Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a

• Type of Material: Article
• Authors: Ying Cheng, Emory University; Z-M Wang, Chinese Academy of Sciences; W Tan, University of Chinese Academy of Sciences; X Wang, University of Chinese Academy of Sciences; Yujing Li, Emory University; B Bai, St Jude Children's Research Hospital; S-F Zhang, Chinese Academy of Sciences; H-L Yan, Chinese Academy of Sciences; Z-L Chen, Chinese Academy of Sciences; C-M Liu, Chinese Academy of Sciences; T-W Mi, Chinese Academy of Sciences; S Xia, Southeast University; Z Zhou, Southeast University; A Liu, Southeast University; G-B Tang, Chinese Academy of Sciences; C Liu, Chinese Academy of Sciences; Z-J Dai, Chinese Academy of Sciences; Y-Y Wang, Chinese Academy of Sciences; H Wang, St Jude Children's Research Hospital; X Wang, St Jude Children's Research Hospital; Y Kang, Emory University
• Language: English
• Date: 2018-12-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41593-018-0261-7
• Title of Journal or Parent Work: Nature Neuroscience
• ISSN: 1097-6256
• Volume: 21
• Issue: 12
• Start Page: 1689
• End Page: +
• Grant/Funding Information: This work was supported by the National Key R&D Program of China (2018YFA0108001 to Z.T.); Natural Science Foundation of China (31590831 and 91640204 to DC, 81571212 to Z.T.); Strategic Priority Research Program of Chinese Academy of Science (Grant XDB 19000000); National Institutes of Health (NS051630, NS079625, and MH102690 to P.J., AG047928 to J.P.); and Simons Foundation Autism Research Initiative (239320 to P.J.).; Hundred Talents Program of Chinese Academy of Science to Z.T.; P.J. is NARSAD Independent Investigator Award-Suzanne and John Golden Investigator.
• Keywords: PROTEIN-ANALYSIS; Science & Technology; Life Sciences & Biomedicine; MICRORNA; GENOME-WIDE ASSOCIATION; Neurosciences & Neurology; COGNITION; EPIGENETIC REGULATION; IDENTIFICATION; PROLIFERATION; LOCUS; Neurosciences; SCHIZOPHRENIA RISK; MASS-SPECTROMETRY
• Research Categories: Biology, Zoology; Biology, Neuroscience; Biology, Genetics

Abstract

Genetic analyses have linked microRNA-137 (MIR137) to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder. miR-137 plays important roles in neurogenesis and neuronal maturation, but the impact of miR-137 loss-of-function in vivo remains unclear. Here we show the complete loss of miR-137 in the mouse germline knockout or nervous system knockout (cKO) leads to postnatal lethality, while heterozygous germline knockout and cKO mice remain viable. Partial loss of miR-137 in heterozygous cKO mice results in dysregulated synaptic plasticity, repetitive behavior, and impaired learning and social behavior. Transcriptomic and proteomic analyses revealed that the miR-137 mRNA target, phosphodiesterase 10a (Pde10a), is elevated in heterozygous knockout mice. Treatment with the Pde10a inhibitor papaverine or knockdown of Pde10a ameliorates the deficits observed in the heterozygous cKO mice. Collectively, our results suggest that MIR137 plays essential roles in postnatal neurodevelopment and that dysregulation of miR-137 potentially contributes to neuropsychiatric disorders in humans.