Local miRNA-Dependent Translational Control of GABAAR Synthesis during Inhibitory Long-Term Potentiation

Abstract

Molecular mechanisms underlying plasticity at brain inhibitory synapses remain poorly characterized. Increased postsynaptic clustering of GABA_A receptors (GABA_ARs) rapidly strengthens inhibition during inhibitory long-term potentiation (iLTP). However, it is unclear how synaptic GABA_AR clustering is maintained to sustain iLTP. Here, we identify a role for miR376c in regulating the translation of mRNAs encoding the synaptic α1 and γ2 GABA_AR subunits, GABRA1 and GABRG2, respectively. Following iLTP induction, transcriptional repression of miR376c is induced through a calcineurin-NFAT-HDAC signaling pathway and promotes increased translation and clustering of synaptic GABA_ARs. This pathway is essential for the long-term expression of iLTP and is blocked by miR376c overexpression, specifically impairing inhibitory synaptic strength. Finally, we show that local de novo synthesis of synaptic GABA_ARs occurs exclusively in dendrites and in a miR376c-dependent manner following iLTP. Together, this work describes a local post-transcriptional mechanism that regulates inhibitory synaptic plasticity via miRNA control of dendritic protein synthesis.