The schizophrenia risk gene product miR-137 alters presynaptic plasticity

• Published in: Nature neuroscience Vol. 18; no. 7; pp. 1008 - 1016
• 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: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-07-2015; Nature Publishing Group
• Subjects: 13/51; 14/28; 14/34; 38/79; 631/337/384/331; 631/378/340; 631/378/548; 64/60; 692/699/476/1799; 82/80; Adaptor Proteins, Vesicular Transport - metabolism; Alleles; Analysis; Animal Genetics and Genomics; Animals; Autism; Behavior, Animal - physiology; Behavioral Sciences; Binding sites; Biological Techniques; Biomedicine; Brain; Chromosomes; Cognitive disorders; Comparative analysis; Disease Models, Animal; Diseases; Fibroblasts; Gene Expression Regulation - genetics; Genes; Genetic aspects; Genetic Loci; Genetic polymorphisms; Genetic research; Genomes; HEK293 Cells; Humans; Kinases; Learning - physiology; Long-Term Potentiation; Memory; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs; MicroRNAs - metabolism; Mossy Fibers, Hippocampal - metabolism; N-Ethylmaleimide-Sensitive Proteins - metabolism; Nerve Tissue Proteins - metabolism; Neurobiology; Neuronal Plasticity - genetics; Neurons; Neurosciences; Phenotypes; Polymorphism, Single Nucleotide; Risk factors; Schizophrenia; Schizophrenia - genetics; Single nucleotide polymorphisms; Synaptic Vesicles - metabolism; Synaptotagmin I - metabolism; United States; United States > US; Massachusetts
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.4023

Neurodevelopmental disorders are frequently associated with synaptic dysfunction. Recent genome-wide association studies associate the gene encoding microRNA-137 with an increased risk for schizophrenia. Using mouse and human models, the authors show that dysregulation of this miRNA leads to presynaptic defects and, consequently, to impaired synaptic plasticity and cognitive dysfunction.
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.