title: The schizophrenia risk gene product miR-137 alters presynaptic plasticity.
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.
authors.affiliation: 1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Siegert
authors.affiliation: 1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA.
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Seo
authors.affiliation: 1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA.
authors.forename: Ester J
authors.initials: EJ
authors.lastname: Kwon
authors.affiliation: 1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA.
authors.forename: Andrii
authors.initials: A
authors.lastname: Rudenko
authors.affiliation: 1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA.
authors.forename: Sukhee
authors.initials: S
authors.lastname: Cho
authors.affiliation: 1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Wang
authors.affiliation: 1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Flood
authors.affiliation: 1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Martorell
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Ericsson
authors.affiliation: 1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Mungenast
authors.affiliation: 1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA. [3] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000235:genetics*; D056426:Genetic Loci; D057809:HEK293 Cells; D006801:Humans; D007858:Learning / Q000502:physiology; D017774:Long-Term Potentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism*; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D013572:Synaptic Vesicles / Q000378:metabolism*; D050863:Synaptotagmin I / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C545567:MIRN137 microRNA, human; C551799:MIRN137 microRNA, mouse; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D050863:Synaptotagmin I; C095992:complexin I; D052066:N-Ethylmaleimide-Sensitive Proteins