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Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5727-5736. doi: 10.1073/pnas.1900338116. Epub 2019 Feb 26.

MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons.

Author information

Synapse Biology Group, Centre for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal.
Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), Centre for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal.
Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal.
Institute of Biomedicine (iBiMED), University of Aveiro, 3810-193 Aveiro, Portugal.
Synapse Biology Group, Centre for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal;
Faculty of Sciences and Technology, Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal.


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.


GluA2; homeostatic plasticity; miR-186-5p; microRNAs; synaptic scaling


Conflict of interest statement

The authors declare no conflict of interest.

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