The schizophrenia risk gene product miR-137 alters presynaptic plasticity.

Nat Neurosci
Authors
Keywords
Abstract

Noncoding variants in the human MIR137 gene locus increase schizophrenia risk with genome-wide significance. However, the functional consequence of these risk alleles is unknown. Here we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms in MIR137. We observed increased MIR137 levels compared to those in major allele-carrying cells. microRNA-137 gain of function caused downregulation of the presynaptic target genes complexin-1 (Cplx1), Nsf and synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain of function resulted in changes in synaptic vesicle pool distribution, impaired induction of mossy fiber long-term potentiation and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus.

Year of Publication
2015
Journal
Nat Neurosci
Volume
18
Issue
7
Pages
1008-16
Date Published
2015 Jul
ISSN
1546-1726
URL
DOI
10.1038/nn.4023
PubMed ID
26005852
PubMed Central ID
PMC4506960
Links
Grant list
R01 MH091115 / MH / NIMH NIH HHS / United States
R01 MH 091115 / MH / NIMH NIH HHS / United States