MicroRNA-137 Controls AMPA-Receptor-Mediated Transmission and mGluR-Dependent LTD

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Abstract

Mutations affecting the levels of microRNA miR-137 are associated with intellectual disability and schizophrenia. However, the pathophysiological role of miR-137 remains poorly understood. Here, we describe a highly conserved miR-137-binding site within the mRNA encoding the GluA1 subunit of AMPA-type glutamate receptors (AMPARs) and confirm that GluA1 is a direct target of miR-137. Postsynaptic downregulation of miR-137 at the CA3-CA1 hippocampal synapse selectively enhances AMPAR-mediated synaptic transmission and converts silent synapses to active synapses. Conversely, miR-137 overexpression selectively reduces AMPAR-mediated synaptic transmission and silences active synapses. In addition, we find that miR-137 is transiently upregulated in response to metabotropic glutamate receptor 5 (mGluR5), but not mGluR1 activation. Consequently, acute interference with miR-137 function impedes mGluR-LTD expression. Our findings suggest that miR-137 is a key factor in the control of synaptic efficacy and mGluR-dependent synaptic plasticity, supporting the notion that glutamatergic dysfunction contributes to the pathogenesis of miR-137-linked cognitive impairments. Olde Loohuis et al. reveal that microRNA miR-137, which is associated with intellectual disability and schizophrenia, controls AMPA-receptor-mediated transmission by targeting AMPA receptor subunit GluA1. miR-137 levels are regulated by mGluR5 activation, and, consequently, acute interference with miR-137 function impedes mGluR5-dependent synaptic plasticity.

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Olde Loohuis, N. F. M., Ba, W., Stoerchel, P. H., Kos, A., Jager, A., Schratt, G., … Aschrafi, A. (2015). MicroRNA-137 Controls AMPA-Receptor-Mediated Transmission and mGluR-Dependent LTD. Cell Reports, 11(12), 1876–1884. https://doi.org/10.1016/j.celrep.2015.05.040

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