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

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

  • Sci Adv. 2022 Aug 19;8(33):eabn7357. doi: 10.1126/sciadv.abn7357.
Wenquan Liang 1,  Yu Hou 1 2,  Weiyuan Huang 3,  Yunqian Wang 1,  Tingyun Jiang 4,  Xingbing Huang 5,  Zhongju Wang 1,  Fengchun Wu 5,  Jiawei Zheng 3 6,  Jie Zhang 4,  Haiyan Ou 1,  Shuyun Li 5,  Junjiao Ping 4,  Yuan Zhang 3,  Junping Ye 1,  Zhongwei Li 1,  Qiong Yang 5,  Jian Zhang 1,  Xianzhen Zheng 7,  Shufen Li 1,  Xin-Hong Zhu 3 8,  Rongqing Chen 3 6 8,  Cunyou Zhao 1 8 9 10
Affiliations

Affiliations

  • 1 Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China.
  • 2 Senior Department of Pediatrics, The Seventh Medical Center of PLA General Hospital, Beijing, China.
  • 3 Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, China.
  • 4 The Third People's Hospital of Zhongshan, Zhongshan, Guangdong, China.
  • 5 Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China.
  • 6 The National Key Clinic Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 7 Guangdong General Hospital, Guangdong Academy of Medical Science and Guangdong Mental Health Center, Guangzhou, China.
  • 8 Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, China.
  • 9 Experimental Education/Administration Center, School of Basic Medical Science, Southern Medical University, Guangzhou, China.
  • 10 Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
PMID: 35984881 DOI: 10.1126/sciadv.abn7357
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.

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