NMDA receptors regulate GABAA receptor lateral mobility and clustering at inhibitory synapses through serine 327 on the γ2 subunit.

Modification of the number of GABA_A receptors (GABA_ARS) clustered at inhibitory synapses can regulate inhibitory synapse strength with important implications for information processing and nervous system plasticity and pathology. Currently, however, the mechanisms that regulate the number of GABA_ARS at synapses remain poorly understood. By imaging superecliptic pHluonn tagged GABAAR subunits we show that synaptic GABA_AR clusters are normally stable, but that increased neuronal activity upon glutamate receptor (GIuR) activation results in their rapid and reversible dispersal. This dispersal correlates with increases in the mobility of single GABA_ARs within the clusters as determined using singleparticle tracking of GABA_ARs labeled with quantum dots. GluRdependent dispersal of GABAAR clusters requires Ca²⁺ influx via NMDA receptors (NMDARs) and activation of the phosphatase calcineurin. Moreover, the dispersal of GABAAR clusters and increased mobility of individual GABA_ARs are dependent on serine 327 within the intracellular loop of the GABA_AR γ2 subunit Thus, NMDAR signaling, via calcineunn and a key GABA_AR phosphorylation site, controls the stability of synaptic GABA_ARS, with important implications for activity dependent control of synaptic inhibition and neuronal plasticity. [ABSTRACT FROM AUTHOR]