The schizophrenia risk gene product miR-137 alters presynaptic plasticity
2015
Online
academicJournal
Zugriff:
Non-coding variants in the human MIR137 gene locus increase schizophrenia risk at a genome-wide significance level. 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 (SNPs) in MIR137, and observed increased MIR137 levels compared to major allele-carrying cells. We found that miR-137 gain-of-function causes 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 results in changes in synaptic vesicle pool distribution, impaired mossy fiber-LTP induction 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.
Titel: |
The schizophrenia risk gene product miR-137 alters presynaptic plasticity
|
---|---|
Autor/in / Beteiligte Person: | 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 |
Link: | |
Veröffentlichung: | 2015 |
Medientyp: | academicJournal |
ISSN: | 1097-6256 (print) |
DOI: | 10.1038/nn.4023 |
Sonstiges: |
|