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

Ying Cheng,Shuang-Feng Zhang,Bing Bai,Ting-Wei Mi,Yujing Li,Xusheng Wang,Yuxin Li,Zikai Zhou,Nina Xie,Xiaona Wang,Cong Liu,Wei Xie,An Liu,Zuo-Lun Chen,Yunhee Kang,Li Lin,Hong Wang,Dahua Chen,Zhenping Chen,Junmin Peng,Shuting Xia,Peng Jin,Guping Tang ,Chang‐Mei Liu ,Qing Sun ,Yingying Wang ,Zhijie Dai ,Wui-Gee Tan ,Zhao‐Qian Teng ,Zhimeng Wang ,Hailiang Yan

doi:10.1038/s41593-018-0261-7

Abstract

Genetic analyses have linked MicroRNA-137 (MIR137) to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder (ASD). 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 (gKO) or nervous system (cKO) leads to postnatal lethality, while heterozygous gKO 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 KO 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.

Highlights

MicroRNAs are a class of endogenous and non-coding single-stranded ~22nucleotide RNAs, many of which are evolutionarily conserved
Genome-wide association studies (GWAS) have identified multiple loci that are likely involved in neuropsychiatric disorders, including schizophrenia, autism spectrum disorders (ASD), bipolar disorder, and depression[7,10,11,39,40]
MIR137 was found significantly associated with schizophrenia and ASD

Summary

Introduction

MicroRNAs (miRNAs) are a class of endogenous and non-coding single-stranded ~22nucleotide RNAs, many of which are evolutionarily conserved. The perturbation of miRNA expression could potentially contribute to the etiology of human diseases, including neuropsychiatric disorders. Four other loci achieving genome-wide significance identified in the same studies contain the genes predicted to be regulated by miR-137. MIR137 is associated with autism spectrum disorders (ASD); such as in a large-scale copy number variation (CNV) analyses of ASD patients, the risk pathogenic CNV overlap with the loci containing MIR137 gene[7,10,11]. Besides schizophrenia and ASD, MIR137 has been linked to bipolar disorder as well[12]. These findings together suggest that miR-137 contributes to the pathogenesis of neuropsychiatric disorders. Whether the dysregulation of miR-137 leads directly to the phenotypes associated with neuropsychiatric disorders remains to be determined

Methods

Results

Conclusion