1. Neuroscience
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ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines

  1. Shu-Xia Cao
  2. Ying Zhang
  3. Xing-Yue Hu
  4. Bin Hong
  5. Peng Sun
  6. Hai-Yang He
  7. Hong-Yan Geng
  8. Ai-Min Bao
  9. Shu-Min Duan
  10. Jian-Ming Yang
  11. Tian-Ming Gao
  12. Hong Lian  Is a corresponding author
  13. Xiao-Ming Li  Is a corresponding author
  1. Zhejiang University School of Medicine, China
  2. Southern Medical University, China
Research Article
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Cite this article as: eLife 2018;7:e39907 doi: 10.7554/eLife.39907

Abstract

Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of bipolar disorder (BPD). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to BPD; however, how ErbB4 regulates NE neuronal function and contributes to BPD pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, Erbb4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.

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, 6, 7 and 8.

Article and author information

Author details

  1. Shu-Xia Cao

    Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Ying Zhang

    Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Xing-Yue Hu

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

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

    Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Hai-Yang He

    Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Hong-Yan Geng

    Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Ai-Min Bao

    Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Shu-Min Duan

    Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Jian-Ming Yang

    Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Tian-Ming Gao

    Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Hong Lian

    Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
    For correspondence
    honglian@zju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  13. Xiao-Ming Li

    Center for Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, 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

National Key R&D Program of China (2016YFA0501003)

  • Xiao-Ming Li

National Natural Science Foundation of China (31700904)

  • Shu-Xia Cao

Zhejiang Provincial Natural Science Foundation of China (LY17C090004)

  • Hong Lian

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Zhejiang University. 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. Eunjoon Kim, Institute for Basic Science, Korea Advanced Institute of Science and Technology, Korea (South), Republic of

Publication history

  1. Received: July 12, 2018
  2. Accepted: September 2, 2018
  3. Accepted Manuscript published: September 4, 2018 (version 1)
  4. Version of Record published: October 12, 2018 (version 2)
  5. Version of Record updated: January 8, 2019 (version 3)

Copyright

© 2018, Cao 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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