title: Synaptic recruitment of gephyrin regulates surface GABAA receptor dynamics for the expression of inhibitory LTP.
abstract: 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.
authors.affiliation: Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy.
authors.forename: Enrica Maria
authors.initials: EM
authors.lastname: Petrini
authors.affiliation: Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ravasenga
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg Eppendorf, D-20251 Hamburg, Germany.
authors.forename: Torben J
authors.initials: TJ
authors.lastname: Hausrat
authors.affiliation: Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Iurilli
authors.affiliation: Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Olcese
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, Singapore 138673, Singapore.
authors.forename: Victor
authors.initials: V
authors.lastname: Racine
authors.affiliation: 1] Interdisciplinary Institute for Neuroscience, University of Bordeaux, F-33000 Bordeaux, France [2] CNRS UMR 5297, F-33000 Bordeaux, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Sibarita
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Tija C
authors.initials: TC
authors.lastname: Jacob
authors.affiliation: Department of Neuroscience, Tufts University, 136 Harrison Avenue, Arnold 207 Boston, Massachusetts 0211, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.affiliation: 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.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.affiliation: Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Medini
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg Eppendorf, D-20251 Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
authors.affiliation: Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Barberis
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology; D017774:Long-Term Potentiation / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate; D014793:Visual Cortex / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C546270:Gabrb3 protein, mouse; C546276:Gabrb3 protein, rat; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; C073441:gephyrin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2