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Orphan receptor GPR158 controls stress-induced depression

  1. Laurie P Sutton
  2. Cesare Orlandi
  3. Chenghui Song
  4. Won Chan Oh
  5. Brian S Muntean
  6. Keqiang Xie
  7. Alice Filippini
  8. Xiangyang Xie
  9. Rachel Satterfield
  10. Jazmine D W Yaeger
  11. Kenneth J Renner
  12. Samuel M Young
  13. Baoji Xu
  14. Hyungbae Kwon
  15. Kirill A Martemyanov Is a corresponding author
  1. The Scripps Research Institute, United States
  2. Max Planck Florida Institute for Neuroscience, United States
  3. University of Brescia, Italy
  4. University of South Dakota, United States
Research Article
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Cite as: eLife 2018;7:e33273 doi: 10.7554/eLife.33273

Abstract

Stress can be a motivational force for decisive action and adapting to novel environment; whereas, exposure to chronic stress contributes to the development of depression and anxiety. However, the molecular mechanisms underlying stress-responsive behaviors are not fully understood. Here, we identified the orphan receptor GPR158 as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression. GPR158 is highly upregulated in the PFC of human subjects with major depressive disorder. Exposure of mice to chronic stress also increased GPR158 protein levels in the PFC in a glucocorticoid-dependent manner. Viral overexpression of GPR158 in the PFC induced depressive-like behaviors. In contrast GPR158 ablation, led to a prominent antidepressant-like phenotype and stress resiliency. We found that GPR158 exerts its effects via modulating synaptic strength altering AMPA receptor activity. Taken together, our findings identify a new player in mood regulation and introduce a pharmacological target for managing depression.

Article and author information

Author details

  1. Laurie P Sutton

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Cesare Orlandi

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chenghui Song

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0003-3289-809X
  4. Won Chan Oh

    Max Planck Florida Institute for Neuroscience, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Brian S Muntean

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Keqiang Xie

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Alice Filippini

    Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiangyang Xie

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rachel Satterfield

    Max Planck Florida Institute for Neuroscience, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jazmine D W Yaeger

    Department of Biology, University of South Dakota, Vermillion, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Kenneth J Renner

    Department of Biology, University of South Dakota, Vermillion, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Samuel M Young

    Max Planck Florida Institute for Neuroscience, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-7589-7612
  13. Baoji Xu

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Hyungbae Kwon

    Max Planck Florida Institute for Neuroscience, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Kirill A Martemyanov

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    For correspondence
    kirill@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-9925-7599

Funding

National Institute of Mental Health (MH105482)

  • Kirill A Martemyanov

National Heart, Lung, and Blood Institute (HL105550)

  • Kirill A Martemyanov

National Institute of Mental Health (MH107460)

  • Hyungbae Kwon

National Institute on Drug Abuse (DA019921)

  • Kenneth J Renner

National Institute on Deafness and Other Communication Disorders (DC014093)

  • Samuel M Young

University of Iowa

  • Samuel M Young

Max Planck Society

  • Samuel M Young

Canadian Institutes of Health Research

  • Laurie P Sutton

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 National Institutes of Health. All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) protocol (#16-032) at The Scripps Research Institute.

Reviewing Editor

  1. Richard D Palmiter, Reviewing Editor, Howard Hughes Medical Institute, University of Washington, United States

Publication history

  1. Received: November 1, 2017
  2. Accepted: February 6, 2018
  3. Accepted Manuscript published: February 8, 2018 (version 1)

Copyright

© 2018, Sutton 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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