Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Liang, Wenquan, Hou, Yu, Huang, Weiyuan, Wang, Yunqian, Jiang, Tingyun, Huang, Xingbing, Wang, Zhongju, Wu, Fengchun, Zheng, Jiawei, Zhang, Jie, Ou, Haiyan, Li, Shuyun, Ping, Junjiao, Zhang, Yuan, Ye, Junping, Li, Zhongwei, Yang, Qiong, Zhang, Jian, Zheng, Xianzhen, Li, Shufen, Zhu, Xin-Hong, Chen, Rongqing, Zhao, Cunyou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9390987/
https://www.ncbi.nlm.nih.gov/pubmed/35984881
http://dx.doi.org/10.1126/sciadv.abn7357
_version_ 1784770769482416128
author Liang, Wenquan
Hou, Yu
Huang, Weiyuan
Wang, Yunqian
Jiang, Tingyun
Huang, Xingbing
Wang, Zhongju
Wu, Fengchun
Zheng, Jiawei
Zhang, Jie
Ou, Haiyan
Li, Shuyun
Ping, Junjiao
Zhang, Yuan
Ye, Junping
Li, Zhongwei
Yang, Qiong
Zhang, Jian
Zheng, Xianzhen
Li, Shufen
Zhu, Xin-Hong
Chen, Rongqing
Zhao, Cunyou
author_facet Liang, Wenquan
Hou, Yu
Huang, Weiyuan
Wang, Yunqian
Jiang, Tingyun
Huang, Xingbing
Wang, Zhongju
Wu, Fengchun
Zheng, Jiawei
Zhang, Jie
Ou, Haiyan
Li, Shuyun
Ping, Junjiao
Zhang, Yuan
Ye, Junping
Li, Zhongwei
Yang, Qiong
Zhang, Jian
Zheng, Xianzhen
Li, Shufen
Zhu, Xin-Hong
Chen, Rongqing
Zhao, Cunyou
author_sort Liang, Wenquan
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9390987
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher American Association for the Advancement of Science
record_format MEDLINE/PubMed
spelling pubmed-93909872022-08-26 Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission Liang, Wenquan Hou, Yu Huang, Weiyuan Wang, Yunqian Jiang, Tingyun Huang, Xingbing Wang, Zhongju Wu, Fengchun Zheng, Jiawei Zhang, Jie Ou, Haiyan Li, Shuyun Ping, Junjiao Zhang, Yuan Ye, Junping Li, Zhongwei Yang, Qiong Zhang, Jian Zheng, Xianzhen Li, Shufen Zhu, Xin-Hong Chen, Rongqing Zhao, Cunyou Sci Adv Neuroscience 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. American Association for the Advancement of Science 2022-08-19 /pmc/articles/PMC9390987/ /pubmed/35984881 http://dx.doi.org/10.1126/sciadv.abn7357 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Neuroscience
Liang, Wenquan
Hou, Yu
Huang, Weiyuan
Wang, Yunqian
Jiang, Tingyun
Huang, Xingbing
Wang, Zhongju
Wu, Fengchun
Zheng, Jiawei
Zhang, Jie
Ou, Haiyan
Li, Shuyun
Ping, Junjiao
Zhang, Yuan
Ye, Junping
Li, Zhongwei
Yang, Qiong
Zhang, Jian
Zheng, Xianzhen
Li, Shufen
Zhu, Xin-Hong
Chen, Rongqing
Zhao, Cunyou
Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission
title Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission
title_full Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission
title_fullStr Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission
title_full_unstemmed Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission
title_short Loss of schizophrenia-related miR-501-3p in mice impairs sociability and memory by enhancing mGluR5-mediated glutamatergic transmission
title_sort loss of schizophrenia-related mir-501-3p in mice impairs sociability and memory by enhancing mglur5-mediated glutamatergic transmission
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9390987/
https://www.ncbi.nlm.nih.gov/pubmed/35984881
http://dx.doi.org/10.1126/sciadv.abn7357
work_keys_str_mv AT liangwenquan lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT houyu lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT huangweiyuan lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT wangyunqian lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT jiangtingyun lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT huangxingbing lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT wangzhongju lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT wufengchun lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT zhengjiawei lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT zhangjie lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT ouhaiyan lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT lishuyun lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT pingjunjiao lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT zhangyuan lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT yejunping lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT lizhongwei lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT yangqiong lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT zhangjian lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT zhengxianzhen lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT lishufen lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT zhuxinhong lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT chenrongqing lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission
AT zhaocunyou lossofschizophreniarelatedmir5013pinmiceimpairssociabilityandmemorybyenhancingmglur5mediatedglutamatergictransmission