Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission.

Abstract

Schizophrenia is a polygenetic disease, the heterogeneity of which is likely complicated by epigenetic modifications yet to be elucidated. Here, we performed transcriptomic analysis of peripheral blood RNA from monozygotic twins discordant for schizophrenia and identified a schizophrenia-associated down-regulated microRNA, miR-501-3p. We showed that the loss of miR-501-3p in germline knockout (KO) male mice resulted in dendritic structure defects, glutamatergic transmission enhancement, and sociability, memory, and sensorimotor gating disruptions, which were attenuated when miR-501 expression was conditionally restored in the nervous system. Combining the results of proteomic analyses with the known genes linked to schizophrenia revealed that metabotropic glutamate receptor 5 (mGluR5) was one of the miR-501-3p targets and was elevated in vivo upon loss of miR-501. Treatment with the mGluR5 negative allosteric modulator 3-2((-methyl-4-thiazolyl) ethynyl) pyridine or the N-methyl-d-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid ameliorated the deficits observed in Mir501-KO mice. The epigenetic and pathophysiological mechanism that links miR-501-3p to the modulation of glutamatergic transmission provides etiological implications for schizophrenia.

• Authors: Wenquan Liang, Yu Hou, Weiyuan Huang, Yunqian Wang, Tingyun Jiang, Xingbing Huang, Zhongju Wang, Fengchun Wu, Jiawei Zheng, Jie Zhang, Haiyan Ou, Shuyun Li, Junjiao Ping, Yuan Zhang, Junping Ye, Zhongwei Li, Qiong Yang, Jian Zhang, Xianzhen Zheng, Shufen Li, Xin-Hong Zhu, Rongqing Chen, Cunyou Zhao
• Journal: Science advances (Sci Adv) Vol. 8 Issue 33 Pg. eabn7357 (08 19 2022) ISSN: 2375-2548 [Electronic] United States
• PMID: 35984881 (Publication Type: Journal Article)

Chemical References

• MIRN501 microRNA, mouse
• MicroRNAs
• Receptor, Metabotropic Glutamate 5

Topics

• Animals
• Male
• Mice
• Mice, Knockout
• MicroRNAs (genetics)
• Proteomics
• Receptor, Metabotropic Glutamate 5 (genetics, metabolism)
• Schizophrenia (genetics)