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

摘要

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 pHluorin tagged GABA_AR subunits we show that synaptic GABA_AR clusters are normally stable, but that increased neuronal activity upon glutamate receptor (GluR) 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 single-particle tracking of GABA_ARs labeled with quantum dots. GluR-dependent dispersal of GABA_AR clusters requires Ca~(2+) influx via NMDA receptors (NMDARs) and activation of the phosphatase calci-neurin. Moreover, the dispersal of GABA_AR dusters 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 caldneurin 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.