Synaptic recruitment of gephyrin regulates surface GABAA receptor dynamics for the expression of inhibitory LTP
Nat Commun. 2014-06-04; 5(1):
DOI: 10.1038/ncomms4921
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1. 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.
Petrini EM(1), Ravasenga T(1), Hausrat TJ(2), Iurilli G(1), Olcese U(1), Racine
V(3), Sibarita JB(4), Jacob TC(5), Moss SJ(6), Benfenati F(7), Medini P(1),
Kneussel M(2), Barberis A(1).
Author information:
(1)Department of Neuroscience and Brain Technologies, The Italian Institute of
Technology, Via Morego 30, 16163 Genova, Italy.
(2)Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg
Eppendorf, D-20251 Hamburg, Germany.
(3)Institute of Molecular and Cell Biology, Proteos, Singapore 138673, Singapore.
(4)1] Interdisciplinary Institute for Neuroscience, University of Bordeaux,
F-33000 Bordeaux, France [2] CNRS UMR 5297, F-33000 Bordeaux, France.
(5)Department of Pharmacology and Chemical Biology, University of Pittsburgh,
Pittsburgh, Pennsylvania 15261, USA.
(6)Department of Neuroscience, Tufts University, 136 Harrison Avenue, Arnold 207
Boston, Massachusetts 0211, USA.
(7)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.
DOI: 10.1038/ncomms4921
PMCID: PMC4059940
PMID: 24894704 [Indexed for MEDLINE]