The schizophrenia risk gene product miR-137 alters presynaptic plasticity
Name
Tsai_The schizophrenia risk.pdf
Size
1.77 MB
Format
Adobe PDF
Checksum (MD5)
ac09084131736665464e541f4865a09e
Author(s)
Siegert, Sandra
Seo, Jinsoo
Kwon, Ester
Rudenko, Andrii
Cho, Sukhee
Wang, Wenyuan
Flood, Zachary
Martorell, Anthony
Ericsson, Maria
Mungenast, Alison
Date Issued
May 2015
Journal
Nature Neuroscience
Publisher
Nature Publishing Group
Citation
Siegert, Sandra, Jinsoo Seo, Ester J Kwon, Andrii Rudenko, Sukhee Cho, Wenyuan Wang, Zachary Flood, et al. “The Schizophrenia Risk Gene Product miR-137 Alters Presynaptic Plasticity.” Nat Neurosci 18, no. 7 (May 25, 2015): 1008–1016.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/nn.4023
