Postsynaptic long-term potentiation of inhibition (iLTP) can rely on increased GABAA receptors (GABAARs) at synapses by promoted exocytosis. However, the molecular mechanisms that enhance the clustering of postsynaptic GABAARs during iLTP remain obscure. This study demonstrates that, during iLTP, GABAARs are immobilized and confined at synapses, as revealed by single particle tracking of individual GABAARs in cultured hippocampal neurons. iLTP expression requires the synaptic recruitment of the scaffold protein gephyrin from extrasynaptic areas, which in turn is promoted by CaMKII-dependent phosphorylation of GABAAR-β3-Ser383. We also report that gephyrin moderately contributes to the maintenance of GABAAR synaptic clustering in basal conditions, whereas it is essential for the postsynaptic rearrangements underlying receptor accumulation at synapses during iLTP. Indeed, impairment of gephyrin assembly preventsiLTP and, in parallel, blocksthe accumulation and immobilization of GABAARs at synapses. Importantly, increases of synaptic GABAARs and gephyrin similar to those observed during iLTP in culture are found in the rat visual cortex following an experience-dependent plasticity protocol that potentiates inhibitory transmission in vivo. Thus, phosphorylation-dependent accumulation of gephyrin at synapses and GABAAR immobilization are crucial for iLTP and are likely to have a strong impact on network excitability.
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