49 results match your criteria phosphorylation gephyrin

Differential regulation of glycinergic and GABAergic nanocolumns at mixed inhibitory synapses.

EMBO Rep 2021 May 28:e52154. Epub 2021 May 28.

Institute of Biology of the École Normale Supérieure (IBENS), CNRS, Inserm, PSL Research University, Paris, France.

Super-resolution imaging has revealed that key synaptic proteins are dynamically organized within sub-synaptic domains (SSDs). To examine how different inhibitory receptors are regulated, we carried out dual-color direct stochastic optical reconstruction microscopy (dSTORM) of GlyRs and GABA Rs at mixed inhibitory synapses in spinal cord neurons. We show that endogenous GlyRs and GABA Rs as well as their common scaffold protein gephyrin form SSDs that align with pre-synaptic RIM1/2, thus creating trans-synaptic nanocolumns. Read More

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Artemisinin-treatment in pre-symptomatic APP-PS1 mice increases gephyrin phosphorylation at Ser270: a modification regulating postsynaptic GABAR density.

Biol Chem 2021 Apr 20. Epub 2021 Apr 20.

Institute of Anatomy and Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, D-69120Heidelberg, Germany.

Artemisinins, a group of plant-derived sesquiterpene lactones, are efficient antimalarial agents. They also share anti-inflammatory and anti-viral activities and were considered for treatment of neurodegenerative disorders like Alzheimer's disease (AD). Additionally, artemisinins bind to gephyrin, the multifunctional scaffold of GABAergic synapses, and modulate inhibitory neurotransmission . Read More

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Binding of gephyrin to microtubules is regulated by its phosphorylation at Ser270.

Histochem Cell Biol 2021 Apr 1. Epub 2021 Apr 1.

Department of Anatomy and Cell Biology, Institut für Anatomie und Zellbiologie, University of Heidelberg, Lehrstuhl II, Im Neuenheimer Feld 307, 69120, Heidelberg, Germany.

Gephyrin is a multifunctional scaffolding protein anchoring glycine- and subtypes of GABA type A- receptors at inhibitory postsynaptic membrane specializations by binding to the microtubule (MT) and/or the actin cytoskeleton. However, the conditions under which gephyrin can bind to MTs and its regulation are currently unknown. Here, we demonstrate that during the purification of MTs from rat brain by sedimentation of polymerized tubulin using high-speed centrifugation a fraction of gephyrin was bound to MTs, whereas gephyrin phosphorylated at the CDK5-dependent site Ser270 was detached from MTs and remained in the soluble protein fraction. Read More

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Gephyrin-mediated formation of inhibitory postsynaptic density sheet via phase separation.

Cell Res 2021 Mar 2;31(3):312-325. Epub 2020 Nov 2.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

Inhibitory synapses are also known as symmetric synapses due to their lack of prominent postsynaptic densities (PSDs) under a conventional electron microscope (EM). Recent cryo-EM tomography studies indicated that inhibitory synapses also contain PSDs, albeit with a rather thin sheet-like structure. It is not known how such inhibitory PSD (iPSD) sheet might form. Read More

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Phosphorylation on Ser-359 of the α2 subunit in GABA type A receptors down-regulates their density at inhibitory synapses.

J Biol Chem 2020 08 3;295(35):12330-12342. Epub 2020 Jul 3.

Department of Neuroscience, Tufts University, School of Medicine, Boston, Massachusetts, USA

GABA type A receptors (GABARs) mediate fast synaptic inhibition and are trafficked to functionally diverse synapses. However, the precise molecular mechanisms that regulate the synaptic targeting of these receptors are unclear. Whereas it has been previously shown that phosphorylation events in α4, β, and γ subunits of GABARs govern their function and trafficking, phosphorylation of other subunits has not yet been demonstrated. Read More

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Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

Proc Natl Acad Sci U S A 2020 05 20;117(18):9991-10002. Epub 2020 Apr 20.

Department of Neuroscience, Columbia University, New York, NY 10032;

The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain's initial molecular and epigenetic response to cocaine. Read More

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Amyloid-β Fosters p35/CDK5 Signaling Contributing to Changes of Inhibitory Synapses in Early Stages of Cerebral Amyloidosis.

J Alzheimers Dis 2020 ;74(4):1167-1187

Institute of Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany.

Early changes in inhibitory synapse connectivities are thought to contribute to the excitation/inhibition imbalance preceding neurodegeneration in Alzheimer's disease (AD). Recently, we reported a robust increase in the level of different key-proteins of inhibitory synapses in hippocampal subregions of pre-symptomatic APPswe-PS1 mice, a model of cerebral amyloidosis. Besides increased inhibitory synaptic clusters on parvalbumin-positive projections in CA1 and CA3, we observed impaired communication between these two hippocampal areas of young APP-PS1 mice. Read More

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cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABAR Trapping at Inhibitory Synapses.

iScience 2019 Dec 9;22:453-465. Epub 2019 Nov 9.

École Normale Supérieure, PSL Research University, CNRS, Inserm, Institute of Biology (IBENS), Paris 75005, France. Electronic address:

GABA and glycine receptors are thought to compete for gephyrin-binding sites at mixed inhibitory synapses. Changes in the occupancy of one receptor type are therefore expected to have opposite effects on the clustering of the other receptors. This does not explain, however, whether different receptors can be regulated independently from one another. Read More

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December 2019

Phosphorylation of Gephyrin in Zebrafish Mauthner Cells Governs Glycine Receptor Clustering and Behavioral Desensitization to Sound.

J Neurosci 2019 11 26;39(45):8988-8997. Epub 2019 Sep 26.

Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, Sagamihara, 252-5258, Japan,

The process by which future behavioral responses are shaped by past experiences is one of the central questions in neuroscience. To gain insight into this process at the molecular and cellular levels, we have applied zebrafish larvae to explore behavioral desensitization to sound. A sudden loud noise often evokes a defensive response known as the acoustic startle response (ASR), which is triggered by firing Mauthner cells in teleosts and amphibians. Read More

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November 2019

Diazepam Accelerates GABAR Synaptic Exchange and Alters Intracellular Trafficking.

Front Cell Neurosci 2019 26;13:163. Epub 2019 Apr 26.

Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.

Despite 50+ years of clinical use as anxiolytics, anti-convulsants, and sedative/hypnotic agents, the mechanisms underlying benzodiazepine (BZD) tolerance are poorly understood. BZDs potentiate the actions of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, through positive allosteric modulation of γ2 subunit containing GABA type A receptors (GABARs). Here we define key molecular events impacting γ2 GABAR and the inhibitory synapse gephyrin scaffold following initial sustained BZD exposure and . Read More

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The key genes, phosphoproteins, processes, and pathways affected by efavirenz-activated CYP46A1 in the amyloid-decreasing paradigm of efavirenz treatment.

FASEB J 2019 08 7;33(8):8782-8798. Epub 2019 May 7.

Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA.

Efavirenz (EFV) is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is the major brain cholesterol hydroxylase. Previously, we discovered that EFV activates CYP46A1 and improves behavioral performance in 5XFAD mice, an Alzheimer's disease model. Herein, the unbiased omics and other approaches were used to study 5XFAD mice in the amyloid-decreasing paradigm of CYP46A1 activation by EFV. Read More

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A unique intracellular tyrosine in neuroligin-1 regulates AMPA receptor recruitment during synapse differentiation and potentiation.

Nat Commun 2018 09 28;9(1):3979. Epub 2018 Sep 28.

Interdisciplinary Institute for Neuroscience, UMR 5297, Univ. Bordeaux, F-33000, Bordeaux, France.

To better understand the molecular mechanisms by which early neuronal connections mature into synapses, we examined the impact of neuroligin-1 (Nlg1) phosphorylation on synapse differentiation, focusing on a unique intracellular tyrosine (Y782), which differentially regulates Nlg1 binding to PSD-95 and gephyrin. By expressing Nlg1 point mutants (Y782A/F) in hippocampal neurons, we show using imaging and electrophysiology that Y782 modulates the recruitment of functional AMPA receptors (AMPARs). Nlg1-Y782F impaired both dendritic spine formation and AMPAR diffusional trapping, but not NMDA receptor recruitment, revealing the assembly of silent synapses. Read More

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September 2018

Activity-Dependent Inhibitory Synapse Scaling Is Determined by Gephyrin Phosphorylation and Subsequent Regulation of GABA Receptor Diffusion.

eNeuro 2018 Jan-Feb;5(1). Epub 2018 Jan 18.

INSERM UMR-S, Paris, 75005, France.

Synaptic plasticity relies on the rapid changes in neurotransmitter receptor number at postsynaptic sites. Using superresolution photoactivatable localization microscopy imaging and quantum dot-based single-particle tracking in rat hippocampal cultured neurons, we investigated whether the phosphorylation status of the main scaffolding protein gephyrin influenced the organization of the gephyrin scaffold and GABA receptor (GABAR) membrane dynamics. We found that gephyrin phosphorylation regulates gephyrin microdomain compaction. Read More

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January 2019

Several posttranslational modifications act in concert to regulate gephyrin scaffolding and GABAergic transmission.

Nat Commun 2016 11 7;7:13365. Epub 2016 Nov 7.

Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH 8057 Zurich, Switzerland.

GABA receptors (GABARs) mediate the majority of fast inhibitory neurotransmission in the brain via synergistic association with the postsynaptic scaffolding protein gephyrin and its interaction partners. However, unlike their counterparts at glutamatergic synapses, gephyrin and its binding partners lack canonical protein interaction motifs; hence, the molecular basis for gephyrin scaffolding has remained unclear. In this study, we identify and characterize two new posttranslational modifications of gephyrin, SUMOylation and acetylation. Read More

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November 2016

Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses.

Elife 2016 11 2;5. Epub 2016 Nov 2.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.

Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. Read More

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November 2016

Gephyrin and the regulation of synaptic strength and dynamics at glycinergic inhibitory synapses.

Brain Res Bull 2017 03 6;129:50-65. Epub 2016 Sep 6.

Department of Physiology, Emory University, Atlanta, GA 30322-3110, United States. Electronic address:

Glycinergic synapses predominate in brainstem and spinal cord where they modulate motor and sensory processing. Their postsynaptic mechanisms have been considered rather simple because they lack a large variety of glycine receptor isoforms and have relatively simple postsynaptic densities at the ultrastructural level. However, this simplicity is misleading being their postsynaptic regions regulated by a variety of complex mechanisms controlling the efficacy of synaptic inhibition. Read More

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Proteomic Characterization of Inhibitory Synapses Using a Novel pHluorin-tagged γ-Aminobutyric Acid Receptor, Type A (GABAA), α2 Subunit Knock-in Mouse.

J Biol Chem 2016 Jun 4;291(23):12394-407. Epub 2016 Apr 4.

From the Department of Neuroscience, Tufts University School of Medicine, Boston Massachusetts 02111 and the Department of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United Kingdom

The accumulation of γ-aminobutyric acid receptors (GABAARs) at the appropriate postsynaptic sites is critical for determining the efficacy of fast inhibitory neurotransmission. Although we know that the majority of synaptic GABAAR subtypes are assembled from α1-3, β, and γ2 subunits, our understanding of how neurons facilitate their targeting to and stabilization at inhibitory synapses is rudimentary. To address these issues, we have created knock-in mice in which the pH-sensitive green fluorescent protein (GFP) and the Myc epitope were introduced to the extracellular domain of the mature receptor α2 subunit (pHα2). Read More

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Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism.

Eur J Hum Genet 2016 Jan 22;24(1):59-65. Epub 2015 Apr 22.

Hospital Israelita Albert Einstein, Instituto de Ensino e Pesquisa, São Paulo, Brazil.

Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuron-specific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Read More

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January 2016

Postsynaptic gephyrin clustering controls the development of adult-born granule cells in the olfactory bulb.

J Comp Neurol 2015 Sep;523(13):1998-2016

University of Zurich, Institute of Pharmacology and Toxicology, 8057, Zurich, Switzerland.

In adult rodent olfactory bulb, GABAergic signaling regulates migration, differentiation, and synaptic integration of newborn granule cells (GCs), migrating from the subventricular zone. Here we show that these effects depend on the formation of a postsynaptic scaffold organized by gephyrin-the main scaffolding protein of GABAergic synapses, which anchors receptors and signaling molecules to the postsynaptic density-and are regulated by the phosphorylation status of gephyrin. Using lentiviral vectors to selectively transfect adult-born GCs, we observed that overexpression of the phospho-deficient gephyrin mutant eGFP-gephyrin(S270A), which facilitates the formation of supernumerary GABAergic synapses in vitro, favors dendritic branching and the formation of transient GABAergic synapses on spines, identified by the presence of α2-GABAA Rs. Read More

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September 2015

Protein kinase C-dependent growth-associated protein 43 phosphorylation regulates gephyrin aggregation at developing GABAergic synapses.

Mol Cell Biol 2015 May 9;35(10):1712-26. Epub 2015 Mar 9.

Department and Institute of Physiology and Brain Research Center, National Yang-Ming University, Taipei, Taiwan Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan

Growth-associated protein 43 (GAP43) is known to regulate axon growth, but whether it also plays a role in synaptogenesis remains unclear. Here, we found that GAP43 regulates the aggregation of gephyrin, a pivotal protein for clustering postsynaptic GABA(A) receptors (GABA(A)Rs), in developing cortical neurons. Pharmacological blockade of either protein kinase C (PKC) or neuronal activity increased both GAP43-gephyrin association and gephyrin misfolding-induced aggregation, suggesting the importance of PKC-dependent regulation of GABAergic synapses. Read More

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Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation.

Proc Natl Acad Sci U S A 2015 Jan 22;112(1):E65-72. Epub 2014 Dec 22.

Département des Neurosciences Fondamentales, Faculté de Médecine, Centre Médical Universitaire, Université de Genève, 1211 Geneve 4, Switzerland; and

Maintaining a proper balance between excitation and inhibition is essential for the functioning of neuronal networks. However, little is known about the mechanisms through which excitatory activity can affect inhibitory synapse plasticity. Here we used tagged gephyrin, one of the main scaffolding proteins of the postsynaptic density at GABAergic synapses, to monitor the activity-dependent adaptation of perisomatic inhibitory synapses over prolonged periods of time in hippocampal slice cultures. Read More

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January 2015

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

Nat Commun 2014 Oct 9;5:5066. Epub 2014 Oct 9.

Department of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy.

The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis-trans isomerase Pin1. Read More

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October 2014

Diffusion dynamics of synaptic molecules during inhibitory postsynaptic plasticity.

Front Cell Neurosci 2014 23;8:300. Epub 2014 Sep 23.

Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia Genoa, Italy.

The plasticity of inhibitory transmission is expected to play a key role in the modulation of neuronal excitability and network function. Over the last two decades, the investigation of the determinants of inhibitory synaptic plasticity has allowed distinguishing presynaptic and postsynaptic mechanisms. While there has been a remarkable progress in the characterization of presynaptically-expressed plasticity of inhibition, the postsynaptic mechanisms of inhibitory long-term synaptic plasticity only begin to be unraveled. Read More

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October 2014

Cyclin-dependent kinase 5 is involved in the phosphorylation of gephyrin and clustering of GABAA receptors at inhibitory synapses of hippocampal neurons.

PLoS One 2014 5;9(8):e104256. Epub 2014 Aug 5.

Department of Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany.

CDK5 has been implicated in neural functions including growth, neuronal migration, synaptic transmission and plasticity of excitatory chemical synapses. Here we report robust effects of CDK5 on phosphorylation of the postsynaptic scaffold protein gephyrin and clustering of inhibitory GABAA receptors in hippocampal neurons. shRNA-mediated knockdown of CDK5 and pharmacological inhibition of cyclin-dependent kinases reduced phosphorylated gephyrin clusters and postsynaptic γ2-containing GABAA receptors. Read More

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November 2015

Synaptic recruitment of gephyrin regulates surface GABAA receptor dynamics for the expression of inhibitory LTP.

Nat Commun 2014 Jun 4;5:3921. Epub 2014 Jun 4.

Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy.

Postsynaptic long-term potentiation of inhibition (iLTP) can rely on increased GABAA receptors (GABA(A)Rs) at synapses by promoted exocytosis. However, the molecular mechanisms that enhance the clustering of postsynaptic GABA(A)Rs during iLTP remain obscure. Here we demonstrate that during chemically induced iLTP (chem-iLTP), GABA(A)Rs are immobilized and confined at synapses, as revealed by single-particle tracking of individual GABA(A)Rs in cultured hippocampal neurons. Read More

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Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses.

Front Cell Neurosci 2014 9;8:103. Epub 2014 Apr 9.

Department of Neurosciences, Scuola Internazionale Superiore di Studi Avanzati Trieste, Italy ; European Brain Research Institute Roma, Italy.

Gephyrin is a multifunctional scaffold protein essential for accumulation of inhibitory glycine and GABAA receptors at post-synaptic sites. The molecular events involved in gephyrin-dependent GABAA receptor clustering are still unclear. Evidence has been recently provided that gephyrin phosphorylation plays a key role in these processes. Read More

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GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system.

Eur J Neurosci 2014 Jun 15;39(11):1845-65. Epub 2014 Mar 15.

Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH, Zurich, Switzerland.

GABAA receptors (GABAA Rs) are ligand-gated Cl(-) channels that mediate most of the fast inhibitory neurotransmission in the central nervous system (CNS). Multiple GABAA R subtypes are assembled from a family of 19 subunit genes, raising the question of the significance of this heterogeneity. In this review, we discuss the evidence that GABAA R subtypes represent distinct receptor populations with a specific spatio-temporal expression pattern in the developing and adult CNS, being endowed with unique functional and pharmacological properties, as well as being differentially regulated at the transcriptional, post-transcriptional and translational levels. Read More

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GABA(A) receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia.

Neurobiol Dis 2014 May 7;65:220-32. Epub 2014 Feb 7.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal. Electronic address:

Cerebral ischemia is characterized by an early disruption of GABAergic neurotransmission contributing to an imbalance of the excitatory/inhibitory equilibrium and neuronal death, but the molecular mechanisms involved are not fully understood. Here we report a downregulation of GABA(A) receptor (GABA(A)R) expression, affecting both mRNA and protein levels of GABA(A)R subunits, in hippocampal neurons subjected to oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Similar alterations in the abundance of GABA(A)R subunits were observed in in vivo brain ischemia. Read More

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Activity-dependent regulation of dendritic growth and maintenance by glycogen synthase kinase 3β.

Nat Commun 2013 ;4:2628

1] Department of Cell Biology and Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, USA [2] Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Activity-dependent dendritic development represents a crucial step in brain development, but its underlying mechanisms remain to be fully elucidated. Here we report that glycogen synthase kinase 3β (GSK3β) regulates dendritic development in an activity-dependent manner. We find that GSK3β in somatodendritic compartments of hippocampal neurons becomes highly phosphorylated at serine-9 upon synaptogenesis. Read More

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Gephyrin plays a key role in BDNF-dependent regulation of amygdala surface GABAARs.

Neuroscience 2013 3;255:33-44. Epub 2013 Oct 3.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Brain-derived neurotrophic factor (BDNF) is critically involved in synaptic plasticity and neurotransmission. Our lab has previously found that BDNF activation of neurotrophic tyrosine kinase, receptor, type 2 (TrkB) is required for fear memory formation and that GABAA receptor (GABAAR) subunits and the GABAA clustering protein gephyrin are dynamically regulated during fear memory consolidation. We hypothesize that TrkB-dependent internalization of GABAARs may partially underlie a transient period of amygdala hyperactivation during fear memory consolidation. Read More

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