1. Neuroscience
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MeCP2 in cholinergic interneurons of nucleus accumbens regulates fear learning

  1. Ying Zhang
  2. Yi Zhu
  3. Shu-Xia Cao
  4. Peng Sun
  5. Jian-Ming Yang
  6. Yan-Fang Xia
  7. Shi-Ze Xie
  8. Xiao-Dan Yu
  9. Jia-Yu Fu
  10. Chen-Jie Shen
  11. Hai-Yang He
  12. Hao-Qi Pan
  13. Xiao-Juan Chen
  14. Hao Wang
  15. Xiao-Ming Li  Is a corresponding author
  1. Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, China
  2. Sir Run Run Shaw Hospital, China
Research Article
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Cite this article as: eLife 2020;9:e55342 doi: 10.7554/eLife.55342

Abstract

Methyl-CpG-binding protein 2 (MeCP2) encoded by the MECP2 gene is a transcriptional regulator whose mutations cause Rett syndrome (RTT). Mecp2-deficient mice show fear regulation impairment; however, the cellular and molecular mechanisms underlying this abnormal behavior are largely uncharacterized. Here, we showed that Mecp2 gene deficiency in cholinergic interneurons of the nucleus accumbens (NAc) dramatically impaired fear learning. We further found that spontaneous activity of cholinergic interneurons in Mecp2-deficient mice decreased, mediated by enhanced inhibitory transmission via α2-containing GABAA receptors. With MeCP2 restoration, opto- and chemo-genetic activation, and RNA interference in ChAT-expressing interneurons of the NAc, impaired fear retrieval was rescued. Taken together, these results reveal a previously unknown role of MeCP2 in NAc cholinergic interneurons in fear regulation, suggesting that modulation of neurons in the NAc may ameliorate fear-related disorders.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3, 4, 5 and 6.

Article and author information

Author details

  1. Ying Zhang

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Yi Zhu

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Shu-Xia Cao

    Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Peng Sun

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Jian-Ming Yang

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yan-Fang Xia

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Shi-Ze Xie

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiao-Dan Yu

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Jia-Yu Fu

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Chen-Jie Shen

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Hai-Yang He

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Hao-Qi Pan

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Xiao-Juan Chen

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Hao Wang

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Xiao-Ming Li

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    For correspondence
    lixm@zju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8617-1702

Funding

The National Key Research and Development Plan of Ministry of Science and Technology of China (2016YF051000)

  • Xiao-Ming Li

Key Project of the National Natural Science Foundation of China (31430034)

  • Xiao-Ming Li

Science and Technology Program of Guangdong (2018B030334001)

  • Xiao-Ming Li

Key Realm R&D Prgram of Guangdong Province (2019B030335001)

  • Xiao-Ming Li

Funds for Creative Research Groups of China from the National Natural Science Foundation of China (81521062)

  • Xiao-Ming Li

Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2019PT310023)

  • Xiao-Ming Li

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Mouse care and use followed the guidelines of the Animal Advisory Committee at Zhejiang University and the US National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. The care and use of the mice in this work were reviewed and approved by the Animal Advisory Committee at Zhejiang University (ZJU201553001). Every effort was made to minimize suffering.

Reviewing Editor

  1. Mary Kay Lobo, University of Maryland, United States

Publication history

  1. Received: January 21, 2020
  2. Accepted: May 18, 2020
  3. Accepted Manuscript published: May 18, 2020 (version 1)
  4. Version of Record published: May 29, 2020 (version 2)

Copyright

© 2020, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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