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云南省快乐十分走势图:MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons
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Homeostatic mechanisms maintain stable neuronal and circuit function in the brain, in particular during development and learning, when synapses undergo constant changes. Synaptic scaling is a form of homeostatic synaptic plasticity responsible for maintaining neuronal network activity within a physiological range, mainly through the regulation of AMPA receptors at synaptic sites. However, the intrinsic mechanisms promoting synaptic scaling are still largely unknown. Here, we have uncovered miR-186-5p as an activity-regulated miRNA, which targets the GluA2 AMPA receptor subunit and mediates synaptic scaling triggered by prolonged blockade of synaptic activity.
Homeostatic synaptic scaling is a negative feedback response to fluctuations in synaptic strength induced by developmental or learning-related processes, which maintains neuronal activity stable. Although several components of the synaptic scaling apparatus have been characterized, the intrinsic regulatory mechanisms promoting scaling remain largely unknown. MicroRNAs may contribute to posttranscriptional control of mRNAs implicated in different stages of synaptic scaling, but their role in these mechanisms is still undervalued. Here, we report that chronic blockade of glutamate receptors of the AMPA and NMDA types in hippocampal neurons in culture induces changes in the neuronal mRNA and miRNA transcriptomes, leading to synaptic upscaling. Specifically, we show that synaptic activity blockade persistently down-regulates miR-186-5p. Moreover, we describe a conserved miR-186-5p-binding site within the 3′UTR of the mRNA encoding the AMPA receptor GluA2 subunit, and demonstrate that GluA2 is a direct target of miR-186-5p. Overexpression of miR-186 decreased GluA2 surface levels, increased synaptic expression of GluA2-lacking AMPA receptors, and blocked synaptic scaling, whereas inhibition of miR-186-5p increased GluA2 surface levels and the amplitude and frequency of AMPA receptor-mediated currents, and mimicked excitatory synaptic scaling induced by synaptic inactivity. Our findings elucidate an activity-dependent miRNA-mediated mechanism for regulation of AMPA receptor expression.
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Author contributions: M.M.S., B.R., S.D.S., L.C., M.A.S.S., P.P., and A.L.C. designed research; M.M.S., B.R., J.F., S.D.S., and L.C. performed research; M.M.S., B.R., J.F., L.C., and A.L.C. analyzed data; and M.M.S. and A.L.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. Y.G. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1900338116/-/DCSupplemental.
Published under the PNAS license.