Synaptic recruitment of gephyrin regulates surface GABA A receptor dynamics for the expression of inhibitory LTP

Abstract

Postsynaptic long-term potentiation of inhibition (iLTP) can rely on increased GABA A 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. © 2014 Macmillan Publishers Limited.