Bidirectional Control of Synaptic GABAAR Clustering by Glutamate and Calcium

•Bidirectional synaptic control system by glutamate and Ca2+ signaling•Stabilization of GABA synapses by mGluR-dependent Ca2+ release from IP3R via PKC•Synaptic GABAAR clusters stabilized through regulation of GABAAR lateral diffusion•Competition with an NMDAR-dependent Ca2+ pathway driving synaptic destabilization

SummaryGABAergic synaptic transmission regulates brain function by establishing the appropriate excitation-inhibition (E/I) balance in neural circuits. The structure and function of GABAergic synapses are sensitive to destabilization by impinging neurotransmitters. However, signaling mechanisms that promote the restorative homeostatic stabilization of GABAergic synapses remain unknown. Here, by quantum dot single-particle tracking, we characterize a signaling pathway that promotes the stability of GABAA receptor (GABAAR) postsynaptic organization. Slow metabotropic glutamate receptor signaling activates IP3 receptor-dependent calcium release and protein kinase C to promote GABAAR clustering and GABAergic transmission. This GABAAR stabilization pathway counteracts the rapid cluster dispersion caused by glutamate-driven NMDA receptor-dependent calcium influx and calcineurin dephosphorylation, including in conditions of pathological glutamate toxicity. These findings show that glutamate activates distinct receptors and spatiotemporal patterns of calcium signaling for opposing control of GABAergic synapses.

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