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Sample records for itinerant synaptic receptors

  1. 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

  2. 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

  3. Regulation of AMPA Receptor Trafficking and Synaptic Plasticity

    PubMed Central

    Anggono, Victor; Huganir, Richard L.

    2012-01-01

    AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain. Dynamic changes in neuronal synaptic efficacy, termed synaptic plasticity, are thought to underlie information coding and storage in learning and memory. One major mechanism that regulates synaptic strength involves the tightly regulated trafficking of AMPARs into and out of synapses. The life cycle of AMPARs from their biosynthesis, membrane trafficking and synaptic targeting to their degradation are controlled by a series of orchestrated interactions with numerous intracellular regulatory proteins. Here we review recent progress made towards the understanding the regulation of AMPAR trafficking, focusing on the roles of several key intracellular AMPAR interacting proteins. PMID:22217700

  4. Calcineurin Mediates Synaptic Scaling Via Synaptic Trafficking of Ca2+-Permeable AMPA Receptors

    PubMed Central

    Kim, Seonil; Ziff, Edward B.

    2014-01-01

    Homeostatic synaptic plasticity is a negative-feedback mechanism for compensating excessive excitation or inhibition of neuronal activity. When neuronal activity is chronically suppressed, neurons increase synaptic strength across all affected synapses via synaptic scaling. One mechanism for this change is alteration of synaptic AMPA receptor (AMPAR) accumulation. Although decreased intracellular Ca2+ levels caused by chronic inhibition of neuronal activity are believed to be an important trigger of synaptic scaling, the mechanism of Ca2+-mediated AMPAR-dependent synaptic scaling is not yet understood. Here, we use dissociated mouse cortical neurons and employ Ca2+ imaging, electrophysiological, cell biological, and biochemical approaches to describe a novel mechanism in which homeostasis of Ca2+ signaling modulates activity deprivation-induced synaptic scaling by three steps: (1) suppression of neuronal activity decreases somatic Ca2+ signals; (2) reduced activity of calcineurin, a Ca2+-dependent serine/threonine phosphatase, increases synaptic expression of Ca2+-permeable AMPARs (CPARs) by stabilizing GluA1 phosphorylation; and (3) Ca2+ influx via CPARs restores CREB phosphorylation as a homeostatic response by Ca2+-induced Ca2+ release from the ER. Therefore, we suggest that synaptic scaling not only maintains neuronal stability by increasing postsynaptic strength but also maintains nuclear Ca2+ signaling by synaptic expression of CPARs and ER Ca2+ propagation. PMID:24983627

  5. 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

  6. Synaptic proteins and receptors defects in autism spectrum disorders

    PubMed Central

    Chen, Jianling; Yu, Shunying; Fu, Yingmei; Li, Xiaohong

    2014-01-01

    Recent studies have found that hundreds of genetic variants, including common and rare variants, rare and de novo mutations, and common polymorphisms contribute to the occurrence of autism spectrum disorders (ASDs). The mutations in a number of genes such as neurexin, neuroligin, postsynaptic density protein 95, SH3, and multiple ankyrin repeat domains 3 (SHANK3), synapsin, gephyrin, cadherin, and protocadherin, thousand-and-one-amino acid 2 kinase, and contactin, have been shown to play important roles in the development and function of synapses. In addition, synaptic receptors, such as gamma-aminobutyric acid receptors and glutamate receptors, have also been associated with ASDs. This review will primarily focus on the defects of synaptic proteins and receptors associated with ASDs and their roles in the pathogenesis of ASDs via synaptic pathways. PMID:25309321

  7. GABA(B) receptors and synaptic modulation.

    PubMed

    Kornau, Hans-Christian

    2006-11-01

    GABA(B) receptors modulate transmitter release and postsynaptic membrane potential at various types of central synapses. They function as heterodimers of two related seven-transmembrane domain receptor subunits. Trafficking, activation and signalling of GABA(B) receptors are regulated both by allosteric interactions between the subunits and by the binding of additional proteins. Recent studies have shed light on the roles of GABA(B) receptors in plasticity processes at excitatory synapses. This review summarizes our knowledge of the localization, structure and function of GABA(B) receptors in the central nervous system and their use as drug targets for neurological and psychiatric disorders. PMID:16932937

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

    PubMed

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

    2016-08-11

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

  9. 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

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

    PubMed

    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. PMID:25970033

  11. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location

    PubMed Central

    Lai, Meizan; Hughes, Ethan G.; Peng, Xiaoyu; Zhou, Lei; Gleichman, Amy J.; Shu, Huidy; Matà, Sabrina; Kremens, Daniel; Vitaliani, Roberta; Geschwind, Michael D.; Bataller, Luis; Kalb, Robert G.; Davis, Rebecca; Graus, Francesc; Lynch, David R.; Balice-Gordon, Rita; Dalmau, Josep

    2009-01-01

    Background Limbic encephalitis (LE) frequently associates with antibodies to cell surface antigens. Characterization of these antigens is important because it facilitates the diagnosis of those disorders that are treatment-responsive. We report a novel antigen of LE and the effect of patients' antibodies on neuronal cultures. Methods Clinical analysis of 10 patients with LE. Immunoprecipitation and mass spectrometry were used to identify the antigens. HEK293 cells expressing the antigens were used in immunocytochemistry and ELISA. The effect of patients' antibodies on cultures of live rat hippocampal neurons was determined with confocal microscopy. Results Median age was 60 years (38-87); 9 were women. Seven had tumors of the lung, breast or thymus. Nine patients responded to immunotherapy or oncological therapy but neurologic relapses, without tumor recurrence, were frequent and influenced the long-term outcome. One untreated patient died of LE. All patients had antibodies against neuronal cell surface antigens that by immunoprecipitation were found to be the GluR1 and GluR2 subunits of the AMPA receptor (AMPAR). HEK293 cells expressing GluR1/2 reacted with all patients' sera or CSF, providing a diagnostic test for the disorder. Application of antibodies to cultures of neurons significantly decreased the number of GluR2-containing AMPAR clusters at synapses with a smaller decrease in overall AMPAR cluster density; these effects were reversed after antibody removal. Conclusions Antibodies to GluR1/2 associate with LE that is often paraneoplastic, treatment-responsive, and has a tendency to relapse. Our findings support an antibody-mediated pathogenesis in which patients' antibodies alter the synaptic localization and number of AMPAR. PMID:19338055

  12. AMPA receptor regulation during synaptic plasticity in hippocampus and neocortex

    PubMed Central

    Lee, Hey-Kyoung; Kirkwood, Alfredo

    2011-01-01

    Discovery of long-term potentiation (LTP) in the dentate gyrus of the rabbit hippocampus by Bliss and Lømo opened up a whole new field to study activity-dependent long-term synaptic modifications in the brain. Since then hippocampal synapses have been a key model system to study the mechanisms of different forms of synaptic plasticity. At least for the postsynaptic forms of LTP and long-term depression (LTD), regulation of AMPA receptors (AMPARs) has emerged as a key mechanism. While many of the synaptic plasticity mechanisms uncovered in at the hippocampal synapses apply to synapses across diverse brain regions, there are differences in the mechanisms that often reveal the specific functional requirements of the brain area under study. Here we will review AMPAR regulation underlying synaptic plasticity in hippocampus and neocortex. The main focus of this review will be placed on postsynaptic forms of synaptic plasticity that impinge on the regulation of AMPARs using hippocampal CA1 and primary sensory cortices as examples. And through the comparison, we will highlight the key similarities and functional differences between the two synapses. PMID:21856433

  13. 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.

  14. Synaptic AMPA receptor composition in development, plasticity and disease.

    PubMed

    Henley, Jeremy M; Wilkinson, Kevin A

    2016-06-01

    AMPA receptors (AMPARs) are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs, and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity and in response to neuronal stress in disease. Recently, the subunit dependence of AMPAR trafficking has been questioned, leading to a reappraisal of this field. In this Review, we discuss what is known, uncertain, conjectured and unknown about the roles of the individual subunits, and how they affect AMPAR assembly, trafficking and function under both normal and pathological conditions. PMID:27080385

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

    PubMed

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

    2015-01-01

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

  16. 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

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

    PubMed

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

    2015-04-01

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

  18. 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

  19. 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. PMID:26107874

  20. 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

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

    PubMed

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

    2016-07-01

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

  2. Cytosolic tail sequences and subunit interactions are critical for synaptic localization of glutamate receptors.

    PubMed

    Chang, Howard Chia-Hao; Rongo, Christopher

    2005-05-01

    AMPA-type glutamate receptors mediate excitatory synaptic transmission in the nervous system. The receptor subunit composition and subcellular localization play an important role in regulating synaptic strength. GLR-1 and GLR-2 are the Caenorhabditis elegans subunits most closely related to the mammalian AMPA-type receptors. These subunits are expressed in overlapping sets of interneurons, and contain type-I PDZ binding motifs in their carboxy-terminal cytosolic tail sequences. We report that GLR-1 and GLR-2 may form a heteromeric complex, the localization of which depends on either GLR-1 or GLR-2 tail sequences. Subunit interactions alone can mediate synaptic localization as endogenous GLR-1, or GLR-2 subunits can rescue the localization defects of subunits lacking tail sequences. Moreover, GLR-2 cytosolic tail sequences are sufficient to confer synaptic localization on a heterologous reporter containing a single-transmembrane domain. The localization of this GLR-2 reporter requires both a PDZ-binding motif in the GLR-2 tail sequence, and sequences outside of this motif. The PDZ protein LIN-10 regulates the localization of the reporter through the sequences outside of the PDZ-binding motif. Our results suggest that multiple synaptic localization signals reside in the cytosolic tail sequence of the receptor subunits, and that channel assembly can rescue the synaptic localization defects of individual mutant subunits as long as there are also wild-type subunits in the receptor complex. PMID:15840655

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

    PubMed Central

    Morton, Robin A; Manuel, Nick A; Bulters, Diederick O; Cobb, Stuart R; Davies, Ceri H

    2001-01-01

    Both GABAB and muscarinic acetylcholine receptors (mAChRs) influence hippocampal-dependent mnemonic processing. Here the possibility of a direct interaction between GABAB receptors and mAChR-mediated synaptic responses has been studied using intracellular recording in rat hippocampal slices. The GABAB receptor agonist(−)-baclofen (5–10 μm) depressed an atropine-sensitive slow EPSP (EPSPM) and occluded the GABAB-receptor-mediated IPSP (IPSPB) which preceded it. These inhibitory effects were accompanied by postsynaptic hyperpolarization (9 ± 2 mV) and a reduction in cell input resistance (12 ± 3 %). The selective GABAB receptor antagonist CGP 55845A (1 μm) fully reversed the depressant effects of (−)-baclofen (5–10 μm) such that in the combined presence of (−)-baclofen and CGP 55845A the EPSPM was 134 ± 21 % of control. (−)-Baclofen (5–10 μm) caused a small (28 ± 11 %) inhibition of carbachol-induced (3.0 μm) postsynaptic depolarizations and increases in input resistance. CGP 55845A (1 μm) alone caused an increase in the amplitude of the EPSPM (253 ± 74 % of control) and blocked the IPSPB that preceded it. In contrast, the selective GABA uptake inhibitor NNC 05–0711 (10 μm) increased the amplitude of the IPSPB by 141 ± 38 % and depressed the amplitude of the EPSPM by 58 ± 10 %. This inhibition was abolished by CGP 55845A (1 μm). Taken together these data provide good evidence that synaptically released GABA activates GABAB receptors that inhibit mAChR-mediated EPSPs in hippocampal CA1 pyramidal neurones. The mechanism of inhibition may involve both pre- and postsynaptic elements. PMID:11559773

  4. Sortilin-related receptor SORCS3 is a postsynaptic modulator of synaptic depression and fear extinction.

    PubMed

    Breiderhoff, Tilman; Christiansen, Gitte B; Pallesen, Lone T; Vaegter, Christian; Nykjaer, Anders; Holm, Mai Marie; Glerup, Simon; Willnow, Thomas E

    2013-01-01

    SORCS3 is an orphan receptor of the VPS10P domain receptor family, a group of sorting and signaling receptors central to many pathways in control of neuronal viability and function. SORCS3 is highly expressed in the CA1 region of the hippocampus, but the relevance of this receptor for hippocampal activity remained absolutely unclear. Here, we show that SORCS3 localizes to the postsynaptic density and that loss of receptor activity in gene-targeted mice abrogates NMDA receptor-dependent and -independent forms of long-term depression (LTD). Consistent with a loss of synaptic retraction, SORCS3-deficient mice suffer from deficits in behavioral activities associated with hippocampal LTD, particularly from an accelerated extinction of fear memory. A possible molecular mechanism for SORCS3 in synaptic depression was suggested by targeted proteomics approaches that identified the ability of SORCS3 to functionally interact with PICK1, an adaptor that sorts glutamate receptors at the postsynapse. Faulty localization of PICK1 in SORCS3-deficient neurons argues for altered glutamate receptor trafficking as the cause of altered synaptic plasticity in the SORCS3-deficient mouse model. In conclusion, our studies have identified a novel function for VPS10P domain receptors in control of synaptic depression and suggest SORCS3 as a novel factor modulating aversive memory extinction. PMID:24069373

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

    PubMed

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

    2015-03-01

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

  6. 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

  7. Nogo Receptor Signaling Restricts Adult Neural Plasticity by Limiting Synaptic AMPA Receptor Delivery

    PubMed Central

    Jitsuki, Susumu; Nakajima, Waki; Takemoto, Kiwamu; Sano, Akane; Tada, Hirobumi; Takahashi-Jitsuki, Aoi; Takahashi, Takuya

    2016-01-01

    Experience-dependent plasticity is limited in the adult brain, and its molecular and cellular mechanisms are poorly understood. Removal of the myelin-inhibiting signaling protein, Nogo receptor (NgR1), restores adult neural plasticity. Here we found that, in NgR1-deficient mice, whisker experience-driven synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) insertion in the barrel cortex, which is normally complete by 2 weeks after birth, lasts into adulthood. In vivo live imaging by two-photon microscopy revealed more AMPAR on the surface of spines in the adult barrel cortex of NgR1-deficient than on those of wild-type (WT) mice. Furthermore, we observed that whisker stimulation produced new spines in the adult barrel cortex of mutant but not WT mice, and that the newly synthesized spines contained surface AMPAR. These results suggest that Nogo signaling limits plasticity by restricting synaptic AMPAR delivery in coordination with anatomical plasticity. PMID:26472557

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

    PubMed

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

    2016-09-01

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

  9. 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. PMID:23978820

  10. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists.

    PubMed

    Papouin, Thomas; Ladépêche, Laurent; Ruel, Jérôme; Sacchi, Silvia; Labasque, Marilyne; Hanini, Marwa; Groc, Laurent; Pollegioni, Loredano; Mothet, Jean-Pierre; Oliet, Stéphane H R

    2012-08-01

    N-methyl-d-aspartate receptors (NMDARs) are located in neuronal cell membranes at synaptic and extrasynaptic locations, where they are believed to mediate distinct physiological and pathological processes. Activation of NMDARs requires glutamate and a coagonist whose nature and impact on NMDAR physiology remain elusive. We report that synaptic and extrasynaptic NMDARs are gated by different endogenous coagonists, d-serine and glycine, respectively. The regionalized availability of the coagonists matches the preferential affinity of synaptic NMDARs for d-serine and extrasynaptic NMDARs for glycine. Furthermore, glycine and d-serine inhibit NMDAR surface trafficking in a subunit-dependent manner, which is likely to influence NMDARs subcellular location. Taking advantage of this coagonist segregation, we demonstrate that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only. Conversely, long-term depression requires both synaptic and extrasynaptic receptors. Our observations provide key insights into the operating mode of NMDARs, emphasizing functional distinctions between synaptic and extrasynaptic NMDARs in brain physiology. PMID:22863013

  11. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number

    PubMed Central

    Schnell, Eric; Sizemore, Max; Karimzadegan, Siavash; Chen, Lu; Bredt, David S.; Nicoll, Roger A.

    2002-01-01

    Excitatory synapses in the brain exhibit a remarkable degree of functional plasticity, which largely reflects changes in the number of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). However, mechanisms involved in recruiting AMPARs to synapses are unknown. Here we use hippocampal slice cultures and biolistic gene transfections to study the targeting of AMPARs to synapses. We show that AMPARs are localized to synapses through direct binding of the first two PDZ domains of synaptic PSD-95 (postsynaptic density protein of 95 kDa) to the AMPAR-associated protein, stargazin. Increasing the level of synaptic PSD-95 recruits new AMPARs to synapses without changing the number of surface AMPARs. At the same time, we show that stargazin overexpression drastically increases the number of extra-synaptic AMPARs, but fails to alter synaptic currents if synaptic PSD-95 levels are kept constant. Finally, we make compensatory mutations to both PSD-95 and stargazin to demonstrate the central role of direct interactions between them in determining the number of synaptic AMPARs. PMID:12359873

  12. 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

  13. 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. PMID:22131383

  14. 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

  15. Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity.

    PubMed

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

    2015-03-01

    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

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

    PubMed Central

    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 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. PMID:23978820

  17. NMDA-Receptor Activation but Not Ion Flux Is Required for Amyloid-Beta Induced Synaptic Depression

    PubMed Central

    Tamburri, Albert; Dudilot, Anthony; Licea, Sara; Bourgeois, Catherine; Boehm, Jannic

    2013-01-01

    Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ) in the etiology of Alzheimer’s disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor. PMID:23750255

  18. Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons.

    PubMed

    Rumbaugh, Gavin; Sia, Gek-Ming; Garner, Craig C; Huganir, Richard L

    2003-06-01

    Members of the synapse-associated protein-97 (SAP97) family of scaffold proteins have been implicated as central organizers of synaptic junctions to build macromolecular signaling complexes around specific postsynaptic neurotransmitter receptors. In this regard, SAP97 has been suggested to regulate the synaptic localization of glutamate receptor type 1 subunits of the AMPA-type glutamate receptors. To test this hypothesis directly, we assessed the effects of SAP97 overexpression on surface expression of synaptic AMPA receptors. We find that recombinant SAP97 not only becomes concentrated at synaptic junctions but also leads to an increase in synaptic AMPA receptors, spine enlargement, and an increase in miniature EPSC (mEPSC) frequency, indicating that SAP97 has both postsynaptic and presynaptic effects on synaptic transmission. Synaptic targeting of SAP97, increased surface AMPA receptors, and increased mEPSC frequency are dependent on the presence of specific alternatively spliced sequences in SAP97 that encode a protein 4.1 binding site. These results suggest that SAP97 can affect the synaptic recruitment of AMPA receptors and spine morphology and that these effects may be regulated by alternative splicing. PMID:12805297

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

    PubMed Central

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

    2008-01-01

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

  20. Nitric Oxide–mediated Modulation of Synaptic Activity by Astrocytic P2Y Receptors

    PubMed Central

    Mehta, Bhupesh; Begum, Gulnaz; Joshi, Nanda B.; Joshi, Preeti G.

    2008-01-01

    We investigated the mechanism of synaptic suppression by P2Y receptors in mixed hippocampal cultures wherein networked neurons exhibit synchronized Ca2+ oscillations (SCO) due to spontaneous glutamatergic synaptic transmission. Pharmacological studies suggested that SCO suppression was mediated by P2Y2/P2Y4 receptors. Immunostaining studies and characterization of ATP/UTP-stimulated Ca2+ responses in solitary neurons and astrocytes revealed that the SCO attenuation was effectuated by astrocytes. We demonstrate that nitric oxide released from activated astrocytes causes synaptic suppression by inhibiting neurotransmitter release. Physiological concentrations of ATP and UTP evoked NO production in astrocytes. SCO suppression was considerably diminished by removal of extracellular NO by membrane-impermeable scavenger c-PTIO or by pretreatment of cells with nitric oxide synthase inhibitor L-NAME. The nitric oxide donor DETA/NO effectively suppressed the SCO. ATP/UTP inhibited KCl-induced exocytosis at presynaptic terminals in an NO-dependent manner. In the absence of exogenously added ATP/UTP, both the NO scavenger and NOS inhibitor enhanced the frequency of SCO, implying that astrocytes release NO during spontaneous synaptic activity and exert a suppressive effect. We report for the first time that under physiological conditions astrocytes use NO as a messenger molecule to modulate the synaptic strength in the networked neurons. PMID:18725529

  1. Targeting of GLUR4-containing AMPA receptors to synaptic sites during in vitro classical conditioning.

    PubMed

    Mokin, M; Keifer, J

    2004-01-01

    The synaptic delivery of GluR4-containing AMPA receptors during in vitro classical conditioning of a neural correlate of an eyeblink response was examined by fluorescence imaging of punctate staining for glutamate receptor subunits and the presynaptic marker synaptophysin. There was a significant increase in GluR4-containing AMPA receptors to synaptic sites after conditioning as determined by colocalization of GluR4 subunit puncta with synaptophysin. Moreover, the trafficking of these receptor subunits requires NMDA receptor activation as it was blocked by D,L-2-amino-5-phosphonovaleric acid (AP-5). In contrast, colocalization of NR1 subunits with synaptophysin was stable regardless of whether the preparations had undergone conditioning or had been treated by AP-5. The enhanced colocalization of GluR4 and synaptophysin was accompanied by an increase in both the total number and size of puncta for both proteins, suggesting greater synthesis and aggregation during conditioning. Western blot analysis confirmed upregulation of synaptophysin and GluR4 following conditioning. These data support the hypothesis that GluR4-containing AMPA receptors are delivered to synaptic sites during conditioning. Further, they suggest coordinate presynaptic and postsynaptic modifications during in vitro classical conditioning. PMID:15350635

  2. Synaptic actions of neuropeptide FF in the rat parabrachial nucleus: interactions with opioid receptors.

    PubMed

    Chen, X; Zidichouski, J A; Harris, K H; Jhamandas, J H

    2000-08-01

    The pontine parabrachial nucleus (PBN) receives both opioid and Neuropeptide FF (NPFF) projections from the lower brain stem and/or the spinal cord. Because of this anatomical convergence and previous evidence that NPFF displays both pro- and anti-opioid activities, this study examined the synaptic effects of NPFF in the PBN and the mechanisms underlying these effects using an in vitro brain slice preparation and the nystatin-perforated patch-clamp recording technique. Under voltage-clamp conditions, NPFF reversibly reduced the evoked excitatory postsynaptic currents (EPSCs) in a dose-dependent fashion. This effect was not accompanied by apparent changes in the holding current, the current-voltage relationship or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced inward currents in the PBN cells. When a paired-pulse protocol was used, NPFF increased the ratio of these synaptic currents. Analysis of miniature EPSCs showed that NPFF caused a rightward shift in the frequency-distribution curve, whereas the amplitude-distribution curve remained unchanged. Collectively, these experiments indicate that NPFF reduces the evoked EPSCs through a presynaptic mechanism of action. The synaptic effects induced by NPFF (5 microM) could not be blocked by the specific mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (1 microM), but application of delta-opioid receptor antagonist Tyr-Tic-Phe-Phe (5 microM) almost completely prevented effects of NPFF. Moreover, the delta-opioid receptor agonist, Deltorphin (1 microM), mimicked the effects as NPFF and also occluded NPFF's actions on synaptic currents. These results indicate that NPFF modulates excitatory synaptic transmission in the PBN through an interaction with presynaptic delta-opioid receptors. These observations provide a cellular basis for NPFF enhancement of the antinociceptive effects consequent to central activation of delta-opioid receptors. PMID:10938301

  3. 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

  4. Ethanol Regulation of Synaptic GABAA α4 Receptors Is Prevented by Protein Kinase A Activation.

    PubMed

    Carlson, Stephen L; Bohnsack, John Peyton; Morrow, A Leslie

    2016-04-01

    Ethanol alters GABAA receptor trafficking and function through activation of protein kinases, and these changes may underlie ethanol dependence and withdrawal. In this study, we used subsynaptic fraction techniques and patch-clamp electrophysiology to investigate the biochemical and functional effects of protein kinase A (PKA) and protein kinase C (PKC) activation by ethanol on synaptic GABAA α4 receptors, a key target of ethanol-induced changes. Rat cerebral cortical neurons were grown for 18 days in vitro and exposed to ethanol and/or kinase modulators for 4 hours, a paradigm that recapitulates GABAergic changes found after chronic ethanol exposure in vivo. PKA activation by forskolin or rolipram during ethanol exposure prevented increases in P2 fraction α4 subunit abundance, whereas inhibiting PKA had no effect. Similarly, in the synaptic fraction, activation of PKA by rolipram in the presence of ethanol prevented the increase in synaptic α4 subunit abundance, whereas inhibiting PKA in the presence of ethanol was ineffective. Conversely, PKC inhibition in the presence of ethanol prevented the ethanol-induced increases in synaptic α4 subunit abundance. Finally, we found that either activating PKA or inhibiting PKC in the presence of ethanol prevented the ethanol-induced decrease in GABA miniature inhibitory postsynaptic current decay τ1, whereas inhibiting PKA had no effect. We conclude that PKA and PKC have opposing effects in the regulation of synaptic α4 receptors, with PKA activation negatively modulating, and PKC activation positively modulating, synaptic α4 subunit abundance and function. These results suggest potential targets for restoring normal GABAergic functioning in the treatment of alcohol use disorders. PMID:26857960

  5. 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

  6. Facilitation of AMPA Receptor Synaptic Delivery as a Molecular Mechanism for Cognitive Enhancement

    PubMed Central

    Sánchez-Puelles, Cristina; Pereda-Peréz, Inmaculada; Franco, Ana; Sandi, Carmen; Suárez, Luz M.; Solís, José M.; Alonso-Nanclares, Lidia; Martín, Eduardo D.; Merino-Serrais, Paula; Borcel, Erika; Li, Shizhong; Chen, Yongshuo; Gonzalez-Soriano, Juncal; Berezin, Vladimir; Bock, Elisabeth; DeFelipe, Javier; Esteban, José A.

    2012-01-01

    Cell adhesion molecules and downstream growth factor-dependent signaling are critical for brain development and synaptic plasticity, and they have been linked to cognitive function in adult animals. We have previously developed a mimetic peptide (FGL) from the neural cell adhesion molecule (NCAM) that enhances spatial learning and memory in rats. We have now investigated the cellular and molecular basis of this cognitive enhancement, using biochemical, morphological, electrophysiological, and behavioral analyses. We have found that FGL triggers a long-lasting enhancement of synaptic transmission in hippocampal CA1 neurons. This effect is mediated by a facilitated synaptic delivery of AMPA receptors, which is accompanied by enhanced NMDA receptor-dependent long-term potentiation (LTP). Both LTP and cognitive enhancement are mediated by an initial PKC activation, which is followed by persistent CaMKII activation. These results provide a mechanistic link between facilitation of AMPA receptor synaptic delivery and improved hippocampal-dependent learning, induced by a pharmacological cognitive enhancer. PMID:22363206

  7. AMPA receptor signaling through BRAG2 and Arf6 critical for long-term synaptic depression.

    PubMed

    Scholz, Ralf; Berberich, Sven; Rathgeber, Louisa; Kolleker, Alexander; Köhr, Georg; Kornau, Hans-Christian

    2010-06-10

    Central nervous system synapses undergo activity-dependent alterations to support learning and memory. Long-term depression (LTD) reflects a sustained reduction of the synaptic AMPA receptor content based on targeted clathrin-mediated endocytosis. Here we report a current-independent form of AMPA receptor signaling, fundamental for LTD. We found that AMPA receptors directly interact via the GluA2 subunit with the synaptic protein BRAG2, which functions as a guanine-nucleotide exchange factor (GEF) for the coat-recruitment GTPase Arf6. BRAG2-mediated catalysis, controlled by ligand-binding and tyrosine phosphorylation of GluA2, activates Arf6 to internalize synaptic AMPA receptors upon LTD induction. Furthermore, acute blockade of the GluA2-BRAG2 interaction and targeted deletion of BRAG2 in mature hippocampal CA1 pyramidal neurons prevents LTD in CA3-to-CA1 cell synapses, irrespective of the induction pathway. We conclude that BRAG2-mediated Arf6 activation triggered by AMPA receptors is the convergent step of different forms of LTD, thus providing an essential mechanism for the control of vesicle formation by endocytic cargo. PMID:20547133

  8. Conformational signaling required for synaptic plasticity by the NMDA receptor complex.

    PubMed

    Aow, Jonathan; Dore, Kim; Malinow, Roberto

    2015-11-24

    The NMDA receptor (NMDAR) is known to transmit important information by conducting calcium ions. However, some recent studies suggest that activation of NMDARs can trigger synaptic plasticity in the absence of ion flow. Does ligand binding transmit information to signaling molecules that mediate synaptic plasticity? Using Förster resonance energy transfer (FRET) imaging of fluorescently tagged proteins expressed in neurons, conformational signaling is identified within the NMDAR complex that is essential for downstream actions. Ligand binding transiently reduces FRET between the NMDAR cytoplasmic domain (cd) and the associated protein phosphatase 1 (PP1), requiring NMDARcd movement, and persistently reduces FRET between the NMDARcd and calcium/calmodulin-dependent protein kinase II (CaMKII), a process requiring PP1 activity. These studies directly monitor agonist-driven conformational signaling at the NMDAR complex required for synaptic plasticity. PMID:26553983

  9. The Sphingolipid Receptor S1PR2 Is a Receptor for Nogo-A Repressing Synaptic Plasticity

    PubMed Central

    Arzt, Michael E.; Weinmann, Oliver; Obermair, Franz J.; Pernet, Vincent; Zagrebelsky, Marta; Delekate, Andrea; Iobbi, Cristina; Zemmar, Ajmal; Ristic, Zorica; Gullo, Miriam; Spies, Peter; Dodd, Dana; Gygax, Daniel; Korte, Martin; Schwab, Martin E.

    2014-01-01

    Nogo-A is a membrane protein of the central nervous system (CNS) restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) as a Nogo-A-Δ20-specific receptor. Nogo-A-Δ20 binds S1PR2 on sites distinct from the pocket of the sphingolipid sphingosine 1-phosphate (S1P) and signals via the G protein G13, the Rho GEF LARG, and RhoA. Deleting or blocking S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth and cell spreading. Blockade of S1PR2 strongly enhances long-term potentiation (LTP) in the hippocampus of wild-type but not Nogo-A−/− mice, indicating a repressor function of the Nogo-A/S1PR2 axis in synaptic plasticity. A similar increase in LTP was also observed in the motor cortex after S1PR2 blockade. We propose a novel signaling model in which a GPCR functions as a receptor for two structurally unrelated ligands, a membrane protein and a sphingolipid. Elucidating Nogo-A/S1PR2 signaling platforms will provide new insights into regulation of synaptic plasticity. PMID:24453941

  10. Dysregulation of synaptic and extrasynaptic N-methyl-D-aspartate receptors induced by amyloid-β.

    PubMed

    Wang, Zhi-Cong; Zhao, Jie; Li, Shao

    2013-12-01

    The toxicity of amyloid-beta (Aβ) is strongly associated with Alzheimer's disease (AD), which has a high incidence in the elderly worldwide. Recent evidence showed that alteration in the activity of N-methyl-D-aspartate receptors (NMDARs) plays a key role in Aβ-induced neurotoxicity. However, the activation of synaptic and extrasynaptic NMDARs has distinct consequences for plasticity, gene regulation, neuronal death, and Aβ production. This review focuses on the dysregulation of synaptic and extrasynaptic NMDARs induced by Aβ. On one hand, Aβ downregulates the synaptic NMDAR response by promoting NMDAR endocytosis, leading to either neurotoxicity or neuroprotection. On the other hand, Aβ enhances the activation of extrasynaptic NMDARs by decreasing neuronal glutamate uptake and inducing glutamate spillover, subsequently causing neurotoxicity. In addition, selective enhancement of synaptic activity by low doses of NMDA, or reduction of extrasynaptic activity by memantine, a non-competitive NMDAR antagonist, halts Aβ-induced neurotoxicity. Therefore, future neuroprotective drugs for AD should aim at both the enhancement of synaptic activity and the disruption of extrasynaptic NMDAR-dependent death signaling. PMID:24136243

  11. Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory.

    PubMed

    Hausrat, Torben J; Muhia, Mary; Gerrow, Kimberly; Thomas, Philip; Hirdes, Wiebke; Tsukita, Sachiko; Heisler, Frank F; Herich, Lena; Dubroqua, Sylvain; Breiden, Petra; Feldon, Joram; Schwarz, Jürgen R; Yee, Benjamin K; Smart, Trevor G; Triller, Antoine; Kneussel, Matthias

    2015-01-01

    Neurotransmitter receptor density is a major variable in regulating synaptic strength. Receptors rapidly exchange between synapses and intracellular storage pools through endocytic recycling. In addition, lateral diffusion and confinement exchanges surface membrane receptors between synaptic and extrasynaptic sites. However, the signals that regulate this transition are currently unknown. GABAA receptors containing α5-subunits (GABAAR-α5) concentrate extrasynaptically through radixin (Rdx)-mediated anchorage at the actin cytoskeleton. Here we report a novel mechanism that regulates adjustable plasma membrane receptor pools in the control of synaptic receptor density. RhoA/ROCK signalling regulates an activity-dependent Rdx phosphorylation switch that uncouples GABAAR-α5 from its extrasynaptic anchor, thereby enriching synaptic receptor numbers. Thus, the unphosphorylated form of Rdx alters mIPSCs. Rdx gene knockout impairs reversal learning and short-term memory, and Rdx phosphorylation in wild-type mice exhibits experience-dependent changes when exposed to novel environments. Our data suggest an additional mode of synaptic plasticity, in which extrasynaptic receptor reservoirs supply synaptic GABAARs. PMID:25891999

  12. Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory

    PubMed Central

    Hausrat, Torben J.; Muhia, Mary; Gerrow, Kimberly; Thomas, Philip; Hirdes, Wiebke; Tsukita, Sachiko; Heisler, Frank F.; Herich, Lena; Dubroqua, Sylvain; Breiden, Petra; Feldon, Joram; Schwarz, Jürgen R; Yee, Benjamin K.; Smart, Trevor G.; Triller, Antoine; Kneussel, Matthias

    2015-01-01

    Neurotransmitter receptor density is a major variable in regulating synaptic strength. Receptors rapidly exchange between synapses and intracellular storage pools through endocytic recycling. In addition, lateral diffusion and confinement exchanges surface membrane receptors between synaptic and extrasynaptic sites. However, the signals that regulate this transition are currently unknown. GABAA receptors containing α5-subunits (GABAAR-α5) concentrate extrasynaptically through radixin (Rdx)-mediated anchorage at the actin cytoskeleton. Here we report a novel mechanism that regulates adjustable plasma membrane receptor pools in the control of synaptic receptor density. RhoA/ROCK signalling regulates an activity-dependent Rdx phosphorylation switch that uncouples GABAAR-α5 from its extrasynaptic anchor, thereby enriching synaptic receptor numbers. Thus, the unphosphorylated form of Rdx alters mIPSCs. Rdx gene knockout impairs reversal learning and short-term memory, and Rdx phosphorylation in wild-type mice exhibits experience-dependent changes when exposed to novel environments. Our data suggest an additional mode of synaptic plasticity, in which extrasynaptic receptor reservoirs supply synaptic GABAARs. PMID:25891999

  13. Maximum likelihood estimation of biophysical parameters of synaptic receptors from macroscopic currents

    PubMed Central

    Stepanyuk, Andrey; Borisyuk, Anya; Belan, Pavel

    2014-01-01

    Dendritic integration and neuronal firing patterns strongly depend on biophysical properties of synaptic ligand-gated channels. However, precise estimation of biophysical parameters of these channels in their intrinsic environment is complicated and still unresolved problem. Here we describe a novel method based on a maximum likelihood approach that allows to estimate not only the unitary current of synaptic receptor channels but also their multiple conductance levels, kinetic constants, the number of receptors bound with a neurotransmitter, and the peak open probability from experimentally feasible number of postsynaptic currents. The new method also improves the accuracy of evaluation of unitary current as compared to the peak-scaled non-stationary fluctuation analysis, leading to a possibility to precisely estimate this important parameter from a few postsynaptic currents recorded in steady-state conditions. Estimation of unitary current with this method is robust even if postsynaptic currents are generated by receptors having different kinetic parameters, the case when peak-scaled non-stationary fluctuation analysis is not applicable. Thus, with the new method, routinely recorded postsynaptic currents could be used to study the properties of synaptic receptors in their native biochemical environment. PMID:25324721

  14. SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity

    PubMed Central

    Chamberlain, Sophie E L; González-González, Inmaculada M; Wilkinson, Kevin A; Konopacki, Filip A; Kantamneni, Sriharsha; Henley, Jeremy M; Mellor, Jack R

    2012-01-01

    Summary Phosphorylation or SUMOylation of the kainate receptor (KAR) subunit GluK2 have both individually been shown to regulate KAR surface expression. However, it is unknown if phosphorylation and SUMOylation of GluK2 are important for activity-dependent KAR synaptic plasticity. Here, we show that PKC-mediated phosphorylation of GluK2 at serine 868 promotes GluK2 SUMOylation at lysine 886 and that both these events are necessary for the internalization of GluK2 containing KARs that occurs during long-term depression of KAR-mediated synaptic transmission at rat hippocampal mossy fiber synapses. Conversely, phosphorylation of GluK2 at serine 868 in the absence of SUMOylation leads to an increase in KAR surface expression by facilitating receptor recycling between endosomal compartments and the plasma membrane. Thus, we describe a role for the dynamic control of synaptic SUMOylation in the regulation of KAR synaptic transmission and plasticity. PMID:22522402

  15. 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. PMID:23576886

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

    PubMed

    Matott, Michael P; Kline, David D

    2016-03-15

    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

  18. NMDA Receptor-Dependent Synaptic Reinforcement as a Crucial Process for Memory Consolidation

    NASA Astrophysics Data System (ADS)

    Shimizu, Eiji; Tang, Ya-Ping; Rampon, Claire; Tsien, Joe Z.

    2000-11-01

    The hippocampal CA1 region is crucial for converting new memories into long-term memories, a process believed to continue for week(s) after initial learning. By developing an inducible, reversible, and CA1-specific knockout technique, we could switch N-methyl-D-aspartate (NMDA) receptor function off or on in CA1 during the consolidation period. Our data indicate that memory consolidation depends on the reactivation of the NMDA receptor, possibly to reinforce site-specific synaptic modifications to consolidate memory traces. Such a synaptic reinforcement process may also serve as a cellular means by which the new memory is transferred from the hippocampus to the cortex for permanent storage.

  19. Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors

    PubMed Central

    Maltese, M.; Martella, G.; Madeo, G.; Fagiolo, I.; Tassone, A.; Ponterio, G.; Sciamanna, G.; Burbaud, P.; Conn, P.J.; Bonsi, P.; Pisani, A.

    2014-01-01

    Background Broad spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. Methods We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a+/Δgag) mice heterozygous for ΔE-torsinA and their controls (Tor1a+/+ mice). Results Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a+/Δgag mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1-preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the non-selective antagonists orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1-dependent potentiation of NMDA current recorded from striatal neurons. Conclusions Our study demonstrate that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder. PMID:25195914

  20. 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

  1. 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.

  2. Identification of the synaptic vesicle glycoprotein 2 receptor binding site in botulinum neurotoxin A.

    PubMed

    Strotmeier, Jasmin; Mahrhold, Stefan; Krez, Nadja; Janzen, Constantin; Lou, Jianlong; Marks, James D; Binz, Thomas; Rummel, Andreas

    2014-04-01

    Botulinum neurotoxins (BoNTs) inhibit neurotransmitter release by hydrolysing SNARE proteins. The most important serotype BoNT/A employs the synaptic vesicle glycoprotein 2 (SV2) isoforms A-C as neuronal receptors. Here, we identified their binding site by blocking SV2 interaction using monoclonal antibodies with characterised epitopes within the cell binding domain (HC). The site is located on the backside of the conserved ganglioside binding pocket at the interface of the HCC and HCN subdomains. The dimension of the binding pocket was characterised in detail by site directed mutagenesis allowing the development of potent inhibitors as well as modifying receptor binding properties. PMID:24583011

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

    PubMed

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

    2015-03-01

    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

  4. Effects of testosterone on synaptic plasticity mediated by androgen receptors in male SAMP8 mice.

    PubMed

    Jia, Jian-Xin; Cui, Cheng-Li; Yan, Xu-Sheng; Zhang, Bai-Feng; Song, Wei; Huo, Dong-Sheng; Wang, He; Yang, Zhan-Jun

    2016-01-01

    Synaptic changes are closely associated with cognitive deficits. In addition, testosterone (T) is known to exert regulative effects on synaptic plasticity. T may improve cognitive deficits in Alzheimer's disease (AD) patients, but the underlying mechanisms of androgenic action on cognitive performance remain unclear. The aim of this study was thus to examine the protective mechanism attributed to T on cognitive performance in an AD senescence, accelerated mouse prone 8 (SAMP8) animal model. Using Golgi staining to quantify the dendritic spine density in hippocampal CA1 region, molecular biomarkers of synapse function were analyzed using immunohistochemistry and western blot. T significantly increased the dendritic spine density in hippocampal CA1 region, while flutamide (F) inhibited these T-mediated effects. Immunohistochemistry and western blot analysis showed that the expression levels of brain derived neurotrophic factor (BDNF), postsynaptic density 95 (PSD-95), and p-cyclic-AMP response element binding protein (CREB)/CREB levels were significantly elevated in the T group, but F reduced the T-induced effects in these biomarkers to control levels. There were no significant differences in the expression levels of PSD-95, BDNF, and p-CREB/CREB between C and F. These findings indicate that the effects of T on improvement in synaptic plasticity were mediated via androgen receptor (AR). It is conceivable that new treatments targeted toward preventing synaptic pathology in AD may involve the use of androgen-acting drugs. PMID:27599230

  5. 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

  6. Fractional vesamicol receptor occupancy and acetylcholine active transport inhibition in synaptic vesicles.

    PubMed

    Kaufman, R; Rogers, G A; Fehlmann, C; Parsons, S M

    1989-09-01

    Vesamicol [(-)-(trans)-2-(4-phenylpiperidino)cyclohexanol] receptor binding and inhibition of acetylcholine (AcCh) active transport by cholinergic synaptic vesicles that were isolated from Torpedo electric organ were studied for 23 vesamicol enantiomers, analogues, and other drugs. Use of trace [3H]vesamicol and [14C]AcCh allowed simultaneous determination of the concentrations of enantiomer, analogue, or drug required to half-saturate the vesamicol receptor (Ki) and to half-inhibit transport (IC50), respectively. Throughout a wide range of potencies for different compounds, the Ki/IC50 ratios varied from 1.5 to 24. Compounds representative of the diverse structures studied, namely deoxyvesamicol, chloroquine, and levorphanol, were competitive inhibitors of vesamicol binding. It is concluded that many drugs can bind to the vesamicol receptor and binding to only a small fraction of the receptors can result in AcCh active transport inhibition. Possible mechanisms for this effect are discussed. PMID:2550778

  7. Spontaneous Synaptic Activation of Muscarinic Receptors by Striatal Cholinergic Neuron Firing.

    PubMed

    Mamaligas, Aphroditi A; Ford, Christopher P

    2016-08-01

    Cholinergic interneurons (CHIs) play a major role in motor and learning functions of the striatum. As acetylcholine does not directly evoke postsynaptic events at most striatal synapses, it remains unclear how postsynaptic cholinergic receptors encode the firing patterns of CHIs in the striatum. To examine the dynamics of acetylcholine release, we used optogenetics and paired recordings from CHIs and medium spiny neurons (MSNs) virally overexpressing G-protein-activated inwardly rectifying potassium (GIRK) channels. Due to the efficient coupling between endogenous muscarinic receptors and GIRK channels, we found that firing of individual CHIs resulted in monosynaptic spontaneous inhibitory post-synaptic currents (IPSCs) in MSNs. Paired CHI-MSN recordings revealed that the high probability of acetylcholine release at these synapses allowed muscarinic receptors to faithfully encode physiological activity patterns from individual CHIs without failure. These results indicate that muscarinic receptors in striatal output neurons reliably decode CHI firing. PMID:27373830

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

    PubMed

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

    2009-08-01

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

  9. Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss

    PubMed Central

    Birnbaum, J H; Bali, J; Rajendran, L; Nitsch, R M; Tackenberg, C

    2015-01-01

    Synaptic loss is one of the major features of Alzheimer's disease (AD) and correlates with the degree of dementia. N-methyl-d-aspartate receptors (NMDARs) have been shown to mediate downstream effects of the β-amyloid peptide (Aβ) in AD models. NMDARs can trigger intracellular cascades via Ca2+ entry, however, also Ca2+-independent (metabotropic) functions of NMDARs have been described. We aimed to determine whether ionotropic or metabotropic NMDAR signaling is required for the induction of synaptic loss by Aβ. We show that endogenous Aβ as well as exogenously added synthetic Aβ oligomers induced dendritic spine loss and reductions in pre- and postsynaptic protein levels in hippocampal slice cultures. Synaptic alterations were mitigated by blocking glutamate binding to NMDARs using NMDAR antagonist APV, but not by preventing ion flux with Ca2+ chelator BAPTA or open-channel blockers MK-801 or memantine. Aβ increased the activity of p38 MAPK, a kinase involved in long-term depression and inhibition of p38 MAPK abolished the loss of dendritic spines. Aβ-induced increase of p38 MAPK activity was prevented by APV but not by BAPTA, MK-801 or memantine treatment highlighting the role of glutamate binding to NMDARs but not Ca2+ flux for synaptic degeneration by Aβ. We further show that treatment with the G protein inhibitor pertussis toxin (PTX) did not prevent dendritic spine loss in the presence of Aβ oligomers. Our data suggest that Aβ induces the activation of p38 MAPK and subsequent synaptic loss through Ca2+ flux- and G protein-independent mechanisms. PMID:26086964

  10. Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss.

    PubMed

    Birnbaum, J H; Bali, J; Rajendran, L; Nitsch, R M; Tackenberg, C

    2015-01-01

    Synaptic loss is one of the major features of Alzheimer's disease (AD) and correlates with the degree of dementia. N-methyl-D-aspartate receptors (NMDARs) have been shown to mediate downstream effects of the β-amyloid peptide (Aβ) in AD models. NMDARs can trigger intracellular cascades via Ca(2+) entry, however, also Ca(2+)-independent (metabotropic) functions of NMDARs have been described. We aimed to determine whether ionotropic or metabotropic NMDAR signaling is required for the induction of synaptic loss by Aβ. We show that endogenous Aβ as well as exogenously added synthetic Aβ oligomers induced dendritic spine loss and reductions in pre- and postsynaptic protein levels in hippocampal slice cultures. Synaptic alterations were mitigated by blocking glutamate binding to NMDARs using NMDAR antagonist APV, but not by preventing ion flux with Ca(2+) chelator BAPTA or open-channel blockers MK-801 or memantine. Aβ increased the activity of p38 MAPK, a kinase involved in long-term depression and inhibition of p38 MAPK abolished the loss of dendritic spines. Aβ-induced increase of p38 MAPK activity was prevented by APV but not by BAPTA, MK-801 or memantine treatment highlighting the role of glutamate binding to NMDARs but not Ca(2+) flux for synaptic degeneration by Aβ. We further show that treatment with the G protein inhibitor pertussis toxin (PTX) did not prevent dendritic spine loss in the presence of Aβ oligomers. Our data suggest that Aβ induces the activation of p38 MAPK and subsequent synaptic loss through Ca(2+) flux- and G protein-independent mechanisms. PMID:26086964

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

    PubMed

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

    2016-05-01

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

  12. Group I Metabotropic Glutamate Receptor-Mediated Gene Transcription and Implications for Synaptic Plasticity and Diseases

    PubMed Central

    Wang, Hansen; Zhuo, Min

    2012-01-01

    Stimulation of group I metabotropic glutamate receptors (mGluRs) initiates a wide variety of signaling pathways. Group I mGluR activation can regulate gene expression at both translational and transcriptional levels, and induces translation or transcription-dependent synaptic plastic changes in neurons. The group I mGluR-mediated translation-dependent neural plasticity has been well reviewed. In this review, we will highlight group I mGluR-induced gene transcription and its role in synaptic plasticity. The signaling pathways (PKA, CaMKs, and MAPKs) which have been shown to link group I mGluRs to gene transcription, the relevant transcription factors (CREB and NF-κB), and target proteins (FMRP and ARC) will be documented. The significance and future direction for characterizing group I mGluR-mediated gene transcription in fragile X syndrome, schizophrenia, drug addiction, and other neurological disorders will also be discussed. PMID:23125836

  13. Neurotransmitters and synaptic components in the Merkel cell-neurite complex, a gentle touch receptor

    PubMed Central

    Maksimovic, Srdjan; Baba, Yoshichika; Lumpkin, Ellen A.

    2013-01-01

    Merkel cells are an enigmatic group of rare cells found in the skin of vertebrates. Most make contacts with somatosensory afferents to form Merkel cell-neurite complexes, which are gentle-touch receptors that initiate slowly adapting type I responses. The function of Merkel cells within the complex remains debated despite decades of research. Numerous anatomical studies demonstrate that Merkel cells form synaptic-like contacts with sensory afferent terminals. Moreover, recent molecular analysis reveals that Merkel cells express dozens of presynaptic molecules that are essential for synaptic vesicle release in neurons. Merkel cells also produce a host of neuro-active substances that can act as fast excitatory neurotransmitters or neuromodulators. Here, we review the major neurotransmitters found in Merkel cells and discuss these findings in relation to the potential function of Merkel cells in touch reception. PMID:23530998

  14. Coordinated activation of distinct Ca(2+) sources and metabotropic glutamate receptors encodes Hebbian synaptic plasticity.

    PubMed

    Tigaret, Cezar M; Olivo, Valeria; Sadowski, Josef H L P; Ashby, Michael C; Mellor, Jack R

    2016-01-01

    At glutamatergic synapses, induction of associative synaptic plasticity requires time-correlated presynaptic and postsynaptic spikes to activate postsynaptic NMDA receptors (NMDARs). The magnitudes of the ensuing Ca2+ transients within dendritic spines are thought to determine the amplitude and direction of synaptic change. In contrast, we show that at mature hippocampal Schaffer collateral synapses the magnitudes of Ca2+ transients during plasticity induction do not match this rule. Indeed, LTP induced by time-correlated pre- and postsynaptic spikes instead requires the sequential activation of NMDARs followed by voltage-sensitive Ca2+ channels within dendritic spines. Furthermore, LTP requires inhibition of SK channels by mGluR1, which removes a negative feedback loop that constitutively regulates NMDARs. Therefore, rather than being controlled simply by the magnitude of the postsynaptic calcium rise, LTP induction requires the coordinated activation of distinct sources of Ca2+ and mGluR1-dependent facilitation of NMDAR function. PMID:26758963

  15. Coordinated activation of distinct Ca2+ sources and metabotropic glutamate receptors encodes Hebbian synaptic plasticity

    PubMed Central

    Tigaret, Cezar M.; Olivo, Valeria; Sadowski, Josef H.L.P.; Ashby, Michael C.; Mellor, Jack R.

    2016-01-01

    At glutamatergic synapses, induction of associative synaptic plasticity requires time-correlated presynaptic and postsynaptic spikes to activate postsynaptic NMDA receptors (NMDARs). The magnitudes of the ensuing Ca2+ transients within dendritic spines are thought to determine the amplitude and direction of synaptic change. In contrast, we show that at mature hippocampal Schaffer collateral synapses the magnitudes of Ca2+ transients during plasticity induction do not match this rule. Indeed, LTP induced by time-correlated pre- and postsynaptic spikes instead requires the sequential activation of NMDARs followed by voltage-sensitive Ca2+ channels within dendritic spines. Furthermore, LTP requires inhibition of SK channels by mGluR1, which removes a negative feedback loop that constitutively regulates NMDARs. Therefore, rather than being controlled simply by the magnitude of the postsynaptic calcium rise, LTP induction requires the coordinated activation of distinct sources of Ca2+ and mGluR1-dependent facilitation of NMDAR function. PMID:26758963

  16. NAAG fails to antagonize synaptic and extrasynaptic NMDA receptors in cerebellar granule neurons.

    PubMed

    Losi, G; Vicini, S; Neale, J

    2004-03-01

    The peptide transmitter N-acetylaspartylglutamate (NAAG) selectively activates the group II metabotropic glutamate receptors. Several reports also suggest that this peptide acts as a partial agonist at N-methyl-D-aspartate (NMDA) receptors but its putative antagonist effects have not been directly tested. To do this, we used whole cell recordings from cerebellar granule cells (CGC) in culture that allow the highest possible resolution of NMDA channel activation. When CGC were activated with equimolar concentrations of NMDA and NAAG, the peptide failed to alter the peak current elicited by NMDA. Very high concentrations of NAAG (100-200 microM) did not significantly reduce the current elicited by 10 microM NMDA or 0.1 microM glutamate, while 400 microM NAAG produced only a very small (less than 15%) reduction in these whole cell currents. Similarly, NAAG (400 microM) failed to significantly alter the average decay time constant or the peak amplitude of NMDA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs). We conclude that high concentrations of the peptide do not exert physiologically relevant antagonist actions on synaptic NMDA receptor activation following vesicular release of glutamate. As an agonist, purified NAAG was found to be at least 10,000-fold less potent than glutamate in increasing "background" current via NMDA receptors on CGC. Inasmuch as it is difficult to confirm that NAAG preparations are completely free from contamination with glutamate at the 0.01% level, the peptide itself appears unlikely to have a direct agonist activity at the NMDA receptor subtypes found in CGC. Recent reports indicate that enhancing the activity of endogenous NAAG may be an important therapeutic approach to excitotoxicity and chronic pain perception. These effects are likely mediated by group II mGluRs, not NMDA receptors. PMID:14975672

  17. Colocalization of synaptic GABA(C)-receptors with GABA (A)-receptors and glycine-receptors in the rodent central nervous system.

    PubMed

    Frazao, Renata; Nogueira, Maria Ines; Wässle, Heinz

    2007-10-01

    Fast inhibition in the nervous system is preferentially mediated by GABA- and glycine-receptors. Two types of ionotropic GABA-receptor, the GABA(A)-receptor and GABA(C)-receptor, have been identified; they have specific molecular compositions, different sensitivities to GABA, different kinetics, and distinct pharmacological profiles. We have studied, by immunocytochemistry, the synaptic localization of glycine-, GABA(A)-, and GABA(C)-receptors in rodent retina, spinal cord, midbrain, and brain-stem. Antibodies specific for the alpha1 subunit of the glycine-receptor, the gamma2 subunit of the GABA(A)-receptor, and the rho subunits of the GABA(C)-receptor have been applied. Using double-immunolabeling, we have determined whether these receptors are expressed at the same postsynaptic sites. In the retina, no such colocalization was observed. However, in the spinal cord, we found the colocalization of glycine-receptors with GABA(A)- or GABA(C)-receptors and the colocalization of GABA(A)- and GABA(C)-receptors in approximately 25% of the synapses. In the midbrain and brain-stem, GABA(A)- and GABA(C)-receptors were colocalized in 10%-15% of the postsynaptic sites. We discuss the possible expression of heteromeric (hybrid) receptors assembled from GABA(A)- and GABA(C)-receptor subunits. Our results suggest that GABA(A)- and GABA(C)-receptors are colocalized in a minority of synapses of the central nervous system. PMID:17610086

  18. Role of Spinophilin in Group I Metabotropic Glutamate Receptor Endocytosis, Signaling, and Synaptic Plasticity.

    PubMed

    Di Sebastiano, Andrea R; Fahim, Sandra; Dunn, Henry A; Walther, Cornelia; Ribeiro, Fabiola M; Cregan, Sean P; Angers, Stephane; Schmid, Susanne; Ferguson, Stephen S G

    2016-08-19

    Activation of Group I metabotropic glutamate receptors (mGluRs) activates signaling cascades, resulting in calcium release from intracellular stores, ERK1/2 activation, and long term changes in synaptic activity that are implicated in learning, memory, and neurodegenerative diseases. As such, elucidating the molecular mechanisms underlying Group I mGluR signaling is important for understanding physiological responses initiated by the activation of these receptors. In the current study, we identify the multifunctional scaffolding protein spinophilin as a novel Group I mGluR-interacting protein. We demonstrate that spinophilin interacts with the C-terminal tail and second intracellular loop of Group I mGluRs. Furthermore, we show that interaction of spinophilin with Group I mGluRs attenuates receptor endocytosis and phosphorylation of ERK1/2, an effect that is dependent upon the interaction of spinophilin with the C-terminal PDZ binding motif encoded by Group I mGluRs. Spinophilin knock-out results in enhanced mGluR5 endocytosis as well as increased ERK1/2, AKT, and Ca(2+) signaling in primary cortical neurons. In addition, the loss of spinophilin expression results in impaired mGluR5-stimulated LTD. Our results indicate that spinophilin plays an important role in regulating the activity of Group I mGluRs as well as their influence on synaptic activity. PMID:27358397

  19. Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors.

    PubMed

    Mu, Yuanyue; Otsuka, Takeshi; Horton, April C; Scott, Derek B; Ehlers, Michael D

    2003-10-30

    Activity-dependent targeting of NMDA receptors (NMDARs) is a key feature of synapse formation and plasticity. Although mechanisms for rapid trafficking of glutamate receptors have been identified, the molecular events underlying chronic accumulation or loss of synaptic NMDARs have remained unclear. Here we demonstrate that activity controls NMDAR synaptic accumulation by regulating forward trafficking at the endoplasmic reticulum (ER). ER export is accelerated by the alternatively spliced C2' domain of the NR1 subunit and slowed by the C2 splice cassette. This mRNA splicing event at the C2/C2' site is activity dependent, with C2' variants predominating upon activity blockade and C2 variants abundant with increased activity. The switch to C2' accelerates NMDAR forward trafficking by enhancing recruitment of nascent NMDARs to ER exit sites via binding of a divaline motif within C2' to COPII coats. These results define a novel pathway underlying activity-dependent targeting of glutamate receptors, providing an unexpected mechanistic link between activity, mRNA splicing, and membrane trafficking during excitatory synapse modification. PMID:14642281

  20. Sensitivity of binding of high-affinity dopamine receptor radioligands to increased synaptic dopamine.

    PubMed

    Gatley, S J; Gifford, A N; Carroll, F I; Volkow, N D

    2000-12-15

    PET and SPECT studies have documented that D2 radioligands of moderate affinity, but not radioligands of high affinity, are sensitive to pharmacological challenges that alter synaptic dopamine levels. The objective of this work was to determine whether the brain kinetics of high-affinity radioligands for dopamine D1 ([(3)H]SCH 23390) and D2 ([(123)I]epidepride) receptors were altered by a prolonged elevation of synaptic dopamine induced by the potent cocaine analog RTI-55. Mice were injected intravenously with radioligands either 30 min after or 4 h before intraperitoneal administration of RTI-55 (2 mg/kg). In separate experiments, the pharmacological effects of RTI-55 were assessed biochemically by measuring uptake of dopamine in synaptosomes prepared from RTI-treated mice and behaviorally by monitoring locomotor activity. Consistent with the expected elevation of synaptic dopamine, RTI-55 induced a long-lasting decrement in dopamine uptake measured ex vivo, and a prolonged increase in locomotor activity. RTI-55 injected prior to the radioligands induced a significant (P < 0.05) increase in striatal concentration of [(123)I]epidepride at 15 min, relative to saline-treated controls, but there were no differences between the two groups at later time-points. For [(3)H]SCH 23390, both initial striatal uptake and subsequent clearance were slightly increased by preadministration of RTI-55. Administration of RTI-55 4 h after the radioligands (i.e., when it was presumed that a state of near equilibrium binding of the radioligands had been reached), was associated with a significant reduction of striatal radioactivity for both radiotracers. Our results are consistent with increased competition between dopamine and radioligand for binding to both D1 and D2 receptors after treatment with RTI-55. We suggest that the magnitude of the competition is reduced by failure of the receptor binding of high-affinity radioligands to rapidly attain equilibrium. PMID:11044896

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

    PubMed

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

    2011-02-15

    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

  2. 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

  3. Estrous Cycle-Dependent Phasic Changes in the Stoichiometry of Hippocampal Synaptic AMPA Receptors in Rats.

    PubMed

    Tada, Hirobumi; Koide, Mayu; Ara, Wakana; Shibata, Yusuke; Funabashi, Toshiya; Suyama, Kumiko; Goto, Takahisa; Takahashi, Takuya

    2015-01-01

    Cognitive function can be affected by the estrous cycle. However, the effect of the estrous cycle on synaptic functions is poorly understood. Here we show that in female rats, inhibitory-avoidance (IA) task (hippocampus-dependent contextual fear-learning task) drives GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) into the hippocampal CA3-CA1 synapses during all periods of the estrous cycle except the proestrous period, when estrogen levels are high. In addition, IA task failed to drive CP-AMPARs into the CA3-CA1 synapses of ovariectomized rats only when estrogen was present. Thus, changes in the stoichiometry of AMPA receptors during learning depend on estrogen levels. Furthermore, the induction of long-term potentiation (LTP) after IA task was prevented during the proestrous period, while intact LTP is still expressed after IA task during other period of the estrous cycle. Consistent with this finding, rats conditioned by IA training failed to acquire hippocampus-dependent Y-maze task during the proestrous period. On the other hand, during other estrous period, rats were able to learn Y-maze task after IA conditioning. These results suggest that high estrogen levels prevent the IA learning-induced delivery of CP-AMPARs into hippocampal CA3-CA1 synapses and limit synaptic plasticity after IA task, thus preventing the acquisition of additional learning. PMID:26121335

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

    PubMed

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

    2016-06-22

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

  5. 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. PMID:27418511

  6. 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

  7. Effects of white spirits on rat brain 5-HT receptor functions and synaptic remodeling.

    PubMed

    Lam, H R; Plenge, P; Jørgensen, O S

    2001-01-01

    Previously, inhalation exposure to different types of white spirit (i.e. complex mixtures of aliphatic, aromatic, alkyl aromatic, and naphthenic hydrocarbons) has been shown to induce neurochemical effects in rat brains. Especially, the serotonergic system was involved at the global, regional, and subcellular levels. This study investigates the effects of two types of white spirit on 5-hydroxytryptamine (5-HT) transporters (5-HTT), 5-HT(2A) and 5-HT(4) receptor expression in forebrain, and on neural cell adhesion molecule (NCAM) and 25-kDa synaptosomal associated protein (SNAP-25) concentrations when applied as indices for synaptic remodeling in forebrain, hippocampus, and entorhinal cortex. Male Wistar rats were exposed to 0, 400, or 800 ppm of aromatic (20 vol.% aromatic hydrocarbons) or dearomatized white spirit (catalytically hydrogenated white spirit) in the inhaled air for 6 h/day, 7 days/week for 3 weeks. The 5-HTT B(max) and K(d) were not affected. Both types of white spirit at 800 ppm decreased B(max) for the 5-HT(2A) receptor. The aromatic type decreased the K(d) of the 5-HT(2A) and 5-HT(4) receptors at 800 ppm. Aromatic white spirit did not affect NCAM or SNAP-25 concentrations or NCAM/SNAP-25 ratio in forebrain, whereas NCAM increased in hippocampus and the NCAM/SNAP-25 ratio decreased in entorhinal cortex. Dearomatized white spirit did not affect NCAM, SNAP-25, or NCAM/SNAP-25 ratio in any brain region. The affected 5-HT receptor expression and synaptic plasticity marker proteins indicate that inhalation exposure to high concentrations of white spirit may be neurotoxic to rats, especially the aromatic white spirit type. PMID:11792528

  8. Evidence that receptors mediating central synaptic potentials extend beyond the postsynaptic density.

    PubMed Central

    Faber, D S; Funch, P G; Korn, H

    1985-01-01

    Physiological recordings and computer simulations of unitary inhibitory postsynaptic potentials in the Mauthner cell of the goldfish central nervous system have been used to estimate the expected size of the postsynaptic receptor matrix at individual junctions. Simultaneous pre- and postsynaptic recordings were used to determine the kinetic parameters of the quantal responses under normal conditions and in the presence of strychnine, a competitive antagonist of glycine, which is the putative transmitter at these synapses. Calculations indicate that if the postsynaptic density, which has a radius of 0.1 micron, were to accommodate the population of channels estimated to be opened during a quantal response, the glycine binding site density in that region would be unrealistically high. Computer simulation of the quantal responses included transmitter diffusion, transmitter-receptor interactions, and channel activation under conditions including both normal and lowered binding site densities, the latter corresponding to the experimental data obtained with strychnine. The data indicate that the synaptic receptors involved in generating unitary responses are widely distributed to include regions located outside the junctional area, which directly faces the presynaptic release sites. We further suggest that the receptor matrix is surrounded by a restricted diffusional space; this geometrical organization may underlie the finding that response rise times are relatively independent of receptor binding site densities. PMID:2582417

  9. 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

  10. In vivo synaptic scaling is mediated by GluA2-lacking AMPA receptors in the embryonic spinal cord

    PubMed Central

    Garcia-Bereguiain, Miguel Angel; Gonzalez-Islas, Carlos; Lindsly, Casie; Butler, Ellie; Hill, Atlantis Wilkins; Wenner, Peter

    2013-01-01

    When spiking activity within a network is perturbed for hours to days, compensatory changes in synaptic strength are triggered that are thought to be important for the homeostatic maintenance of network or cellular spiking activity. In one form of this homeostatic plasticity, called synaptic scaling, all of a cell’s AMPAergic miniature postsynaptic currents (mEPSCs) are increased or decreased by some scaling factor. While synaptic scaling has been observed in a variety of systems, the mechanisms that underlie AMPAergic scaling have been controversial. Certain studies find that synaptic scaling is mediated by GluA2-lacking calcium permeable receptors (CP-AMPARs), while others have found that scaling is mediated by GluA2-containing calcium impermeable receptors (CI-AMPARs). Spontaneous network activity is observed in most developing circuits, and in the spinal cord this activity drives embryonic movements. Blocking spontaneous network activity in the chick embryo by infusing lidocaine in vivo triggers synaptic scaling in spinal motoneurons; here we show that AMPAergic scaling occurs through increases in mEPSC conductance that appear to be mediated by the insertion of GluA2-lacking AMPA receptors at the expense of GluA2-containing receptors. We have previously reported that in vivo blockade of GABAA transmission, at a developmental stage when GABA is excitatory, also triggered AMPAergic synaptic scaling. Here, we show that this form of AMPAergic scaling is also mediated by CP-AMPARs. These findings suggest that AMPAergic scaling triggered by blocking spiking activity or GABAA receptor transmission represent similar phenomenon, supporting the idea that activity-blockade triggers scaling by reducing GABAA transmission. PMID:23595738

  11. Calmodulin activity regulates group I metabotropic glutamate receptor-mediated signal transduction and synaptic depression.

    PubMed

    Sethna, Ferzin; Zhang, Ming; Kaphzan, Hanoch; Klann, Eric; Autio, Dawn; Cox, Charles L; Wang, Hongbing

    2016-05-01

    Group I metabotropic glutamate receptors (mGluR), including mGluR1 and mGluR 5 (mGluR1/5), are coupled to Gq and modulate activity-dependent synaptic plasticity. Direct activation of mGluR1/5 causes protein translation-dependent long-term depression (LTD). Although it has been established that intracellular Ca(2+) and the Gq-regulated signaling molecules are required for mGluR1/5 LTD, whether and how Ca(2+) regulates Gq signaling and upregulation of protein expression remain unknown. Through pharmacological inhibition, we tested the function of the Ca(2+) sensor calmodulin (CaM) in intracellular signaling triggered by the activation of mGluR1/5. CaM inhibitor N-[4-aminobutyl]-5-chloro-2-naphthalenesulfonamide hydrochloride (W13) suppressed the mGluR1/5-stimulated activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p70-S6 kinase 1 (S6K1) in hippocampal neurons. W13 also blocked the mGluR1/5 agonist-induced synaptic depression in hippocampal slices and in anesthetized mice. Consistent with the function of CaM, inhibiting the downstream targets Ca(2+) /CaM-dependent protein kinases (CaMK) blocked ERK1/2 and S6K1 activation. Furthermore, disruption of the CaM-CaMK-ERK1/2 signaling cascade suppressed the mGluR1/5-stimulated upregulation of Arc expression. Altogether, our data suggest CaM as a new Gq signaling component for coupling Ca(2+) and protein upregulation and regulating mGluR1/5-mediated synaptic modification. PMID:26864654

  12. Previous ethanol experience enhances synaptic plasticity of NMDA receptors in the ventral tegmental area.

    PubMed

    Bernier, Brian E; Whitaker, Leslie R; Morikawa, Hitoshi

    2011-04-01

    Alcohol addiction (alcoholism) is one of the most prevalent substance abuse disorders worldwide. Addiction is thought to arise, in part, from a maladaptive learning process in which enduring memories of drug experiences are formed. However, alcohol (ethanol) generally interferes with synaptic plasticity mechanisms in the CNS and thus impairs various types of learning and memory. Therefore, it is unclear how powerful memories associated with alcohol experience are formed during the development of alcoholism. Here, using brain slice electrophysiology in mice, we show that repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 d) causes increased susceptibility to the induction of long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated transmission in mesolimbic dopamine neurons, a form of synaptic plasticity that may drive the learning of stimuli associated with rewards, including drugs of abuse. Enhancement of NMDAR plasticity results from an increase in the potency of inositol 1,4,5-trisphosphate (IP(3)) in producing facilitation of action potential-evoked Ca(2+) signals, which is critical for LTP induction. This increase in IP(3) effect, which lasts for a week but not a month after ethanol withdrawal, occurs through a protein kinase A (PKA)-dependent mechanism. Corticotropin-releasing factor, a stress-related neuropeptide implicated in alcoholism and other addictions, further amplifies the PKA-mediated increase in IP(3) effect in ethanol-treated mice. Finally, we found that ethanol-treated mice display enhanced place conditioning induced by the psychostimulant cocaine. These data suggest that repeated ethanol experience may promote the formation of drug-associated memories by enhancing synaptic plasticity of NMDARs in dopamine neurons. PMID:21471355

  13. MAGI-1 modulates AMPA receptor synaptic localization and behavioral plasticity in response to prior experience.

    PubMed

    Emtage, Lesley; Chang, Howard; Tiver, Rebecca; Rongo, Christopher

    2009-01-01

    It is well established that the efficacy of synaptic connections can be rapidly modified by neural activity, yet how the environment and prior experience modulate such synaptic and behavioral plasticity is only beginning to be understood. Here we show in C. elegans that the broadly conserved scaffolding molecule MAGI-1 is required for the plasticity observed in a glutamatergic circuit. This mechanosensory circuit mediates reversals in locomotion in response to touch stimulation, and the AMPA-type receptor (AMPAR) subunits GLR-1 and GLR-2, which are required for reversal behavior, are localized to ventral cord synapses in this circuit. We find that animals modulate GLR-1 and GLR-2 localization in response to prior mechanosensory stimulation; a specific isoform of MAGI-1 (MAGI-1L) is critical for this modulation. We show that MAGI-1L interacts with AMPARs through the intracellular domain of the GLR-2 subunit, which is required for the modulation of AMPAR synaptic localization by mechanical stimulation. In addition, mutations that prevent the ubiquitination of GLR-1 prevent the decrease in AMPAR localization observed in previously stimulated magi-1 mutants. Finally, we find that previously-stimulated animals later habituate to subsequent mechanostimulation more rapidly compared to animals initially reared without mechanical stimulation; MAGI-1L, GLR-1, and GLR-2 are required for this change in habituation kinetics. Our findings demonstrate that prior experience can cause long-term alterations in both behavioral plasticity and AMPAR localization at synapses in an intact animal, and indicate a new, direct role for MAGI/S-SCAM proteins in modulating AMPAR localization and function in the wake of variable sensory experience. PMID:19242552

  14. CPG2 Recruits Endophilin B2 to the Cytoskeleton for Activity-Dependent Endocytosis of Synaptic Glutamate Receptors.

    PubMed

    Loebrich, Sven; Benoit, Marc Robert; Konopka, Jaclyn Aleksandra; Cottrell, Jeffrey Richard; Gibson, Joanne; Nedivi, Elly

    2016-02-01

    Internalization of glutamate receptors at the postsynaptic membrane via clathrin-mediated endocytosis (CME) is a key mechanism for regulating synaptic strength. A role for the F-actin cytoskeleton in CME is well established, and recently, PKA-dependent association of candidate plasticity gene 2 (CPG2) with the spine-cytoskeleton has been shown to mediate synaptic glutamate receptor internalization. Yet, how the endocytic machinery is physically coupled to the actin cytoskeleton to facilitate glutamate receptor internalization has not been demonstrated. Moreover, there has been no distinction of endocytic-machinery components that are specific to activity-dependent versus constitutive glutamate receptor internalization. Here, we show that CPG2, through a direct physical interaction, recruits endophilin B2 (EndoB2) to F-actin, thus anchoring the endocytic machinery to the spine cytoskeleton and facilitating glutamate receptor internalization. Regulation of CPG2 binding to the actin cytoskeleton by protein kinase A directly impacts recruitment of EndoB2 and clathrin. Specific disruption of EndoB2 or the CPG2-EndoB2 interaction impairs activity-dependent, but not constitutive, internalization of both NMDA- and AMPA-type glutamate receptors. These results demonstrate that, through direct interactions with F-actin and EndoB2, CPG2 physically bridges the spine cytoskeleton and the endocytic machinery, and this tripartite association is critical specifically for activity-dependent CME of synaptic glutamate receptors. PMID:26776730

  15. Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain.

    PubMed

    Li, Lingyong; Chen, Shao-Rui; Chen, Hong; Wen, Lei; Hittelman, Walter N; Xie, Jing-Dun; Pan, Hui-Lin

    2016-05-17

    Chronic neuropathic pain is a debilitating condition that remains difficult to treat. Diminished synaptic inhibition by GABA and glycine and increased NMDA receptor (NMDAR) activity in the spinal dorsal horn are key mechanisms underlying neuropathic pain. However, the reciprocal relationship between synaptic inhibition and excitation in neuropathic pain is unclear. Here, we show that intrathecal delivery of K(+)-Cl(-) cotransporter-2 (KCC2) using lentiviral vectors produces a complete and long-lasting reversal of pain hypersensitivity induced by nerve injury. KCC2 gene transfer restores Cl(-) homeostasis disrupted by nerve injury in both spinal dorsal horn and primary sensory neurons. Remarkably, restoring Cl(-) homeostasis normalizes both presynaptic and postsynaptic NMDAR activity increased by nerve injury in the spinal dorsal horn. Our findings indicate that nerve injury recruits NMDAR-mediated signaling pathways through the disruption of Cl(-) homeostasis in spinal dorsal horn and primary sensory neurons. Lentiviral vector-mediated KCC2 expression is a promising gene therapy for the treatment of neuropathic pain. PMID:27160909

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

    PubMed

    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

  17. The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice.

    PubMed

    Bachis, Alessia; Wenzel, Erin; Boelk, Allyssia; Becker, Jodi; Mocchetti, Italo

    2016-10-01

    Human immunodeficiency virus 1 and its envelope protein gp120 reduce synaptodendritic complexity. However, the mechanisms contributing to this pathological feature are still not understood. The proneurotrophin brain-derived neurotrophic factor promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR). Here, we have used gp120 transgenic (gp120tg) mice to investigate whether p75NTR has a role in gp120-mediated neurotoxicity. Old (∼10 months) gp120tg mice exhibited an increase in proneurotrophin brain-derived neurotrophic factor levels in the hippocampus as well as a decrease in the number of dendritic spines when compared to age-matched wild type. These effects were not observed in 3- or 6-month-old mice. To test if the reduction in spine density and morphology is caused by the activation of p75NTR, we crossed gp120tg mice with p75NTR null mice. We found that deletion of only 1 copy of the p75NTR gene in gp120tg mice is sufficient to normalize the number of hippocampal spines, strongly suggesting that the neurotoxic effect of gp120 is mediated by p75NTR. These data indicate that p75NTR antagonists could provide an adjunct therapy against synaptic simplification caused by human immunodeficiency virus 1. PMID:27498053

  18. 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

  19. Loss of estrogen-related receptor alpha disrupts ventral-striatal synaptic function in female mice.

    PubMed

    De Jesús-Cortés, Héctor; Lu, Yuan; Anderson, Rachel M; Khan, Michael Z; Nath, Varun; McDaniel, Latisha; Lutter, Michael; Radley, Jason J; Pieper, Andrew A; Cui, Huxing

    2016-08-01

    Eating disorders (EDs), including anorexia nervosa, bulimia nervosa and binge-ED, are mental illnesses characterized by high morbidity and mortality. While several studies have identified neural deficits in patients with EDs, the cellular and molecular basis of the underlying dysfunction has remained poorly understood. We previously identified a rare missense mutation in the transcription factor estrogen-related receptor alpha (ESRRA) associated with development of EDs. Because ventral-striatal signaling is related to the reward and motivation circuitry thought to underlie EDs, we performed functional and structural analysis of ventral-striatal synapses in Esrra-null mice. Esrra-null female, but not male, mice exhibit altered miniature excitatory postsynaptic currents on medium spiny neurons (MSNs) in the ventral striatum, including increased frequency, increased amplitude, and decreased paired pulse ratio. These electrophysiological measures are associated with structural and molecular changes in synapses of MSNs in the ventral striatum, including fewer pre-synaptic glutamatergic vesicles and enhanced GluR1 function. Neuronal Esrra is thus required for maintaining normal synaptic function in the ventral striatum, which may offer mechanistic insights into the behavioral deficits observed in Esrra-null mice. PMID:27155145

  20. 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

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

    PubMed

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

    2016-02-01

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

  2. 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

  3. AMPA receptor synaptic plasticity induced by psychostimulants: the past, present, and therapeutic future

    PubMed Central

    Bowers, M. Scott; Chen, Billy T.; Bonci, Antonello

    2010-01-01

    Experience-dependent plasticity at excitatory synapses of the mesocorticolimbic system is a fundamental brain mechanism that enables adaptation to an ever-changing environment. These synaptic responses are critical for the planning and execution of adaptive behaviors that maximize survival. The mesocorticolimbic system mediates procurement of positive reinforcers such as food and sex; however, drugs of abuse re-sculpt this crucial circuitry to promote compulsive drug-seeking behavior. This review will discuss the long-term changes in glutamatergic neurotransmission that occur within the mesolimbic system following cocaine exposure. In addition, we will examine how these long-lasting neuroadaptations may drive the pathology of psychostimulant addiction. Finally, we review clinical trials that highlight antagonists at excitatory AMPA receptors as promising targets against cocaine abuse. PMID:20624588

  4. 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

    2015-01-01

    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. PMID:26531194

  5. Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus.

    PubMed

    Rombo, Diogo M; Newton, Kathryn; Nissen, Wiebke; Badurek, Sylvia; Horn, Jacqueline M; Minichiello, Liliana; Jefferys, John G R; Sebastiao, Ana M; Lamsa, Karri P

    2015-05-01

    Adenosine inhibits excitatory neurons widely in the brain through adenosine A1 receptor, but activation of adenosine A2A receptor (A2A R) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A2A R expression level is low, and the receptor's effect on identified neuronal circuits is unknown. Using optogenetic afferent stimulation and whole-cell recording from identified postsynaptic neurons we show that A2A R facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons. In addition, A2A R enhances GABAergic inhibitory transmission between CA1 area interneurons leading to disinhibition of pyramidal cells. Adenosine A2A R has no direct modulatory effect on GABAergic synapses to pyramidal cells. As a result adenosine A2A R activation alters the synaptic excitation - inhibition balance in the CA1 area resulting in increased pyramidal cell discharge to glutamatergic Schaffer collateral stimulation. In line with this, we show that A2A R promotes synchronous pyramidal cell firing in hyperexcitable conditions where extracellular potassium is elevated or following high-frequency electrical stimulation. Our results revealed selective synapse- and cell type specific adenosine A2A R effects in hippocampal CA1 area. The uncovered mechanisms help our understanding of A2A R's facilitatory effect on cortical network activity. PMID:25402014

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

    PubMed

    Maroteaux, Matthieu; Liu, Siqiong June

    2016-01-01

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

  7. 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

  8. Cochlear nucleus neurons redistribute synaptic AMPA and glycine receptors in response to monaural conductive hearing loss

    PubMed Central

    Whiting, Brittany; Moiseff, Andrew; Rubio, María E.

    2009-01-01

    Neurons restore their function in response to external or internal perturbations and maintain neuronal or network stability through a homeostatic scaling mechanism. Homeostatic responses at synapses along the auditory system would be important for adaptation to normal and abnormal fluctuations in the sensory environment. We investigated at the electron microscopic level and after postembedding immunogold labeling whether projection neurons in the cochlear nucleus responded to modifications of auditory nerve activity. After unilaterally reducing the level of auditory inputs by ~ 20 dB by monaural earplugging, auditory nerve synapses on bushy cells somata and basal dendrites of fusiform cells of the ventral and dorsal cochlear nucleus, respectively, upregulated GluR3 AMPA receptor subunit, while inhibitory synapses decreased the expression of GlyRα1 subunit. These changes in expression levels were fully reversible once the earplug was removed, indicating that activity affects the trafficking of receptors at synapses. Excitatory synapses on apical dendrites of fusiform cells (parallel fibers) with different synaptic AMPA receptor subunit composition, were not affected by sound attenuation, as the expression levels of AMPA receptor subunits were the same as in normal hearing littermates. GlyRα1 subunit expression at inhibitory synapses on apical dendrites of fusiform cells was also found unaffected. Furthermore, fusiform and bushy cells of the contralateral side to the earplugging upregulated the GluR3 subunit at auditory nerve synapses. These results show that cochlear nucleus neurons innervated by the auditory nerve, are able to respond to small changes in sound levels by redistributing specific AMPA and glycine receptor subunits. PMID:19646510

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

    PubMed

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

    2015-08-20

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

  10. The interactive role of CB(1) and GABA(B) receptors in hippocampal synaptic plasticity in rats.

    PubMed

    Nazari, Masoumeh; Komaki, Alireza; Karamian, Ruhollah; Shahidi, Siamak; Sarihi, Abdolrahman; Asadbegi, Masoumeh

    2016-01-01

    Long-term potentiation (LTP) of synaptic transmission is a cellular process underlying learning and memory. Cannabinoids are known to be powerful modulators of this kind of synaptic plasticity. Changes in GABAergic inhibition have also been shown to affect synaptic plasticity in the hippocampus. GABA receptor type B (GABAB) and cannabinoid receptor type 1 (CB1) exhibit overlapping anatomical localization in some brain areas including the hippocampus. CB1 and GABAB are also localized to the same cells and share a common signaling pathway in some brain areas. In this study, we examined the hippocampal effects of co-administrating AM251 and CGP55845, which are CB1 and GABAB antagonists, respectively, on LTP induction in the dentate gyrus (DG) of rats. LTP in the hippocampal area was induced by high-frequency stimulation (HFS) of the perforant path. Our results showed that HFS coupled with administration of the CB1 antagonist increased both the population spike (PS) amplitude and field excitatory post-synaptic potential (fEPSP). Conversely, the GABAB antagonist decreased these parameters along with decreased LTP induction. We also demonstrated that the co-administration of CB1 and GABAB antagonists had different effects on the PS amplitude and fEPSP slope. It is likely that GABAB receptor antagonists modulate cannabinoid outputs that cause a decrease in synaptic plastisity, while in the simultaneous consumption of two antagonists, CB1 antagonists can alter the release of GABA which in turn results in enhancement of LTP induction. These findings suggest that there are functional interactions between the CB1 and GABAB receptor in the hippocampus. PMID:26611204

  11. 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. PMID:10561868

  12. 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

  13. 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.

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

    PubMed

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

    2016-06-01

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

  15. 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

  16. 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

  17. 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

  18. 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. PMID:26482421

  19. Classical Conditioning of the Rabbit Eyelid Response Increases Glutamate Receptor Binding in Hippocampal Synaptic Membranes

    NASA Astrophysics Data System (ADS)

    Mamounas, Laura A.; Thompson, Richard F.; Lynch, Gary; Baudry, Michel

    1984-04-01

    Hippocampal pyramidal neurons exhibit a rapid within-trial increase in firing frequency during classical conditioning of the rabbit eyelid response. It has been proposed that the cellular mechanisms responsible for hippocampal long-term potentiation (LTP) may also mediate this learning-dependent increase in neuronal activity. The induction of LTP in rat hippocampal slices results in an increase in the number of [3H]glutamate-binding sites in the potentiated region. The present study investigates the kinetics of [3H]glutamate binding to hippocampal synaptic membranes after eyelid conditioning in the rabbit. We report that the regional distribution of [3H]glutamate binding across the layers of rabbit hippocampus is compatible with a dendritic localization. The pharmacological and ionic properties of the binding suggest that it is associated with an excitatory amino acid receptor. After eyelid conditioning, the maximal number of hippocampal [3H]glutamate-binding sites is increased in animals receiving paired presentations of the tone conditioned stimulus and corneal air-puff unconditioned stimulus relative to that found in naive or unpaired control animals. These results strengthen the hypothesis that an LTP-like mechanism underlies the increase in hippocampal firing frequency during rabbit eyelid conditioning.

  20. 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

  1. Synaptic abnormalities of mice lacking toll-like receptor (TLR)-9.

    PubMed

    Patel, V; Patel, A M; McArdle, J J

    2016-06-01

    Motor, sensory, and autonomic abnormalities are reported for toll-like receptor 9 (TLR9) knock-out (KO) mice. However, a physiological role of TLR9 in the nervous system is largely unknown. Since altered synaptic transmission can contribute to sensory and motor abnormalities, we evaluated neuromuscular junction (NMJ) function and morphology of TLR9 KO mice. Triangularis sterni nerve-muscle preparations were dissected from TLR9 KO and age-matched control mice. Two-electrode voltage clamp of the motor endplate revealed that the amplitude and frequency of miniature end plate currents (mEPCs) for TLR9 KO NMJs were significantly greater than control. In contrast, mean endplate current (EPC, 1Hz) amplitude was equivalent to control. The ratio of mean EPC to mean mEPC amplitude indicated a decline of quantal content (m) for TLR9 KO NMJs. Furthermore, m declined more rapidly than control in response to 50-Hz stimulus trains. A rightward shift of the mEPC amplitude distribution suggested formation of vesicles containing larger amounts of acetylcholine (ACh). Staining with rhodamine α-bungarotoxin revealed a significant decline of endplate size in TLR9 KO mice. This alteration may result from ACh-induced decline of acetylcholine receptor (AChR) expression resulting from increased frequency and amplitude of mEPCs. At the same time, excessive spontaneous vesicular ACh release may initiate retrograde suppression of excitation-secretion coupling. These data suggest a novel role of TLR9 in the development of the NMJ. PMID:26955780

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

    PubMed Central

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

    2009-01-01

    Neuromodulators that alter the balance between lower-frequency glutamate-mediated excitatory and higher-frequency GABA-mediated inhibitory synaptic transmission are likely to participate in core mechanisms for CNS function and may contribute to the pathophysiology of neurological disorders such as schizophrenia and Alzheimer's disease. Pregnenolone sulfate (PS) modulates both ionotropic glutamate and GABAA receptor mediated synaptic transmission. The enzymes necessary for PS synthesis and degradation are found in brain tissue of several species including human and rat, and up to 5 nM PS has been detected in extracts of postmortem human brain. Here, we ask whether PS could modulate transmitter release from nerve terminals located in the striatum. Superfusion of a preparation of striatal nerve terminals comprised of mixed synaptosomes and synaptoneurosomes with brief-duration (2 min) pulses of 25 nM PS demonstrates that PS increases the release of newly accumulated [3H]dopamine ([3H]DA), but not [14C]glutamate or [3H]GABA, whereas pregnenolone is without effect. PS does not affect dopamine transporter (DAT) mediated uptake of [3H]DA, demonstrating that it specifically affects the transmitter release mechanism. The PS-induced [3H]DA release occurs via an NMDA receptor (NMDAR) dependent mechanism as it is blocked by D-2-amino-5-phosphonovaleric acid. PS modulates DA release with very high potency, significantly increasing [3H]DA release at PS concentrations as low as 25 pM. This first report of a selective direct enhancement of synaptosomal dopamine release by PS at picomolar concentrations via an NMDAR dependent mechanism raises the possibility that dopaminergic axon terminals may be a site of action for this neurosteroid. PMID:18710414

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

    PubMed

    Lindquist, B E; Shuttleworth, C W

    2012-10-25

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

  4. GluN2B subunit-containing NMDA receptor antagonists prevent Abeta-mediated synaptic plasticity disruption in vivo.

    PubMed

    Hu, Neng-Wei; Klyubin, Igor; Anwyl, Roger; Anwy, Roger; Rowan, Michael J

    2009-12-01

    Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-beta protein (Abeta) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Abeta in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Abeta(1-42) -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFalpha mediates this deleterious action of Ass was provided by the ability of TNFalpha antagonists to prevent Abeta(1-42) inhibition of plasticity and the abrogation of a similar disruptive effect of TNFalpha using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFalpha, Abeta(1-42) did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease. PMID:19918059

  5. NMDA receptors amplify mossy fiber synaptic inputs at frequencies up to at least 750 Hz in cerebellar granule cells.

    PubMed

    Baade, Carolin; Byczkowicz, Niklas; Hallermann, Stefan

    2016-07-01

    Neuronal integration of high-frequency signals is important for rapid information processing. Cerebellar mossy fiber axons (MFs) can fire action potentials (APs) at frequencies of more than one kilohertz. However, it is unclear whether and how the postsynaptic cerebellar granule cells (GCs) are able to process these high-frequency MF inputs. Here, we measured AP firing in GCs during high-frequency MF stimulation and show that GC firing frequency increased non-linearly when MF stimulation frequency was increased from 100 to 750 Hz. To investigate the mechanisms enabling such high-frequency signaling, we analyzed the role of N-methyl-d-aspartate receptors (NMDARs), which have been implicated in synaptic signaling at lower frequencies. Application of D-2-amino-5-phosphonopentanoic acid (APV), a potent inhibitor of NMDARs, strongly impaired the GC firing frequency during high-frequency MF stimulation. APV had no significant effect on single excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) evoked at 1 Hz at resting membrane potentials. However, the time course of EPSCs evoked at 1 Hz at depolarized potentials or following high-frequency MF stimulation was accelerated by APV. Thus, our results show that NMDAR-mediated currents amplify high-frequency MF inputs by prolonging the time courses of synaptic inputs, thereby causing greater synaptic summation of inputs. Hence, NMDARs support the integration of MF synaptic input at frequencies up to at least 750 Hz. Synapse 70:269-276, 2016. © 2016 Wiley Periodicals, Inc. PMID:26887562

  6. 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

  7. 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

  8. A Comprehensive Optogenetic Pharmacology Toolkit for In Vivo Control of GABA(A) Receptors and Synaptic Inhibition.

    PubMed

    Lin, Wan-Chen; Tsai, Ming-Chi; Davenport, Christopher M; Smith, Caleb M; Veit, Julia; Wilson, Neil M; Adesnik, Hillel; Kramer, Richard H

    2015-12-01

    Exogenously expressed opsins are valuable tools for optogenetic control of neurons in circuits. A deeper understanding of neural function can be gained by bringing control to endogenous neurotransmitter receptors that mediate synaptic transmission. Here we introduce a comprehensive optogenetic toolkit for controlling GABA(A) receptor-mediated inhibition in the brain. We developed a series of photoswitch ligands and the complementary genetically modified GABA(A) receptor subunits. By conjugating the two components, we generated light-sensitive versions of the entire GABA(A) receptor family. We validated these light-sensitive receptors for applications across a broad range of spatial scales, from subcellular receptor mapping to in vivo photo-control of visual responses in the cerebral cortex. Finally, we generated a knockin mouse in which the "photoswitch-ready" version of a GABA(A) receptor subunit genomically replaces its wild-type counterpart, ensuring normal receptor expression. This optogenetic pharmacology toolkit allows scalable interrogation of endogenous GABA(A) receptor function with high spatial, temporal, and biochemical precision. PMID:26606997

  9. Properties and molecular identity of NMDA receptors at synaptic and non-synaptic inputs in cerebellar molecular layer interneurons

    PubMed Central

    Bidoret, Céline; Bouvier, Guy; Ayon, Annick; Szapiro, Germán; Casado, Mariano

    2015-01-01

    N-methyl-D-aspartate receptors (NMDARs) in cerebellar molecular layer interneurons (MLIs) are expressed and activated in unusual ways: at parallel fibre (PF) synapses they are only recruited by repetitive stimuli, suggesting an extrasynaptic location, whereas their activation by climbing fibre is purely mediated by spillover. NMDARs are thought to play an important role in plasticity at different levels of the cerebellar circuitry. Evaluation of the location, functional properties and physiological roles of NMDARs will be facilitated by knowledge of the NMDAR isoforms recruited. Here we show that MLI-NMDARs activated by both PF and climbing fibre inputs have similar kinetics and contain GluN2B but not GluN2A subunits. On the other hand, no evidence was found of functional NMDARs in the axons of MLIs. At the PF-Purkinje cell (PF-PC) synapse, the activation of GluN2A-containing NMDARs has been shown to be necessary for the induction of long-term depression (LTD). Our results therefore provide a clear distinction between the NMDARs located on MLIs and those involved in plasticity at PF-PC synapses. PMID:25750623

  10. 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

  11. 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. PMID:25622751

  12. 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

  13. 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

    Li, Chenchen; Rainnie, Donald G

    2014-10-01

    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

  14. 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

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

    PubMed Central

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

    2014-01-01

    We examined the synaptic structure, quantity and distribution of AMPA- and 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 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 intra-synapse-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. PMID:25041792

  16. 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.

  17. Frequency-dependent facilitation of synaptic throughput via postsynaptic NMDA receptors in the nucleus of the solitary tract.

    PubMed

    Zhao, Huan; Peters, James H; Zhu, Mingyan; Page, Stephen J; Ritter, Robert C; Appleyard, Suzanne M

    2015-01-01

    Hindbrain NMDA receptors play important roles in reflexive and behavioural responses to vagal activation. NMDA receptors have also been shown to contribute to the synaptic responses of neurons in the nucleus of the solitary tract (NTS), but their exact role remains unclear. In this study we used whole cell patch-clamping techniques in rat horizontal brain slice to investigate the role of NMDA receptors in the fidelity of transmission across solitary tract afferent-NTS neuron synapses. Results show that NMDA receptors contribute up to 70% of the charge transferred across the synapse at high (>5 Hz) firing rates, but have little contribution at lower firing frequencies. Results also show that NMDA receptors critically contribute to the fidelity of transmission across these synapses during high frequency (>5 Hz) afferent discharge rates. This novel role of NMDA receptors may explain in part how primary visceral afferents, including vagal afferents, can maintain fidelity of transmission across a broad range of firing frequencies. Neurons within the nucleus of the solitary tract (NTS) receive vagal afferent innervations that initiate gastrointestinal and cardiovascular reflexes. Glutamate is the fast excitatory neurotransmitter released in the NTS by vagal afferents, which arrive there via the solitary tract (ST). ST stimulation elicits excitatory postsynaptic currents (EPSCs) in NTS neurons mediated by both AMPA- and NMDA-type glutamate receptors (-Rs). Vagal afferents exhibit a high probability of vesicle release and exhibit robust frequency-dependent depression due to presynaptic vesicle depletion. Nonetheless, synaptic throughput is maintained even at high frequencies of afferent activation. Here we test the hypothesis that postsynaptic NMDA-Rs are essential in maintaining throughput across ST-NTS synapses. Using patch clamp electrophysiology in horizontal brainstem slices, we found that NMDA-Rs, including NR2B subtypes, carry up to 70% of the charge transferred

  18. The expression of GABAA beta subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells.

    PubMed

    Herd, Murray B; Haythornthwaite, Alison R; Rosahl, Thomas W; Wafford, Keith A; Homanics, Gregg E; Lambert, Jeremy J; Belelli, Delia

    2008-02-15

    The subunit composition of GABA(A) receptors influences their biophysical and pharmacological properties, dictates neuronal location and the interaction with associated proteins, and markedly influences the impact of intracellular biochemistry. The focus has been on alpha and gamma subunits, with little attention given to beta subunits. Dentate gyrus granule cells (DGGCs) express all three beta subunit isoforms and exhibit both synaptic and extrasynaptic receptors that mediate 'phasic' and 'tonic' transmission, respectively. To investigate the subcellular distribution of the beta subunits we have utilized the patch-clamp technique to compare the properties of 'tonic' and miniature inhibitory postsynaptic currents (mIPSCs) recorded from DGGCs of hippocampal slices of P20-26 wild-type (WT), beta(2)(-/-), beta(2N265S) (etomidate-insensitive), alpha(1)(-/-) and delta(-/-) mice. Deletion of either the beta(2) or the delta subunit produced a significant reduction of the tonic current and attenuated the increase of this current induced by the delta subunit-preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). By contrast, mIPSCs were not influenced by deletion of these genes. Enhancement of the tonic current by the beta(2/3) subunit-selective agent etomidate was significantly reduced for DGGCs derived from beta(2N265S) mice, whereas this manipulation had no effect on the prolongation of mIPSCs produced by this anaesthetic. Collectively, these observations, together with previous studies on alpha(4)(-/-) mice, identify a population of extrasynaptic alpha(4)beta(2)delta receptors, whereas synaptic GABA(A) receptors appear to primarily incorporate the beta(3) subunit. A component of the tonic current is diazepam sensitive and is mediated by extrasynaptic receptors incorporating alpha(5) and gamma(2) subunits. Deletion of the beta(2) subunit had no effect on the diazepam-induced current and therefore these extrasynaptic receptors do not contain this

  19. Role of the vasopressin 1b receptor in rodent aggressive behavior and synaptic plasticity in hippocampal area CA2.

    PubMed

    Pagani, J H; Zhao, M; Cui, Z; Avram, S K Williams; Caruana, D A; Dudek, S M; Young, W S

    2015-04-01

    The vasopressin 1b receptor (Avpr1b) is critical for social memory and social aggression in rodents, yet little is known about its specific roles in these behaviors. Some clues to Avpr1b function can be gained from its profile of expression in the brain, which is largely limited to the pyramidal neurons of the CA2 region of the hippocampus, and from experiments showing that inactivation of the gene or antagonism of the receptor leads to a reduction in social aggression. Here we show that partial replacement of the Avpr1b through lentiviral delivery into the dorsal CA2 region restored the probability of socially motivated attack behavior in total Avpr1b knockout mice, without altering anxiety-like behaviors. To further explore the role of the Avpr1b in this hippocampal region, we examined the effects of Avpr1b agonists on pyramidal neurons in mouse and rat hippocampal slices. We found that selective Avpr1b agonists induced significant potentiation of excitatory synaptic responses in CA2, but not in CA1 or in slices from Avpr1b knockout mice. In a way that is mechanistically very similar to synaptic potentiation induced by oxytocin, Avpr1b agonist-induced potentiation of CA2 synapses relies on NMDA (N-methyl-D-aspartic acid) receptor activation, calcium and calcium/calmodulin-dependent protein kinase II activity, but not on cAMP-dependent protein kinase activity or presynaptic mechanisms. Our data indicate that the hippocampal CA2 is important for attacking in response to a male intruder and that the Avpr1b, likely through its role in regulating CA2 synaptic plasticity, is a necessary mediator. PMID:24863146

  20. 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

  1. 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. PMID:26687360

  2. 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. PMID:25511993

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

    PubMed Central

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

    2005-01-01

    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 γ-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 μm bicuculline abolished the spontaneous inhibitory post-synaptic currents (IPSCs) in 40/45 neurones, and 93% of the evoked IPSCs. The addition of 1 μm 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 μm 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. PMID:15817633

  4. 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. PMID

  5. Activation of synaptic group II metabotropic glutamate receptors induces long-term depression at GABAergic synapses in CNS neurons.

    PubMed

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

    2013-10-01

    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

  6. 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

  7. Synaptic commitment: developmentally regulated reciprocal changes in hippocampal granule cell NMDA and AMPA receptors over the lifespan.

    PubMed

    Yang, Zhiyong; Krause, Michael; Rao, Geeta; McNaughton, Bruce L; Barnes, C A

    2008-06-01

    Synaptic transmission in hippocampal field CA1 is largely N-methyl-d-aspartate receptor (NMDA(R)) dependent during the early postnatal period. It becomes increasingly mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors until an adult ratio of AMPA to NMDA receptors is achieved. It is shown here that increases in the AMPA receptor (AMPA(R))-mediated field potential response continue over the life span of the F-344 rat at the perforant path-granule cell synapse in the dentate gyrus. In contrast, the NMDA(R)-dependent component of the response decreases with age between 1 and 27 mo, leading to an increase of AMPA(R)/NMDA(R) ratio with age. One possible explanation of this age difference is that the AMPA(R)/NMDA(R) ratio can be modified by experience. To test the idea that the changed ratio is caused by the old rats' longer lives, an intensive 10-mo period of enrichment treatment was given to a group of animals, beginning at 3 mo of age. Compared with animals housed in standard cages, the enrichment treatment did not alter the glutamatergic response ratio measured with field potential recording methods. These data provide support for the conclusion that the observed change with age is developmentally regulated rather than experience dependent. Given the role of the NMDA(R) in synaptic plasticity, these changes suggest a progressive commitment of perforant path synapses to particular weights over the life span. One possible implication of this effect includes preservation of selected memories, ultimately at the expense of a reduced capacity to store new information. PMID:18417629

  8. Activity and protein kinase C regulate synaptic accumulation of N-methyl-D-aspartate (NMDA) receptors independently of GluN1 splice variant.

    PubMed

    Ferreira, Joana S; Rooyakkers, Amanda; She, Kevin; Ribeiro, Luis; Carvalho, Ana Luísa; Craig, Ann Marie

    2011-08-12

    NMDA receptors are calcium-permeable ionotropic receptors that detect coincident glutamate binding and membrane depolarization and are essential for many forms of synaptic plasticity in the mammalian brain. The obligatory GluN1 subunit of NMDA receptors is alternatively spliced at multiple sites, generating forms that vary in N-terminal N1 and C-terminal C1, C2, and C2' cassettes. Based on expression of GluN1 constructs in heterologous cells and in wild type neurons, the prevalent view is that the C-terminal cassettes regulate synaptic accumulation and its modulation by homeostatic activity blockade and by protein kinase C (PKC). Here, we tested the role of GluN1 splicing in regulated synaptic accumulation of NMDA receptors by lentiviral expression of individual GluN1 splice variants in hippocampal neurons cultured from GluN1 (-/-) mice. High efficiency transduction of GluN1 at levels similar to endogenous was achieved. Under control conditions, the C2' cassette mediated enhanced synaptic accumulation relative to the alternate C2 cassette, whereas the presence or absence of N1 or C1 had no effect. Surprisingly all GluN1 splice variants showed >2-fold increased synaptic accumulation with chronic blockade of NMDA receptor activity. Furthermore, in this neuronal rescue system, all GluN1 splice variants were equally rapidly dispersed upon activation of PKC. These results indicate that the major mechanisms mediating homeostatic synaptic accumulation and PKC dispersal of NMDA receptors occur independently of GluN1 splice isoform. PMID:21676872

  9. 47 CFR 90.138 - Applications for itinerant frequencies.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 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...

  10. 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...

  11. 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...

  12. 47 CFR 90.138 - Applications for itinerant frequencies.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 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...

  13. 47 CFR 90.138 - Applications for itinerant frequencies.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 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...

  14. 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

  15. S-SCAM/MAGI-2 is an essential synaptic scaffolding molecule for the GluA2-containing maintenance pool of AMPA receptors.

    PubMed

    Danielson, Eric; Zhang, Nanyan; Metallo, Jacob; Kaleka, Kanwardeep; Shin, Seung Min; Gerges, Nashaat; Lee, Sang H

    2012-05-16

    Synaptic plasticity, the cellular basis of learning and memory, involves the dynamic trafficking of AMPA receptors (AMPARs) into and out of synapses. One of the remaining key unanswered aspects of AMPAR trafficking is the mechanism by which synaptic strength is preserved despite protein turnover. In particular, the identity of AMPAR scaffolding molecule(s) involved in the maintenance of GluA2-containing AMPARs is completely unknown. Here we report that the synaptic scaffolding molecule (S-SCAM; also called membrane-associated guanylate kinase inverted-2 and atrophin interacting protein-1) plays the critical role of maintaining synaptic strength. Increasing S-SCAM levels in rat hippocampal neurons led to specific increases in the surface AMPAR levels, enhanced AMPAR-mediated synaptic transmission, and enlargement of dendritic spines, without significantly effecting GluN levels or NMDA receptor (NMDAR) EPSC. Conversely, decreasing S-SCAM levels by RNA interference-mediated knockdown caused the loss of synaptic AMPARs, which was followed by a severe reduction in the dendritic spine density. Importantly, S-SCAM regulated synaptic AMPAR levels in a manner, dependent on GluA2 not GluA1, sensitive to N-ethylmaleimide-sensitive fusion protein interaction, and independent of activity. Further, S-SCAM increased surface AMPAR levels in the absence of PSD-95, while PSD-95 was dependent on S-SCAM to increase surface AMPAR levels. Finally, S-SCAM overexpression hampered NMDA-induced internalization of AMPARs and prevented the induction of long term-depression, while S-SCAM knockdown did not. Together, these results suggest that S-SCAM is an essential AMPAR scaffolding molecule for the GluA2-containing pool of AMPARs, which are involved in the constitutive pathway of maintaining synaptic strength. PMID:22593065

  16. Loss of D2 Dopamine Receptor Function Modulates Cocaine-Induced Glutamatergic Synaptic Potentiation in the Ventral Tegmental Area

    PubMed Central

    Madhavan, Anuradha; Argilli, Emanuela; Bonci, Antonello

    2013-01-01

    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. PMID:23884939

  17. 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. PMID:23884939

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

    PubMed

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

    2015-11-13

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

  19. Involvement of AMPA receptor desensitization in short-term synaptic depression at the calyx of Held in developing rats

    PubMed Central

    Koike-Tani, Maki; Kanda, Takeshi; Saitoh, Naoto; Yamashita, Takayuki; Takahashi, Tomoyuki

    2008-01-01

    Paired-pulse facilitation (PPF) and depression (PPD) are forms of short-term plasticity that are generally thought to reflect changes in transmitter release probability. However, desensitization of postsynaptic AMPA receptors (AMPARs) significantly contributes to PPD at many glutamatergic synapses. To clarify the involvement of AMPAR desensitization in synaptic PPD, we compared PPD with AMPAR desensitization, induced by paired-pulse glutamate application in patches excised from postsynaptic cells at the calyx of Held synapse of developing rats. We found that AMPAR desensitization contributed significantly to PPD before the onset of hearing (P10–12), but that its contribution became negligible after hearing onset. During postnatal development (P7–21) the recovery of AMPARs from desensitization became faster. Concomitantly, glutamate sensitivity of AMPAR desensitization declined. Single-cell reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated a developmental decline of GluR1 expression that correlated with speeding of the recovery of AMPARs from desensitization. Transmitter release probability declined during the second postnatal week (P7–14). Manipulation of the extracellular Ca2+/Mg2+ ratio, to match release probability at P7–8 and P13–15 synapses, revealed that the release probability is also an important factor determining the involvement of AMPAR desensitization in PPD. We conclude that the extent of involvement of AMPAR desensitization in short-term synaptic depression is determined by both pre- and postsynaptic mechanisms. PMID:18339695

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

    PubMed

    Ainsworth, Matthew; Lee, Shane; Kaiser, Marcus; Simonotto, Jennifer; Kopell, Nancy J; Whittington, Miles A

    2016-05-10

    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

  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. 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

  3. 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

    2015-03-01

    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

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

    PubMed

    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

    2015-07-01

    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 Ca(2+)-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

  5. β-Amyloid Impairs AMPA Receptor Trafficking and Function by Reducing Ca2+/Calmodulin-dependent Protein Kinase II Synaptic Distribution*

    PubMed Central

    Gu, Zhenglin; Liu, Wenhua; Yan, Zhen

    2009-01-01

    A fundamental feature of Alzheimer disease (AD) is the accumulation of β-amyloid (Aβ), a peptide generated from the amyloid precursor protein (APP). Emerging evidence suggests that soluble Aβ oligomers adversely affect synaptic function, which leads to cognitive failure associated with AD. The Aβ-induced synaptic dysfunction has been attributed to the synaptic removal of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (AMPARs); however, it is unclear how Aβ induces the loss of AMPARs at the synapses. In this study we have examined the potential involvement of Ca2+/calmodulin-dependent protein kinase II (CaMKII), a signaling molecule critical for AMPAR trafficking and function. We found that the synaptic pool of CaMKII was significantly decreased in cortical neurons from APP transgenic mice, and the density of CaMKII clusters at synapses was significantly reduced by Aβ oligomer treatment. In parallel, the surface expression of GluR1 subunit as well as AMPAR-mediated synaptic response and ionic current was selectively decreased in APP transgenic mice and Aβ-treated cultures. Moreover, the reducing effect of Aβ on AMPAR current density was mimicked and occluded by knockdown of CaMKII and blocked by overexpression of CaMKII. These results suggest that the Aβ-induced change in CaMKII subcellular distribution may underlie the removal of AMPARs from synaptic membrane by Aβ. PMID:19240035

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

    PubMed Central

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

    2003-01-01

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

  7. 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.

  8. An itinerant antiferromagnetic metal without magnetic constituents

    DOE PAGESBeta

    Svanidze, E.; Wang, Jiakui K.; Besara, T.; Liu, L.; Huang, Q.; Siegrist, T.; Frandsen, B.; Lynn, J. W.; Nevidomskyy, Andriy H.; Gamża, Monika B.; et al

    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

  9. 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

  10. Axospinous synaptic subtype-specific differences in structure, size, ionotropic receptor expression, and connectivity in apical dendritic regions of rat hippocampal CA1 pyramidal neurons

    PubMed Central

    Nicholson, Daniel A.; Geinisman, Yuri

    2008-01-01

    The morphology of axospinous synapses and their parent spines varies widely. Additionally, many of these synapses are contacted by multiple synapse boutons (MSBs) and show substantial variability in receptor expression. The two major axospinous synaptic subtypes are perforated and nonperforated, but there are several subcategories within these two classes. The present study used serial section electron microscopy to determine whether perforated and nonperforated synaptic subtypes differed with regard to their distribution, size, receptor expression, and connectivity to MSBs in three apical dendritic regions of rat hippocampal area CA1: the proximal and distal thirds of stratum radiatum, and stratum lacunosum-moleculare. All synaptic subtypes were present throughout the apical dendritic regions, but there were several subclass-specific differences. First, segmented, completely partitioned synapses changed in number, proportion, and AMPA receptor expression with distance from the soma beyond that found within other perforated synaptic subtypes. Second, atypically large nonperforated synapses showed NMDA receptor immunoreactivity identical to perforated synapses, levels of AMPA receptor expression intermediate to nonperforated and perforated synapses, and perforated synapse-like changes in structure with distance from the soma. Finally, MSB connectivity was highest in proximal stratum radiatum, but only for those MSBs comprised of nonperforated synapses. The immunogold data suggest that most MSBs would not generate simultaneous depolarizations in multiple neurons or spines, however, because the vast majority of MSBs are comprised of two synapses with abnormally low levels of receptor expression, or involve one synapse with a high level of receptor expression and another with only a low level. PMID:19006199

  11. Dopamine alters AMPA receptor synaptic expression and subunit composition in dopamine neurons of the ventral tegmental area cultured with prefrontal cortex neurons.

    PubMed

    Gao, Can; Wolf, Marina E

    2007-12-26

    Excitatory synapses onto dopamine (DA) neurons of the ventral tegmental area (VTA) represent a critical site of psychostimulant-induced synaptic plasticity. This plasticity involves alterations in synaptic strength through AMPA receptor (AMPAR) redistribution. Here, we report an in vitro model for studying regulation of AMPAR trafficking in DA neurons under control conditions and after elevation of DA levels, mimicking cocaine exposure. We used cocultures containing rat VTA neurons and prefrontal cortex (PFC) neurons from enhanced cyan fluorescent protein-expressing mice. In VTA-PFC cocultures, D1 receptor activation (10 min) increased synaptic and nonsynaptic glutamate receptor subunit 1 (GluR1) and GluR2 surface expression on DA neurons. NMDA or AMPA receptor antagonists blocked this effect, and it was not observed in pure VTA cultures, suggesting that DA agonists acted on D1 receptors on PFC neurons, altering their excitatory transmission onto VTA DA neurons and, thus, influencing AMPARs. To mimic the longer elevation in extracellular DA levels produced by systemic cocaine, cocultures were incubated with DA for 1 h. Synaptic GluR1 was increased 24 h later, reminiscent of the increased AMPA/NMDA ratio at excitatory synapses onto VTA DA neurons 24 h after cocaine injection (Ungless et al., 2001). In contrast, GluR2 was unchanged. Analysis of colocalization of surface GluR1-3 labeling suggested that control DA neurons express a substantial number of GluR1/2, GluR2/3, and homomeric GluR1 receptors and that the increase in surface AMPARs 24 h after DA exposure may in part reflect increased GluR1/3-containing receptors. These results help define the cellular basis for plasticity underlying the development of behavioral sensitization. PMID:18160635

  12. MAGUKs, Synaptic Development, and Synaptic Plasticity

    PubMed Central

    Zheng, Chan-Ying; Seabold, Gail K.; Horak, Martin; Petralia, Ronald S.

    2011-01-01

    MAGUKs are proteins that act as key scaffolds in surface complexes containing receptors, adhesion proteins, and various signaling molecules. These complexes evolved prior to the appearance of multicellular animals and play key roles in cell-cell intercommunication. A major example of this is the neuronal synapse, which contains several presynaptic and postsynaptic MAGUKs including PSD-95, SAP102, SAP97, PSD-93, CASK, and MAGIs. Here, they play roles in both synaptic development and in later synaptic plasticity events. During development, MAGUKs help to organize the postsynaptic density via associations with other scaffolding proteins, such as Shank, and the actin cytoskeleton. They affect the clustering of glutamate receptors and other receptors, and these associations change with development. MAGUKs are involved in long-term potentiation and depression (e.g., via their phosphorylation by kinases and phosphorylation of other proteins associated with MAGUKs). Importantly, synapse development and function are dependent on the kind of MAGUK present. For example, SAP102 shows high mobility and is present in early synaptic development. Later, much of SAP102 is replaced by PSD-95, a more stable synaptic MAGUK; this is associated with changes in glutamate receptor types that are characteristic of synaptic maturation. PMID:21498811

  13. NR2A/B-containing NMDA receptors mediate cocaine-induced synaptic plasticity in the VTA and cocaine psychomotor sensitization.

    PubMed

    Schumann, Johanna; Matzner, Henry; Michaeli, Avner; Yaka, Rami

    2009-09-18

    Cocaine-induced modifications of glutamatergic synaptic transmission in the mesolimbic system play a key role in adaptations that promote addictive behaviors. In particular, the activation of ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) in the ventral tegmental area (VTA) is critical for both cocaine-induced synaptic plasticity induced by a single cocaine injection and for the initiation of cocaine psychomotor sensitization. In this study, we set to determine whether the NR2 subunits of the NMDAR play a specific role in triggering cocaine-induced alterations in synaptic plasticity and the development of psychomotor sensitization. We found that inhibition of NR2A-containing NMDARs by NVP-AAM077, or NR2B-containing receptors by ifenprodil, blocked cocaine-induced increase in the AMPAR/NMDAR currents ratio, a measure of long-term potentiation (LTP) in vivo, in VTA neurons 24h following a single cocaine injection. Furthermore, inhibition of the NR2A subunit during the development of psychomotor sensitization attenuated the enhanced locomotor activity following repeated cocaine injections. Together, these results suggest that NR2-containing NMDA receptors play an important role in the machinery that triggers synaptic and behavioral adaptations to drugs of abuse such as cocaine. PMID:19524640

  14. Evolution of NMDA receptor cytoplasmic interaction domains: implications for organisation of synaptic signalling complexes

    PubMed Central

    Ryan, Tomás J; Emes, Richard D; Grant, Seth GN; Komiyama, Noboru H

    2008-01-01

    Background Glutamate gated postsynaptic receptors in the central nervous system (CNS) are essential for environmentally stimulated behaviours including learning and memory in both invertebrates and vertebrates. Though their genetics, biochemistry, physiology, and role in behaviour have been intensely studied in vitro and in vivo, their molecular evolution and structural aspects remain poorly understood. To understand how these receptors have evolved different physiological requirements we have investigated the molecular evolution of glutamate gated receptors and ion channels, in particular the N-methyl-D-aspartate (NMDA) receptor, which is essential for higher cognitive function. Studies of rodent NMDA receptors show that the C-terminal intracellular domain forms a signalling complex with enzymes and scaffold proteins, which is important for neuronal and behavioural plasticity Results The vertebrate NMDA receptor was found to have subunits with C-terminal domains up to 500 amino acids longer than invertebrates. This extension was specific to the NR2 subunit and occurred before the duplication and subsequent divergence of NR2 in the vertebrate lineage. The shorter invertebrate C-terminus lacked vertebrate protein interaction motifs involved with forming a signaling complex although the terminal PDZ interaction domain was conserved. The vertebrate NR2 C-terminal domain was predicted to be intrinsically disordered but with a conserved secondary structure. Conclusion We highlight an evolutionary adaptation specific to vertebrate NMDA receptor NR2 subunits. Using in silico methods we find that evolution has shaped the NMDA receptor C-terminus into an unstructured but modular intracellular domain that parallels the expansion in complexity of an NMDA receptor signalling complex in the vertebrate lineage. We propose the NR2 C-terminus has evolved to be a natively unstructured yet flexible hub organising postsynaptic signalling. The evolution of the NR2 C-terminus and its

  15. 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

  16. NMDA receptors activated by subventricular zone astrocytic glutamate are critical for neuroblast survival prior to entering a synaptic network

    PubMed Central

    Platel, Jean-Claude; Dave, Kathleen A.; Gordon, Valerie; Lacar, Benjamin; Rubio, Maria E.; Bordey, Angélique

    2010-01-01

    SUMMARY Even before integrating into existing circuitry, adult-born neurons express receptors for neurotransmitters, but the intercellular mechanisms and their impact on neurogenesis remain largely unexplored. Here, we show that neuroblasts born in the postnatal subventricular zone (SVZ) acquire NMDA receptors (NMDARs) during their migration to the olfactory bulb. Along their route, neuroblasts are ensheathed by astrocyte-like cells expressing vesicular glutamate release machinery. Increasing calcium in these specialized astrocytes induced NMDAR-activity in neuroblasts and blocking astrocytic vesicular release eliminated spontaneous NMDAR-activity. Single-cell knockout of NMDARs using neonatal electroporation resulted in neuroblast apoptosis at the time of NMDAR acquisition. This cumulated in a 40% loss of neuroblasts along their migratory route demonstrating that NMDAR acquisition is critical for neuroblast survival, prior to entering a synaptic network. In addition, our findings suggest an unexpected mechanism where SVZ astrocytes use glutamate signaling through NMDARs to control the number of adult-born neurons reaching their final destination. PMID:20346761

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

    PubMed

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

    2004-04-20

    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

  18. 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

  19. TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons.

    PubMed

    Menigoz, Aurélie; Ahmed, Tariq; Sabanov, Victor; Philippaert, Koenraad; Pinto, Silvia; Kerselaers, Sara; Segal, Andrei; Freichel, Marc; Voets, Thomas; Nilius, Bernd; Vennekens, Rudi; Balschun, Detlef

    2016-04-01

    TRPM4 is a calcium-activated but calcium-impermeable non-selective cation (CAN) channel. Previous studies have shown that TRPM4 is an important regulator of Ca(2+)-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of the central nervous system remained unclear. Here, we report that TRPM4 proteins form a CAN channel in CA1 neurons of the hippocampus and we show that TRPM4 is an essential co-activator of N-methyl-D-aspartate (NMDA) receptors (NMDAR) during the induction of long-term potentiation (LTP). Disrupting the Trpm4 gene in mice specifically eliminates NMDAR-dependent LTP, while basal synaptic transmission, short-term plasticity, and NMDAR-dependent long-term depression are unchanged. The induction of LTP in Trpm4 (-/-) neurons was rescued by facilitating NMDA receptor activation or post-synaptic membrane depolarization. Accordingly, we obtained normal LTP in Trpm4 (-/-) neurons in a pairing protocol, where post-synaptic depolarization was applied in parallel to pre-synaptic stimulation. Taken together, our data are consistent with a novel model of LTP induction in CA1 hippocampal neurons, in which TRPM4 is an essential player in a feed-forward loop that generates the post-synaptic membrane depolarization which is necessary to fully activate NMDA receptors during the induction of LTP but which is dispensable for the induction of long-term depression (LTD). These results have important implications for the understanding of the induction process of LTP and the development of nootropic medication. PMID:26631168

  20. Metabotropic glutamate receptors depress glutamate-mediated synaptic input to rat midbrain dopamine neurones in vitro.

    PubMed

    Wigmore, M A; Lacey, M G

    1998-02-01

    1. Glutamate (AMPA receptor-mediated) excitatory postsynaptic potentials (e.p.s.ps.), evoked by electrical stimulation rostral to the recording site, were examined by intracellular microelectrode recording from dopamine neurones in parasagittal slices of rat ventral midbrain. 2. The e.p.s.p. was depressed by the group III metabotropic glutamate (mGlu) receptor agonist L-2-amino-4-phosphonobutyric acid (L-AP4; 0.01-30 microM) by up to 60% with an EC50 of 0.82 microM. The depression induced by L-AP4 (3 microM) was reversed by the group III preferring mGlu receptor antagonist, alpha-methyl-4-phosphonophenylglycine (MPPG; 250 microM). 3. The group I and II mGlu agonist, 1S,3R-aminocyclopentanedicarboxylic acid (ACPD; 3-30 microM) also depressed the e.p.s.p. in a concentration-dependent manner. The effect of ACPD (10 microM) was reversed by (+)-alpha-methyl-4-carboxyphenylglycine (MCPG; 1 mM; 4 cells). This effect of ACPD was also partially antagonized (by 50.3+/-15.7%, 4 cells) by MPPG (250 microM). 4. The selective agonist at group I mGlu receptors, dihydroxyphenylglycine (DHPG; 100 microM), decreased e.p.s.p. amplitude by 27.1+/-8.2% (7 cells), as did the group II mGlu receptor-selective agonist (1S,1R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; 1 microM) by 26.7+/-4.3% (5 cells). 5. DHPG (10-100 microM) caused a depolarization of the recorded cell, as did ACPD (3-30 microM), whereas no such postsynaptic effect of either L-AP4 or DCG-IV was observed. 6. These results provide evidence for the presence of presynaptic inhibitory metabotropic glutamate autoreceptors from the mGlu receptor groups II and III on descending glutamatergic inputs to midbrain dopamine neurones. Group I mGlu receptors mediate a postsynaptic depolarization, and can also depress glutamatergic transmission, but may not necessarily be localized presynaptically. These sites represent novel drug targets for treatment of schizophrenia and movement disorders of basal ganglia origin. PMID

  1. Metabotropic glutamate receptors depress glutamate-mediated synaptic input to rat midbrain dopamine neurones in vitro

    PubMed Central

    Wigmore, Mark A; Lacey, Michael G

    1998-01-01

    Glutamate (AMPA receptor-mediated) excitatory postsynaptic potentials (e.p.s.ps.), evoked by electrical stimulation rostral to the recording site, were examined by intracellular microelectrode recording from dopamine neurones in parasagittal slices of rat ventral midbrain. The e.p.s.p. was depressed by the group III metabotropic glutamate (mGlu) receptor agonist L-2-amino-4-phosphonobutyric acid (L-AP4; 0.01–30 μM) by up to 60% with an EC50 of 0.82 μM. The depression induced by L-AP4 (3 μM) was reversed by the group III preferring mGlu receptor antagonist, α-methyl-4-phosphonophenylglycine (MPPG; 250 μM). The group I and II mGlu agonist, 1S,3R-aminocyclopentanedicarboxylic acid (ACPD; 3–30 μM) also depressed the e.p.s.p. in a concentration-dependent manner. The effect of ACPD (10 μM) was reversed by (+)-α-methyl-4-carboxyphenylglycine (MCPG; 1 mM; 4 cells). This effect of ACPD was also partially antagonized (by 50.3±15.7%, 4 cells) by MPPG (250 μM). The selective agonist at group I mGlu receptors, dihydroxyphenylglycine (DHPG; 100 μM), decreased e.p.s.p. amplitude by 27.1±8.2% (7 cells), as did the group II mGlu receptor-selective agonist (1S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; 1 μM) by 26.7±4.3% (5 cells). DHPG (10–100 μM) caused a depolarization of the recorded cell, as did ACPD (3–30 μM), whereas no such postsynaptic effect of either L-AP4 or DCG-IV was observed. These results provide evidence for the presence of presynaptic inhibitory metabotropic glutamate autoreceptors from the mGlu receptor groups II and III on descending glutamatergic inputs to midbrain dopamine neurones. Group I mGlu receptors mediate a postsynaptic depolarization, and can also depress glutamatergic transmission, but may not necessarily be localized presynaptically. These sites represent novel drug targets for treatment of schizophrenia and movement disorders of basal ganglia origin. PMID:9517386

  2. Kainate Receptors Mediate Synaptic Input to Transient and Sustained OFF Visual Pathways in Primate Retina

    PubMed Central

    Percival, Kumiko A.; Venkataramani, Sowmya; Gayet-Primo, Jacqueline; Grünert, Ulrike; Taylor, W. Rowland

    2014-01-01

    Visual signals are segregated into parallel pathways at the first synapse in the retina between cones and bipolar cells. Within the OFF pathways of mammals, the selective expression of AMPA or kainate-type glutamate receptors in the dendrites of different OFF-bipolar cell types is thought to contribute to formation of distinct temporal channels. AMPA receptors, with rapid recovery from desensitization, are proposed to transmit high temporal frequency signals, whereas kainate receptors (KARs) are presumed to encode lower temporal frequencies. Here we studied the glutamate receptors expressed by OFF-bipolar cells in slice preparations of macaque monkey retina, where the low (midget/parvocellular) and high-frequency (parasol/magnocellular) temporal channels are well characterized. We found that all OFF-bipolar types receive input primarily through KARs and that KAR antagonists block light-evoked input to both OFF-midget and OFF-parasol ganglion cells. KAR subunits were differentially expressed in OFF-bipolar types; the diffuse bipolar (DB) cells, DB2 and DB3b, expressed GluK1 and showed transient responses to glutamate and the KAR agonist, ATPA. In contrast, flat midget bipolar, DB1, and DB3a cells lacked GluK1 and showed relatively sustained responses. Finally, we found that the KAR accessory protein, Neto1, is expressed at the base of cone pedicles but is not colocalized with the GluK1 subunit. In summary, the results indicate that transient signaling in the OFF pathway of macaques is not dependent on AMPA receptors and that heterogeneity of KARs and accessory proteins may contribute to the formation of parallel temporal channels. PMID:24872565

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

    PubMed

    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

    2015-12-15

    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

  4. 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. PMID:24141311

  5. A model of neuregulin control of NMDA receptors on synaptic spines.

    PubMed

    Bennett, Max R; Farnell, Les; Gibson, William G

    2012-03-01

    Neuregulin (Nrg) through its receptor ErbB4 modulates the activity of the N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) at synapses. As modification of this pathway has been implicated in schizophrenia, it is of great interest to define it in precise quantitative terms. Kinetic models of the epidermal growth factor (EGF)/ErbB receptor signalling pathway describing activation, desensitization, and tyrosine phosphorylation of EGFR/ErbB followed by binding and activation of Src family kinases that is subsequently followed by phosphorylation of target proteins are available. We have adapted these to give a kinetic description of NMDAR modulation by Nrg that recapitulates the observed kinetics of autophosphorylation of the ErbB dimer as well as the modulation of the NMDAR by Src kinase, according to whether the kinases are activated or deactivated. This quantitative description of the Nrg/NMDAR pathway provides a model for experimental elucidation of what goes awry in animal models of schizophrenia. PMID:22147103

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

    PubMed

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

    1999-06-01

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

  7. Synaptic targeting of AMPA receptors is regulated by a CaMKII site in the first intracellular loop of GluA1

    PubMed Central

    Lu, Wei; Isozaki, Kaname; Roche, Katherine W.; Nicoll, Roger A.

    2010-01-01

    The accumulation of AMPA receptors (AMPARs) at synapses is essential for excitatory synaptic transmission. However, the mechanisms underlying synaptic targeting of AMPARs remain elusive. We have now used a molecular replacement approach on an AMPAR-null background to investigate the targeting mechanisms necessary for regulating AMPAR trafficking in the hippocampus. Although there is an extensive literature on the role of the GluA1 C-tail in AMPAR trafficking, there is no effect of overexpressing the C-tail on basal transmission. Instead, we found that the first intracellular loop domain (Loop1) of GluA1, a previously overlooked region within AMPARs, is critical for receptor targeting to synapses, but not for delivery of receptors to the plasma membrane. We also identified a CaMKII phosphorylation site (S567) in the GluA1 Loop1, which is phosphorylated in vitro and in vivo. Furthermore, we show that S567 is a key residue that regulates Loop1-mediated AMPAR trafficking. Thus, our study reveals a unique mechanism for targeting AMPARs to synapses to mediate synaptic transmission. PMID:21135237

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

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    2015-06-01

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

  10. ESTROGEN AND AGING AFFECT THE SYNAPTIC DISTRIBUTION OF ESTROGEN RECEPTOR BETA-IMMUNOREACTIVITY IN THE CA1 REGION OF FEMALE RAT HIPPOCAMPUS

    PubMed Central

    Waters, Elizabeth M.; Yildirim, Murat; Janssen, William G.M.; Lou, W.Y. Wendy; McEwen, Bruce S.; Morrison, John H.; Milner, Teresa A.

    2010-01-01

    Estradiol (E) mediates increased synaptogenesis in the hippocampal CA1 stratum radiatum (sr) and enhances memory in young and some aged female rats, depending on dose and age. Young females rats express more estrogen receptor α (ERα) immunolabeling in CA1sr spine synapse complexes than aged rats and ERα regulation is E sensitive in young but not aged rats. The current study examined whether estrogen receptor β (ERβ) expression in spine synapse complexes may be altered by age or E treatment. Young (3–4 months) and aged (22–23 months) female rats were ovariectomized 7 days prior to implantation of silastic capsules containing either vehicle (cholesterol) or E (10% in cholesterol) for 2 days. ERβ immunoreactivity (ir) in CA1sr was quantitatively analyzed using post-embedding electron microscopy. ERβ-ir was more prominent postsynaptically than presynaptically and both age and E treatment affected its synaptic distribution. While age decreased the spine synaptic complex localization of ERβ-ir (i.e., within 60 nm of the pre- and post-synaptic membranes), E treatment increased synaptic ERβ in both young and aged rats. In addition, the E treatment, but not age, increased dendritic shaft labeling. This data demonstrates that like ERα the levels of ERβ-ir decrease in CA1 axospinous synapses with age, however, unlike ERα the levels of ERβ-ir increase in these synapses in both young and aged rats in response to E. This suggests that synaptic ERβ may be a more responsive target to E, particularly in aged females. PMID:20875808

  11. 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. PMID:24227725

  12. 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

  13. Protein kinase C-mediated changes in synaptic efficacy at the neuromuscular junction in vitro: the role of postsynaptic acetylcholine receptors.

    PubMed

    Lanuza, M A; Li, M X; Jia, M; Kim, S; Davenport, R; Dunlap, V; Nelson, P G

    2000-09-15

    Activation of a mouse in vitro neuromuscular synapse produces a reduction in synaptic efficacy which is greater for nonactivated than for activated inputs to the myotubes. This has been shown to require thrombin and thrombin receptor activation and to involve a protein kinase C (PKC)-mediated step. We show in the present work that phorbol ester activation of PKC produces physiological loss of synapses in a time- and dose-related manner. We observe, using quantitative imaging methods, a parallel loss of acetylcholine receptors (AChR) from synaptically functional neurite-associated receptor aggregates in nerve-muscle cocultures. Biochemical measurements of total AChR show that PKC activation reduces both AChR stability (increases receptor loss) and receptor insertion into the surface membrane. Taken together, the data suggest that PKC activation decreases the stability of AChR aggregates in the muscle surface membrane. We conclude that PKC plays a crucial role in activity-dependent synapse reduction and does so, at least in part, by altering AChR stability. PMID:10972958

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

    PubMed

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

    2015-04-01

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

  15. Metabotropic glutamate receptors modulate synaptic transmission in the perforant path: pharmacology and localization of two distinct receptors.

    PubMed

    Dietrich, D; Beck, H; Kral, T; Clusmann, H; Elger, C E; Schramm, J

    1997-09-01

    Metabotropic glutamate receptors (mGluRs) have emerged as an interesting family of eight different receptor subtypes that can be divided into three groups according to their pharmacology and sequence similarity. In the present study, the specific mGluR agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4) depressed field excitatory postsynaptic potentials (fEPSPs) in the rat dentate gyrus evoked by perforant path stimulation in a concentration-dependent, rapid and reversible manner (EC50: L-AP4 5.9 +/- 1.6 microM, (1S,3R)-ACPD 80 +/- 34 microM). In a 'paired-pulse' stimulation protocol, the first fEPSP showed a stronger reduction, resulting in 'paired-pulse' facilitation. The effects of L-AP4 but not of (1S,3R)-ACPD could be antagonized by the group III mGluR antagonists (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG). Moreover, (1S,3R)-ACPD was still potently depressing fEPSPs after preperfusion of near saturating concentrations of L-AP4. Together, the results suggest that both substances act on different mGluRs. The effects of (1S,3R)-ACPD could not be further differentiated by selective group I or group II mGluR agonists. Although (2S,1'S,2'S)-2-carboxycyclopropylglycine (L-CCG-I) blocked fEPSPs at concentrations > 1 microM, these effects, as well as L-AP4 effects, were potently antagonized by MAP4. This suggests that mGluR8 might be responsible for the actions of L-AP4 and L-CCG-I. The two different mGluRs showed a distinct distribution when fEPSPs were recorded simultaneously in the outer and middle molecular layer (OML/MML): The L-AP4 sensitive receptor, possibly mGluR8, seems to be located in the OML while (1S,3R)-ACPD showed its main effect in the MML. PMID:9367251

  16. 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

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

    PubMed

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

    2016-01-01

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

  19. Wnt signals organize synaptic prepattern and axon guidance through the zebrafish unplugged/MuSK receptor.

    PubMed

    Jing, Lili; Lefebvre, Julie L; Gordon, Laura R; Granato, Michael

    2009-03-12

    Early during neuromuscular development, acetylcholine receptors (AChRs) accumulate at the center of muscle fibers, precisely where motor growth cones navigate and synapses eventually form. Here, we show that Wnt11r binds to the zebrafish unplugged/MuSK ectodomain to organize this central muscle zone. In the absence of such a zone, prepatterned AChRs fail to aggregate and, as visualized by live-cell imaging, growth cones stray from their central path. Using inducible unplugged/MuSK transgenes, we show that organization of the central muscle zone is dispensable for the formation of neural synapses, but essential for AChR prepattern and motor growth cone guidance. Finally, we show that blocking noncanonical dishevelled signaling in muscle fibers disrupts AChR prepatterning and growth cone guidance. We propose that Wnt ligands activate unplugged/MuSK signaling in muscle fibers to restrict growth cone guidance and AChR prepatterns to the muscle center through a mechanism reminiscent of the planar cell polarity pathway. PMID:19285469

  20. L-Stepholidine rescues memory deficit and synaptic plasticity in models of Alzheimer's disease via activating dopamine D1 receptor/PKA signaling pathway

    PubMed Central

    Hao, J-R; Sun, N; Lei, L; Li, X-Y; Yao, B; Sun, K; Hu, R; Zhang, X; Shi, X-D; Gao, C

    2015-01-01

    It is accepted that amyloid β-derived diffusible ligands (ADDLs) have a prominent role in triggering the early cognitive deficits that constitute Alzheimer's disease (AD). However, there is still no effective treatment for preventing or reversing the progression of the disease. Targeting α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor trafficking and its regulation is a new strategy for AD early treatment. Here we investigate the effect and mechanism of L-Stepholidine (L-SPD), which elicits dopamine D1-type receptor agonistic activity, while acting as D2-type receptor antagonist on cognition and synaptic plasticity in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice, and hippocampal cultures or slices treated with ADDLs. L-SPD could improve the hippocampus-dependent memory, surface expression of glutamate receptor A (GluA1)-containing AMPA receptors and spine density in hippocampus of APP/PS1 transgenic mice. L-SPD not only rescued decreased phosphorylation and surface expression of GluA1 in hippocampal cultures but also protected the long-term potentiation in hippocampal slices induced by ADDLs. Protein kinase A (PKA) agonist Sp-cAMPS or D1-type receptor agonist SKF81297 had similar effects, whereas PKA antagonist Rp-cAMPS or D1-type receptor antagonist SCH23390 abolished the effect of L-SPD on GluA1 trafficking. This was mediated mainly by PKA, which could phosphorylate serine residue at 845 of the GluA1. L-SPD may be explored as a potential therapeutic drug for AD through a mechanism that improves AMPA receptor trafficking and synaptic plasticity via activating D1/PKA signaling pathway. PMID:26539912

  1. Mapping itinerant electrons around Kondo impurities.

    PubMed

    Prüser, H; Wenderoth, M; Weismann, A; Ulbrich, R G

    2012-04-20

    We investigate single Fe and Co atoms buried below a Cu(100) surface using low temperature scanning tunneling spectroscopy. By mapping the local density of states of the itinerant electrons at the surface, the Kondo resonance near the Fermi energy is analyzed. Probing bulk impurities in this well-defined scattering geometry allows separating the physics of the Kondo system and the measuring process. The line shape of the Kondo signature shows an oscillatory behavior as a function of depth of the impurity as well as a function of lateral distance. The oscillation period along the different directions reveals that the spectral function of the itinerant electrons is anisotropic. PMID:22680744

  2. Loss of F-box Only Protein 2 (Fbxo2) Disrupts Levels and Localization of Select NMDA Receptor Subunits, and Promotes Aberrant Synaptic Connectivity

    PubMed Central

    Atkin, Graham; Moore, Shannon; Lu, Yuan; Nelson, Rick F.; Tipper, Nathan; Rajpal, Gautam; Hunt, Jack; Tennant, William; Hell, Johannes W.; Murphy, Geoffrey G.

    2015-01-01

    NMDA receptors (NMDARs) play an essential role in some forms of synaptic plasticity, learning, and memory. Therefore, these receptors are highly regulated with respect to their localization, activation, and abundance both within and on the surface of mammalian neurons. Fundamental questions remain, however, regarding how this complex regulation is achieved. Using cell-based models and F-box Only Protein 2 (Fbxo2) knock-out mice, we found that the ubiquitin ligase substrate adaptor protein Fbxo2, previously reported to facilitate the degradation of the NMDAR subunit GluN1 in vitro, also functions to regulate GluN1 and GluN2A subunit levels in the adult mouse brain. In contrast, GluN2B subunit levels are not affected by the loss of Fbxo2. The loss of Fbxo2 results in greater surface localization of GluN1 and GluN2A, together with increases in the synaptic markers PSD-95 and Vglut1. These synaptic changes do not manifest as neurophysiological differences or alterations in dendritic spine density in Fbxo2 knock-out mice, but result instead in increased axo-dendritic shaft synapses. Together, these findings suggest that Fbxo2 controls the abundance and localization of specific NMDAR subunits in the brain and may influence synapse formation and maintenance. PMID:25878288

  3. AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury1,2,3

    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

  4. How Ca2+-permeable AMPA receptors, the kinase PKA, and the phosphatase PP2B are intertwined in synaptic LTP and LTD.

    PubMed

    Hell, Johannes W

    2016-01-01

    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. PMID:27117250

  5. Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors.

    PubMed

    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

  6. 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

  7. Amyloid-β impairs, and ibuprofen restores, the cGMP pathway, synaptic expression of AMPA receptors and long-term potentiation in the hippocampus.

    PubMed

    Monfort, Pilar; Felipo, Vicente

    2010-01-01

    Amyloid-β (Aβ) rapidly impairs hippocampal long-term potentiation (LTP) and cognitive function in rats. We hypothesized that: a) Aβ-induced impairment of LTP would be due to impairment of the nitric oxide (NO)-cGMP pathway and AMPA receptor translocation; and b) treatment with the anti-inflammatory drug ibuprofen would restore the NO-cGMP pathway and LTP. The aims of this work were to assess whether ibuprofen prevents and/or rescues Aβ-induced LTP impairments in hippocampal slices and to analyze the role of the altered NO-cGMP-protein kinase G pathway and AMPA receptor phosphorylation and synaptic expression in the mechanisms by which Aβ impairs and ibuprofen restores LTP. Aβ impairs tetanus-induced activation of guanylate cyclase and cGMP increase, preventing protein kinase G activation, phosphorylation of GluR1 in Ser845 and AMPA receptors translocation to synaptic membranes, which is responsible for LTP impairment by Aβ. Ibuprofen prevents LTP impairment by Aβ by restoring guanylate cyclase activation and increase in cGMP and, subsequently, activation of protein kinase G, phosphorylation of GluR1 in Ser845 and synaptic expression of AMPA receptors. Restoration of cGMP levels is enough to restore all this process as indicated by the fact that the cGMP analog 8-Br-cGMP also normalizes the function of this pathway and restores LTP in the presence of Aβ. These results indicate that Aβ impairs LTP by impairing the NO-cGMP pathway and that ibuprofen restores LTP by restoring this pathway. These data suggest that restoring cGMP levels may have therapeutic utility to improve cognitive function impaired by Aβ. PMID:20858955

  8. A rapid ethnography of itinerant teachers of the deaf.

    PubMed

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

    2004-01-01

    A rapid ethnographic 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 enables better-directed data collection. Interviews with the itinerants and other professionals, direct observation of itinerants at work, and archival data permitted the authors to generate a list of themes reflecting results of other studies which focused on specific skills for itinerant teaching. While knowledge of specific skills cannot be ignored, the study shows that effective itinerants are ones who, through a personality trait, extensive experience, or a specific value system, can generate a positive composite image of their role as itinerants and are then able to interact on the basis of that image. PMID:15332468

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

    PubMed

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

    2015-02-01

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

  10. GABA(A) receptor expression and inhibitory post-synaptic currents in cerebellar Purkinje cells in dystrophin-deficient mdx mice.

    PubMed

    Kueh, S L L; Head, S I; Morley, J W

    2008-02-01

    1. Duchenne muscular dystrophy (DMD) is the second most common fatal genetic disease and arises as a consequence of an absence or disruption of the protein dystrophin. In addition to wasting of the skeletal musculature, boys with DMD have a significant degree of cognitive impairment. 2. We show here that there is no difference between littermate control and mdx mice (a murine model of DMD) in the overall expression of the GABA(A) receptor a1-subunit, supporting the suggestion that it is the clustering at the synapse that is affected and not the expression of the GABA(A) receptor protein. 3. We report a significant reduction in both the frequency and amplitude of spontaneous inhibitory post-synaptic currents in cerebellar Purkinje cells of mdx mice compared with littermate controls, consistent with the reported reduction in the number and size of GABA(A) receptor clusters immunoreactive for a1- and a2-subunits at the post-synaptic densities. 4. These results may explain some of the behavioural problems and cognitive impairment reported in DMD. PMID:17941889

  11. Rabphilin 3A retains NMDA receptors at synaptic sites through interaction with GluN2A/PSD-95 complex

    PubMed Central

    Stanic, Jennifer; Carta, Mario; Eberini, Ivano; Pelucchi, Silvia; Marcello, Elena; Genazzani, Armando A.; Racca, Claudia; Mulle, Christophe; Di Luca, Monica; Gardoni, Fabrizio

    2015-01-01

    NMDA receptor (NMDAR) composition and synaptic retention represent pivotal features in the physiology and pathology of excitatory synapses. Here, we identify Rabphilin 3A (Rph3A) as a new GluN2A subunit-binding partner. Rph3A is known as a synaptic vesicle-associated protein involved in the regulation of exo- and endocytosis processes at presynaptic sites. We find that Rph3A is enriched at dendritic spines. Protein–protein interaction assays reveals that Rph3A N-terminal domain interacts with GluN2A(1349–1389) as well as with PSD-95(PDZ3) domains, creating a ternary complex. Rph3A silencing in neurons reduces the surface localization of synaptic GluN2A and NMDAR currents. Moreover, perturbing GluN2A/Rph3A interaction with interfering peptides in organotypic slices or in vivo induces a decrease of the amplitude of NMDAR-mediated currents and GluN2A density at dendritic spines. In conclusion, Rph3A interacts with GluN2A and PSD-95 forming a complex that regulates NMDARs stabilization at postsynaptic membranes. PMID:26679993

  12. Ischemia-induced synaptic plasticity drives sustained expression of calcium-permeable AMPA receptors in the hippocampus.

    PubMed

    Dias, Raquel B; Rombo, Diogo M; Ribeiro, Joaquim A; Sebastião, Ana M

    2013-02-01

    Long lasting enhancement of synaptic transmission can be triggered by brief bursts of afferent stimulation, underlying long-term potentiation (LTP), and also by brief ischemia in a process known as i-LTP. The extent to which LTP and i-LTP rely on comparable cellular mechanisms remains unclear. Under physiological conditions, LTP induction drives transient expression of calcium-permeable AMPARs (CP-AMPARs) at synapses, whose ability to undergo plasticity is primed by endogenous activation of adenosine A(2A) receptors (A(2A)Rs). The present work thus addressed the contribution of CP-AMPARs and A(2A)Rs to i-LTP, which was induced in rat hippocampal slices by brief (10 min) oxygen/glucose deprivation (OGD). The amplitude of afferent-evoked excitatory postsynaptic currents (EPSCs) recorded from CA1 pyramidal neurons was decreased during OGD but gradually recovered toward values significantly above (157 ± 17%) the baseline (100%) 40-50 min after re-oxygenation. This i-LTP was precluded by CP-AMPAR blockade (internal spermine (500 μM) or extracellular NASPM (20 μM) application) as well as by A(2A)R blockade with a selective antagonist (SCH 58261, 100 nM). OGD prompted sustained (>70 min) facilitation of mEPSC amplitude and frequency, and decreased mEPSC decay time, all of which were prevented by SCH 58261 (100 nM). The ability of NASPM (20 μM) to acutely inhibit EPSCs 1 h after OGD, but not in control conditions nor in OGD-challenged slices when in the presence of SCH 58261 (100 nM), further supports sustained CP-AMPAR recruitment by i-LTP in an A(2A)R-dependent way. We propose that although i-LTP may initially mimic LTP, failure of auto-regulated CP-AMPAR removal from synapses could constitute an early divergent event between these forms of plasticity. PMID:23041538

  13. P2X-mediated AMPA receptor internalization and synaptic depression is controlled by two CaMKII phosphorylation sites on GluA1 in hippocampal neurons.

    PubMed

    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

  14. Itinerant electron model and conductance of DNA

    NASA Astrophysics Data System (ADS)

    Qu, Zhen; Kang, Da-Wei; Gao, Xu-Tuan; Xie, Shi-Jie

    2008-09-01

    DNA (Deoxyribonucleic acid) has recently caught the attention of chemists and physicists. A major reason for this interest is DNA’s potential use in nanoelectronic devices, both as a template for assembling nanocircuits and as an element of such circuits. However, the electronic properties of the DNA molecule remain very controversial. Charge-transfer reactions and conductivity measurements show a large variety of possible electronic behavior, ranging from Anderson and band-gap insulators to effective molecular wires and induced superconductors. In this review article, we summarize the wide-ranging experimental and theoretical results of charge transport in DNA. An itinerant electron model is suggested and the effect of the density of itinerant electrons on the conductivity of DNA is studied. Calculations show that a DNA molecule may show conductivity from insulating to metallic, which explains the controversial and profuse electric characteristics of DNA to some extent.

  15. 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.

  16. Itinerant antiferromagnetism of TiAl alloys

    NASA Astrophysics Data System (ADS)

    Petrişor, T.; Pop, I.; Giurgiu, A.; Farbaş, N.

    1986-06-01

    Magnetic susceptibility measurements of TiAl alloys are reported. Aluminium, by alloying, acts on the Néel temperature of pure titanium giving rise to a complicated phase diagram. A theoretical model, based on the itinerant antiferromagnetism model of chromium is proposed in order to explain the magnetic phase diagram of TiAl alloys. The experimental and theoretical magnetic phase diagram are in good agreement.

  17. α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

    PubMed Central

    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

    2016-01-01

    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. PMID:27114538

  18. 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. PMID:27114538

  19. Nanomechanical detection of itinerant electron spin flip.

    PubMed

    Zolfagharkhani, Guiti; Gaidarzhy, Alexei; Degiovanni, Pascal; Kettemann, Stefan; Fulde, Peter; Mohanty, Pritiraj

    2008-12-01

    Electrons and other fundamental particles have an intrinsic angular momentum called spin. A change in the spin state of such a particle is therefore equivalent to a mechanical torque. This spin-induced torque is central to our understanding of experiments ranging from the measurement of the angular momentum of photons and the g-factor of metals to magnetic resonance and magnetization reversal in magnetic multilayers. When a spin-polarized current passes through a metallic nanowire in which one half is ferromagnetic and the other half is nonmagnetic, the spins of the itinerant electrons are 'flipped' at the interface between the two regions to produces a torque. Here, we report direct measurement of this mechanical torque in an integrated nanoscale torsion oscillator, and measurements of the itinerant electron spin polarization that could yield new information on the itinerancy of the d-band electrons. The unprecedented torque sensitivity of 1 x 10(-22) N-m Hz(-1/2) may have applications in spintronics and precision measurements of charge-parity-violating forces, and might also enable experiments on the untwisting of DNA and torque-generating molecules. PMID:19057590

  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. PMID:24672001

  1. 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

    Wu, T Y; Liu, C I; Chang, Y C

    1996-11-01

    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

  2. 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

  3. 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

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

    PubMed

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

    2016-01-01

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

  5. "Shadowing" Itinerant ECSE Teachers: A Descriptive Study of Itinerant Teacher Activities

    ERIC Educational Resources Information Center

    Dinnebeil, Laurie A.; McInerney, William F.; Hale, Lynette

    2006-01-01

    In an effort to document the responsibilities and professional activities of itinerant early childhood special education (ECSE) teachers, five teachers were asked to participate in an observational study in which they were observed and their behaviors coded. Observations occurred at three different times during the year, during three-week cycles.…

  6. 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…

  7. 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. PMID:17084962

  8. Theory of helimagnons in itinerant quantum systems

    NASA Astrophysics Data System (ADS)

    Belitz, D.; Kirkpatrick, T. R.; Rosch, A.

    2006-02-01

    The nature and effects of the Goldstone mode in the ordered phase of helical or chiral itinerant magnets such as MnSi are investigated theoretically. It is shown that the Goldstone mode, or helimagnon, is a propagating mode with a highly anisotropic dispersion relation, in analogy to the Goldstone mode in chiral liquid crystals. Starting from a microscopic theory, a comprehensive effective theory is developed that allows for an explicit description of the helically ordered phase, including the helimagnons, for both classical and quantum helimagnets. The directly observable dynamical spin susceptibility, which reflects the properties of the helimagnon, is calculated.

  9. Molecular Motors and Synaptic Assembly

    PubMed Central

    Cai, Qian; Sheng, Zu-Hang

    2016-01-01

    Proper synaptic function requires the seamless integration of the transport, assembly, and regulation of synaptic components and structures. Inasmuch as the synapse is often distant from the neuronal cell body, newly synthesized synaptic proteins, the precursors of synaptic vesicles, active zone compartments, channels and receptors, and mitochondria, must be transported along lengthy neuronal processes to participate in synaptogenesis. Neuronal transport is mediated by motor proteins that associate with their cargoes via adaptors (or receptors) and that travel along the cytoskeleton network within the neuronal processes. Thus, the identity of membranous protein cargoes and the specificity of motor-cargo interactions are critical for correctly targeting cargoes and properly assembling synapses in developing neurons and in remodeling synapses of mature neurons in response to neuronal activity. In this article, the authors review recent progress in characterizing microtubule- and actin-based motor proteins that are involved in delivering synaptic components and discuss potential mechanisms underlying the formation of motor- receptor-cargo complexes that contribute to synaptogenesis and activity-induced synaptic plasticity. PMID:19218232

  10. 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

    2016-07-01

    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. PMID:27090818

  11. 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. PMID:25139282

  12. γ-Aminobutyric Acid Type A (GABAA) Receptor Subunits Play a Direct Structural Role in Synaptic Contact Formation via Their N-terminal Extracellular Domains.

    PubMed

    Brown, Laura E; Nicholson, Martin W; Arama, Jessica E; Mercer, Audrey; Thomson, Alex M; Jovanovic, Jasmina N

    2016-07-01

    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

  13. 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

  14. Favouring inhibitory synaptic drive mediated by GABAA receptors in the basolateral nucleus of the amygdala efficiently reduces pain symptoms in neuropathic mice.

    PubMed

    Zeitler, Alexandre; Kamoun, Nisrine; Goyon, Stéphanie; Wahis, Jérôme; Charlet, Alexandre; Poisbeau, Pierrick; Darbon, Pascal

    2016-04-01

    Pain is an emotion and neuropathic pain symptoms are modulated by supraspinal structures such as the amygdala. The central nucleus of the amygdala is often called the 'nociceptive amygdala', but little is known about the role of the basolateral amygdala. Here, we monitored the mechanical nociceptive thresholds in a mouse model of neuropathic pain and infused modulators of the glutamate/GABAergic transmission in the basolateral nucleus of the amygdala (BLA) via chronically-implanted cannulas. We found that an N-methyl-D-aspartate-type glutamate receptor antagonist (MK-801) exerted a potent antiallodynic effect, whereas a transient allodynia was induced after perfusion of bicuculline, a GABAA receptor antagonist. Potentiating GABAA receptor function using diazepam or etifoxine (a non-benzodiazepine anxiolytic) fully but transiently alleviated mechanical allodynia. Interestingly, the antiallodynic effect of etifoxine disappeared in animals that were incapable of producing 3α-steroids. Diazepam had a similar effect but of shorter duration. As indicated by patch-clamp recordings of BLA neurons, these effects were mediated by a potentiation of GABAA receptor-mediated synaptic transmission. Together with a presynaptic elevation of miniature inhibitory postsynaptic current frequency, the duration and amplitude of GABAA miniature inhibitory postsynaptic currents were also increased (postsynaptic effect). The analgesic contribution of endogenous neurosteroid seemed to be exclusively postsynaptic. This study highlights the importance of the BLA and the local inhibitory/excitatory neuronal network activity while setting the mechanical nociceptive threshold. Furthermore, it appears that promoting inhibition in this specific nucleus could fully alleviate pain symptoms. Therefore, the BLA could be a novel interesting target for the development of pharmacological or non-pharmacological therapies. PMID:26913957

  15. New effects of GABAB receptor allosteric modulator rac-BHFF on ambient GABA, uptake/release, Em and synaptic vesicle acidification in nerve terminals.

    PubMed

    Pozdnyakova, N; Dudarenko, M; Borisova, T

    2015-09-24

    Positive allosteric modulators of GABAB receptors have great therapeutic potential for medications of anxiety, depression, etc. The effects of recently discovered modulator rac-BHFF on the key characteristics of GABAergic neurotransmission were investigated in cortical and hippocampal presynaptic nerve terminals of rats (synaptosomes). The ambient level of [(3)H]GABA that is a balance between release and uptake of the neurotransmitter increased significantly in the presence of rac-BHFF (at concentrations 10-30μM). The initial velocity of synaptosomal [(3)H]GABA uptake was suppressed by the modulator. In the presence of GABA transporter blocker NO-711, it was shown that rac-BHFF increased tonic release of [(3)H]GABA from synaptosomes (at concentrations 3-30μM). Rac-BHFF within the concentration range of 0.3-30μM did not enhance inhibiting effect of (±)-baclofen on depolarization-induced exocytotic release of [(3)H]GABA. Rac-BHFF (0.3-30μM) caused dose-dependent depolarization of the plasma membrane and dissipation of the proton gradient of synaptic vesicles in synaptosomes that was shown in the absence/presence of GABAB receptor antagonist saclofen using fluorescent dyes rhodamine 6G and acridine orange, respectively, and so, the above effects of rac-BHFF were not associated with the modulation of presynaptic GABAB receptors. Therefore, drug development strategy of positive allosteric modulation of GABAB receptors is to eliminate the above side effects of rac-BHFF in presynapse, and vice versa, these new properties of rac-BHFF may be exploited appropriately. PMID:26197223

  16. 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

    2015-06-01

    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 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

  17. 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

  18. GluN2B-Containing NMDA Receptors Blockade Rescues Bidirectional Synaptic Plasticity in the Bed Nucleus of the Stria Terminalis of Cocaine Self-Administering Rats

    PubMed Central

    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

  19. GluN2D-containing NMDA receptors-mediate synaptic currents in hippocampal interneurons and pyramidal cells in juvenile mice

    PubMed Central

    von Engelhardt, Jakob; Bocklisch, Christina; Tönges, Lars; Herb, Anne; Mishina, Masayoshi; Monyer, Hannah

    2015-01-01

    The differential regulation of the two major N-methyl-D-aspartate receptor (NMDAR) subunits GluN2A and GluN2B during development in forebrain pyramidal cells has been thoroughly investigated. In contrast, much less is known about the role of GluN2D, which is expressed at low levels and is downregulated following the second postnatal week. However, it appears that few cells, presumably interneurons, continue to express GluN2D also in juvenile mice. To investigate which hippocampal cell types express this subunit, we generated transgenic mice with EGFP-tagged GluN2D receptors. The expression of the transgene was confined to hippocampal interneurons, most of which were parvalbumin- and/or somatostatin-positive. Electrophysiological and morphological analyses showed that GluN2D was present mainly in fast spiking basket and axo-axonic cells. Based on pharmacological evidence and electrophysiological analysis of GluN2D knockout mice, we conclude that GluN2D-containing NMDARs mediate synaptic currents in hippocampal interneurons of young and juvenile mice and in CA1 pyramidal neurons of newborn mice. PMID:25859181

  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 synaptic plasticity and spatial memory for a few days. Drugs that block 5-HT2C receptors might protect the hippocampus against the detrimental effect of environmental stressors. PMID:26145279

  1. 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

  2. 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. PMID:26929363

  3. Chaotic itinerancy, temporal segmentation and spatio-temporal combinatorial codes

    NASA Astrophysics Data System (ADS)

    Dias, Juliana R.; Oliveira, Rodrigo F.; Kinouchi, Osame

    2008-01-01

    We study a deterministic dynamics with two time scales in a continuous state attractor network. To the usual (fast) relaxation dynamics towards point attractors (“patterns”) we add a slow coupling dynamics that makes the visited patterns lose stability, leading to an itinerant behavior in the form of punctuated equilibria. One finds that the transition frequency matrix for transitions between patterns shows non-trivial statistical properties in the chaotic itinerant regime. We show that mixture input patterns can be temporally segmented by the itinerant dynamics. The viability of a combinatorial spatio-temporal neural code is also demonstrated.

  4. Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease.

    PubMed

    Dziewczapolski, Gustavo; Glogowski, Carolina M; Masliah, Eliezer; Heinemann, Stephen F

    2009-07-01

    It has been recently shown that the Alzheimer's disease (AD) pathogenic peptide amyloid beta(1-42) (Abeta(1-42)) binds to the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) with high affinity and the alpha7nAChR and Abeta(1-42) are both found colocalized in neuritic plaques of human brains with AD. Moreover, the intraneuronal accumulation of Abeta(1-42) was shown to be facilitated by its high-affinity binding to the alpha7nAChR, and alpha7nAChR activation mediates Abeta-induced tau protein phosphorylation. To test the hypothesis that alpha7nAChRs are involved in AD pathogenesis, we used a transgenic mouse model of AD overexpressing a mutated form of the human amyloid precursor protein (APP) and lacking the alpha7nAChR gene (APPalpha7KO). We have shown that, despite the presence of high amounts of APP and amyloid deposits, deleting the alpha7nAChR subunit in the mouse model of AD leads to a protection from the dysfunction in synaptic integrity (pathology and plasticity) and learning and memory behavior. Specifically, APPalpha7KO mice express APP and Abeta at levels similar to APP mice, and yet they were able to solve a cognitive challenge such as the Morris water maze test significantly better than APP, with performances comparable to control groups. Moreover, deleting the alpha7nAChR subunit protected the brain from loss of the synaptic markers synaptophysin and MAP2, reduced the gliosis, and preserved the capacity to elicit long-term potentiation otherwise deficient in APP mice. These results are consistent with the hypothesis that the alpha7nAChR plays a role in AD and suggest that interrupting alpha7nAChR function could be beneficial in the treatment of AD. PMID:19587288

  5. Synaptic connections between the hindwing stretch receptor and flight motor neurones in the locust revealed by double cobalt labelling for electron microscopy

    SciTech Connect

    Peters, B.H.; Altman, J.S.; Tyrer, N.M.

    1985-03-08

    Synaptic interactions between sensory and motor neurones in the locust flight system have been investigated by using intracellular labelling with cobalt and nickel for electron microscopy. Simultaneous axonal filling of two neurones with different concentrations of metal ions produces differential labelling, so that contacts between them in the central nervous system can be recognized. We have investigated the connectivity of the hindwing stretch receptor neurone (SR) with a direct hindwing depressor motor neurone (MN 127) known from physiological experiments to receive monosynaptic input from the SR, and an indirect hindwing depressor motor neurone (MN 112/1), for which no monosynaptic connection with the SR has been reported. We have found no direct synapses between the SR and MN 112/1, although some of their branches lie close together in the neuropile. We have, however, found some evidence for polysynaptic connections between them. There are many synapses of conventional dyadic morphology from both the lateral and mediolateral branches of the SR to MN 127; the medial branch was not examined. Those from the lateral branch contact the motor neurone on branches close to the neuropilar segment, while those from the mediolateral branch contact long, thin distal twigs. We estimate that there are about 600 anatomical synapses between these two neurones. Our results suggest that a large number of widely distributed anatomical synapses constitute the physiological synaptic connection between the SR and MN 127. The dyadic arrangement of these synapses provides an anatomical correlate for the physiologically established divergence of SR outputs onto interneurones and motor neurones.

  6. Nicotinic modulation of glutamate receptor function at nerve terminal level: a fine-tuning of synaptic signals.

    PubMed

    Marchi, Mario; Grilli, Massimo; Pittaluga, Anna M

    2015-01-01

    This review focuses on a specific interaction occurring between the nicotinic cholinergic receptors (nAChRs) and the glutamatergic receptors (GluRs) at the nerve endings level. We have employed synaptosomes in superfusion and supplemented and integrated our findings with data obtained using techniques from molecular biology and immuno-cytochemistry, and the assessment of receptor trafficking. In particular, we characterize the following: (1) the direct and unequivocal localization of native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamatergic receptors on specific nerve terminals, (2) their pharmacological characterization and functional co-localization with nAChRs on the same nerve endings, and (3) the existence of synergistic or antagonistic interactions among them. Indeed, in the rat nucleus accumbens (NAc), the function of some AMPA and NMDA receptors present on the dopaminergic and glutamatergic nerve terminals can be regulated negatively or positively in response to a brief activation of nAChRs. This effect occurs rapidly and involves the trafficking of AMPA and NMDA receptors. The event takes place also at very low concentrations of nicotine and involves the activation of several nAChRs subtypes. This dynamic control by cholinergic nicotinic system of glutamatergic NMDA and AMPA receptors might therefore represent an important neuronal presynaptic adaptation associated with nicotine administration. The understanding of the role of these nicotine-induced functional changes might open new and interesting perspectives both in terms of explaining the mechanisms that underlie some of the effects of nicotine addiction and in the development of new drugs for smoking cessation. PMID:25972809

  7. Anomalous quantum criticality in an itinerant ferromagnet.

    PubMed

    Huang, C L; Fuchs, D; Wissinger, M; Schneider, R; Ling, M C; Scheurer, M S; Schmalian, J; Löhneysen, H V

    2015-01-01

    The dynamics of continuous phase transitions is governed by the dynamic scaling exponent relating the correlation length and correlation time. For transitions at finite temperature, thermodynamic critical properties are independent of the dynamic scaling exponent. In contrast, at quantum phase transitions where the transition temperature becomes zero, static and dynamic properties are inherently entangled by virtue of the uncertainty principle. Consequently, thermodynamic scaling equations explicitly contain the dynamic exponent. Here we report on thermodynamic measurements (as a function of temperature and magnetic field) for the itinerant ferromagnet Sr1-xCaxRuO3 where the transition temperature becomes zero for x=0.7. We find dynamic scaling of the magnetization and specific heat with highly unusual quantum critical dynamics. We observe a small dynamic scaling exponent of 1.76 strongly deviating from current models of ferromagnetic quantum criticality and likely being governed by strong disorder in conjunction with strong electron-electron coupling. PMID:26348932

  8. Role of Neurotrophin Receptor TrkB in the Maturation of Rod Photoreceptors and Establishment of Synaptic Transmission to the Inner Retina

    PubMed Central

    Rohrer, Baerbel; Korenbrot, Juan I.; LaVail, Matthew M.; Reichardt, Louis F.; Xu, Baoji

    2009-01-01

    Brain-derived neurotrophic factor (BDNF) acts through TrkB, a receptor with kinase activity, and mitigates light-induced apoptosis in adult mouse rod photoreceptors. To determine whether TrkB signaling is necessary for rod development and function, we examined the retinas of mice lacking all isoforms of the TrkB receptor. Rod migration and differentiation occur in the mutant retina, but proceed at slower rates than in wild-type mice. In postnatal day 16 (P16) mutants, rod outer segment dimensions and rhodopsin content are comparable with those of photoreceptors in P12 wild type (WT). Quantitative analyses of the photoreceptor component in the electroretinogram (ERG) indicate that the gain and kinetics of the rod phototransduction signal in dark-adapted P16 mutant and P12 WT retinas are similar. In contrast to P12 WT, however, the ERG in mutant mice entirely lacks a b-wave, indicating a failure of signal transmission in the retinal rod pathway. In the inner retina of mutant mice, although cells appear anatomically and immunohistochemically normal, they fail to respond to prolonged stroboscopic illumination with the normal expression of c-fos. Absence of the b-wave and failure of c-fos expression, in view of anatomically normal inner retinal cells, suggest that lack of TrkB signaling causes a defect in synaptic signaling between rods and inner retinal cells. Retinal pigment epithelial cells and cells in the inner retina, including Müller, amacrine, and retinal ganglion cells, express the TrkB receptor, but rod photoreceptors do not. Moreover, inner retinal cells respond to exogenous BDNF with c-fos expression and extracellular signal-regulated kinase phosphorylation. Thus, interactions of rods with TrkB-expressing cells must be required for normal rod development. PMID:10516311

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

    PubMed

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

    2016-05-01

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

  10. Joint CP-AMPA and group I mGlu receptor activation is required for synaptic plasticity in dentate gyrus fast-spiking interneurons

    PubMed Central

    Hainmüller, Thomas; Krieglstein, Kerstin; Kulik, Akos; Bartos, Marlene

    2014-01-01

    Hippocampal principal cell (PC) assemblies provide the brain with a mnemonic representation of space. It is assumed that the formation of cell assemblies is supported by long-lasting modification of glutamatergic synapses onto perisomatic inhibitory interneurons (PIIs), which provide powerful feedback inhibition to neuronal networks. Repetitive activation of dentate gyrus PIIs by excitatory mossy fiber (MF) inputs induces Hebbian long-term potentiation (LTP). In contrast, long-term depression (LTD) emerges in the absence of PII activity. However, little is known about the molecular mechanisms underlying synaptic plasticity in PIIs. Here, we examined the role of group I metabotropic glutamate receptors 1 and 5 (mGluRs1/5) in inducing plastic changes at MF-PII synapses. We found that mGluRs1/5 are located perisynaptically and that pharmacological block of mGluR1 or mGluR5 abolished MF-LTP. In contrast, their exogenous activation was insufficient to induce MF-LTP but cleared MF-LTD. No LTP could be elicited in PIIs loaded with blockers of G protein signaling and Ca2+-dependent PKC. Two-photon imaging revealed that the intracellular Ca2+ rise necessary for MF-LTP was largely mediated by Ca2+-permeable AMPA receptors (CP-AMPARs), but less by NMDA receptors or mGluRs1/5. Thus, our data indicate that fast Ca2+ signaling via CP-AMPARs and slow G protein-mediated signaling via mGluRs1/5 converge to a PKC-dependent molecular pathway to induce Hebbian MF-LTP. We further propose that Hebbian activation of mGluRs1/5 gates PIIs into a “readiness mode” to promote MF-LTP, which, in turn, will support timed PII recruitment, thereby assisting in PC assembly formation. PMID:25161282