Siegert, SandraIST Austria ; Seo, Jinsoo; Kwon, Ester J; Rudenko, Andrii; Cho, Sukhee; Wang, Wenyuan; Flood, Zachary C; Martorell, Anthony J; Ericsson, Maria; Mungenast, Alison E; Tsai, Lihuei
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.
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.
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Siegert S, Seo J, Kwon E, et al. The schizophrenia risk gene product miR-137 alters presynaptic plasticity. Nature Neuroscience. 2015;18:1008-1016. doi:10.1038/nn.4023
Siegert, S., Seo, J., Kwon, E., Rudenko, A., Cho, S., Wang, W., … Tsai, L. (2015). The schizophrenia risk gene product miR-137 alters presynaptic plasticity. Nature Neuroscience, 18, 1008–1016. https://doi.org/10.1038/nn.4023
Siegert, Sandra, Jinsoo Seo, Ester Kwon, Andrii Rudenko, Sukhee Cho, Wenyuan Wang, Zachary Flood, et al. “The Schizophrenia Risk Gene Product MiR-137 Alters Presynaptic Plasticity.” Nature Neuroscience 18 (2015): 1008–16. https://doi.org/10.1038/nn.4023.
S. Siegert et al., “The schizophrenia risk gene product miR-137 alters presynaptic plasticity,” Nature Neuroscience, vol. 18, pp. 1008–1016, 2015.
Siegert S, Seo J, Kwon E, Rudenko A, Cho S, Wang W, Flood Z, Martorell A, Ericsson M, Mungenast A, Tsai L. 2015. The schizophrenia risk gene product miR-137 alters presynaptic plasticity. Nature Neuroscience. 18, 1008–1016.
Siegert, Sandra, et al. “The Schizophrenia Risk Gene Product MiR-137 Alters Presynaptic Plasticity.” Nature Neuroscience, vol. 18, Nature Publishing Group, 2015, pp. 1008–16, doi:10.1038/nn.4023.