Local miRNA-Dependent Translational Control of GABA
| Autor: | Dipen, Rajgor, Alicia M, Purkey, Jennifer L, Sanderson, Theresa M, Welle, Joshua D, Garcia, Mark L, Dell'Acqua, Katharine R, Smith |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Cell reports |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY Molecular mechanisms underlying plasticity at brain inhibitory synapses remain poorly characterized. Increased postsynaptic clustering of GABAA receptors (GABAARs) rapidly strengthens inhibition during inhibitory long-term potentiation (iLTP). However, it is unclear how synaptic GABAAR 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 GABAAR 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 GABAARs. 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 GABAARs 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. Graphical Abstract In Brief Clustering of GABAARs at inhibitory synapses is crucial for synaptic inhibition. Rajgor et al. discover that synaptic GABAAR expression is controlled by their local translation, regulated by miR376c. During inhibitory synaptic potentiation, miR376c is downregulated, relieving its translational repression of GABAAR mRNAs and leading to de novo synthesis of dendritic GABAARs. |
| Databáze: | OpenAIRE |
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