nisticò, Robert; Fornai, Francesco; Battaglia, Giuseppe; Nicoletti, Ferdinando; Bruno, Valeria

    2015-09-01

    Exposure to multimodal sensory stressors is an everyday occurrence and sometimes becomes very intense, such as during rave parties or other recreational events. A growing body of evidence suggests that strong environmental stressors might cause neuronal dysfunction on their own in addition to their synergistic action with illicit drugs. Mice were exposed to a combination of physical and sensory stressors that are reminiscent of those encountered in a rave party. However, this is not a model of rave because it lacks the rewarding properties of rave. A 14-h exposure to environmental stressors caused an impairment of hippocampal long-term potentiation (LTP) and spatial memory, and an enhanced phosphorylation of tau protein in the CA1 and CA3 regions. These effects were transient and critically depended on the activation of 5-HT2C serotonin receptors, which are highly expressed in the CA1 region. Acute systemic injection of the selective 5-HT2C antagonist, RS-102,221 (2 mg/kg, i.p., 2 min prior the onset of stress), prevented tau hyperphosphorylation and also corrected the defects in hippocampal LTP and spatial memory. These findings suggest that passive exposure to a combination of physical and sensory stressors causes a reversible hippocampal dysfunction, which might compromise mechanisms of