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

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.

Reversal of dendritic phenotypes in 16p11.2 microduplication mouse model neurons by pharmacological targeting of a network hub

“…Abnormalities in dendrite arborization have been reported in several neuropsychiatric disorders. Surprisingly, our findings of increased dendrite arborization did not parallel previous postmortem findings in schizophrenia (41); despite this, the increased dendrite arborization associated with 16p11.2 duplication during development may lead to premature maturation of synapses, as has been shown when schizophrenia-associated MIR137 expression is reduced (42,43). However, 16p11.2 duplications are also associated with ASD and seizure disorder, and the cellular phenotypes we identified may be more reflective of these disorders (16,44,45), such as the hypothesized increased brain connectivity in ASD.…”

Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction

“…miR-137 OE increased miR-137 levels (Fig. S1A) and reduced GluA1, a validated miR-137 target (Olde Loohuis et al, 2015) (Fig. S1B-D).…”

MicroRNAs in neural development: from master regulators to fine-tuners

“…Accordingly, miR-137 gain of function in multiple cell lines was shown in another study to lead to decreased mRNA translation of numerous mRNAs encoding presynaptic proteins (Siegert et al, 2015), which in turn resulted in impaired presynaptic function due to a decreased number of neurotransmitter vesicles close to the synaptic cleft (Siegert et al, 2015). Intriguingly, miR-137 function is not restricted to the presynapse: miR-137 was also shown to target mRNA encoding the AMPA-type glutamate receptor subunit GluA1 (Olde Loohuis et al, 2015). A postsynaptic role of this interaction is supported by the finding that downregulation of miR-137 selectively enhances AMPA receptor-mediated synaptic transmission and converts silent synapses to active synapses.…”

“…In addition, the virus-directed overexpression of miR-137 selectively in postsynaptic CA1 pyramidal cells has no effect on the pairedpulse ratio, a classical parameter of presynaptic function, further invoking an additional postsynaptic role of miR-137 (Olde Loohuis et al, 2015). It should also be noted that miR-137 function at the postsynapse is not limited to basal synaptic transmission: activitydependent regulation is also required for long-term depression, a form of long-term synaptic plasticity (Olde Loohuis et al, 2015). In D. melanogaster, miR-1000, which harbors a very similar seed to mammalian miR-137, targets the vesicular glutamate transporter (vGlut), a protein responsible for glutamate loading into presynaptic vesicles (Verma et al, 2015).…”

“…A postsynaptic role of this interaction is supported by the finding that downregulation of miR-137 selectively enhances AMPA receptor-mediated synaptic transmission and converts silent synapses to active synapses. In addition, the virus-directed overexpression of miR-137 selectively in postsynaptic CA1 pyramidal cells has no effect on the pairedpulse ratio, a classical parameter of presynaptic function, further invoking an additional postsynaptic role of miR-137 (Olde Loohuis et al, 2015). It should also be noted that miR-137 function at the postsynapse is not limited to basal synaptic transmission: activitydependent regulation is also required for long-term depression, a form of long-term synaptic plasticity (Olde Loohuis et al, 2015).…”