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Nat Commun. 2014 Jun 4;5:3921. doi: 10.1038/ncomms4921.

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

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Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy.
Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg Eppendorf, D-20251 Hamburg, Germany.
Institute of Molecular and Cell Biology, Proteos, Singapore 138673, Singapore.
1] Interdisciplinary Institute for Neuroscience, University of Bordeaux, F-33000 Bordeaux, France [2] CNRS UMR 5297, F-33000 Bordeaux, France.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Department of Neuroscience, Tufts University, 136 Harrison Avenue, Arnold 207 Boston, Massachusetts 0211, USA.
1] Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy [2] Department of Experimental Medicine, University of Genova, 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. Chem-iLTP expression requires synaptic recruitment of the scaffold protein gephyrin from extrasynaptic areas, which in turn is promoted by CaMKII-dependent phosphorylation of GABA(A)R-β3-Ser(383). Impairment of gephyrin assembly prevents chem-iLTP and, in parallel, blocks the accumulation and immobilization of GABA(A)Rs at synapses. Importantly, an increase of gephyrin and GABA(A)R similar to those observed during chem-iLTP in cultures were found in the rat visual cortex following an experience-dependent plasticity protocol that potentiates inhibitory transmission in vivo. Thus, phospho-GABA(A)R-β3-dependent accumulation of gephyrin at synapses and receptor immobilization are crucial for iLTP expression and are likely to modulate network excitability.

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