The Schizophrenia Risk Gene Product Mir-137 Alters Presynaptic Plasticity

• Published in: European neuropsychopharmacology 2017, Vol.27, p.S497-S498
• Main Authors: Siegert, Sandra, Seo, Jinsoo, Kwon, Ester J, Rudenko, Andrii, Cho, Sukhee, Wang, Wenyuan, Flood, Zachary, Martorell, Anthony J, Ericsson, Maria, Mungenast, Alison E, Tsai, Li-Huei
• Format: Article
• Language: English
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2016.09.595

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.