AI Article Synopsis
- Noncoding variants in the MIR137 gene are significantly linked to an increased risk of schizophrenia, yet their exact effects remain unclear.
- Induced human neurons with risk-associated alleles showed elevated levels of microRNA-137, leading to decreased expression of essential presynaptic genes and impairments in vesicle release.
- Experiments in living organisms revealed that increased miR-137 levels disrupted synaptic plasticity and memory functions, but reducing miR-137 helped improve these deficits, highlighting the critical role of the target gene Syt1 in this process.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506960 | PMC |
| http://dx.doi.org/10.1038/nn.4023 | DOI Listing |
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