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 _ARs) at synapses by promoted exocytosis. However, the molecular mechanisms that enhance the clustering of postsynaptic GABA _ARs during iLTP remain obscure. Here we demonstrate that during chemically induced iLTP (chem-iLTP), GABA _ARs are immobilized and confined at synapses, as revealed by single-particle tracking of individual GABA _ARs 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 _AR-β3-Ser ³⁸³. Impairment of gephyrin assembly prevents chem-iLTP and, in parallel, blocks the accumulation and immobilization of GABA _ARs at synapses. Importantly, an increase of gephyrin and GABA _AR 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 _AR-β3-dependent accumulation of gephyrin at synapses and receptor immobilization are crucial for iLTP expression and are likely to modulate network excitability.

Abstract

GABA receptors are implicated in neuronal postsynaptic long-term potentiation of inhibition (iLTP). Here, Petrini et al. show that iLTP depends on recruitment of the scaffold protein gephyrin at synapses, which is enhanced by CaMKII-dependent phosphorylation of a specific residue on GABA _A receptors.