The schizophrenia risk gene product miR-137 alters presynaptic plasticity Journal Article

Author(s): Siegert, Sandra; Seo, Jinsoo; Kwon, Ester J; Rudenko, Andrii; Cho, Sukhee; Wang, Wenyuan; Flood, Zachary C; Martorell, Anthony J; Ericsson, Maria; Mungenast, Alison E; Tsai, Lihuei
Article Title: The schizophrenia risk gene product miR-137 alters presynaptic plasticity
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.
Keywords: Synaptic Transmission; miRNAs; Molecular neuroscience; Schizophrenia
Journal Title: Nature Neuroscience
Volume: 18
ISSN: 1546-1726
Publisher: Nature Publishing Group  
Date Published: 2015-07-01
Start Page: 1008
End Page: 1016
DOI: 10.1038/nn.4023
Notes: S.S. was supported by a Human Frontier Science Program (HFSP) long-term postdoctoral fellowship and a Swiss National Science Foundation fellowship for prospective researchers. E.J.K. was supported by a Simons Foundation Postdoctoral Fellowship. A.R. was supported by a NARSAD Young Investigator Award. This work was supported by a Seed Grant from the Simons Center for the Social Brain and US National Institutes of Health grant RO1 MH 091115 to L.-H.T.
Open access: no