1. Neuroscience
Download icon

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
  • Cited 17
  • Views 6,150
  • Annotations
Cite this article 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 "This ORCID iD identifies the author of this article:" 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 "This ORCID iD identifies the author of this article:" 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 "This ORCID iD identifies the author of this article:" 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, 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)
  4. Version of Record published: February 22, 2018 (version 2)

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.

Metrics

  • 6,150
    Page views
  • 872
    Downloads
  • 17
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organisms

Further reading

    1. Neuroscience

    Subcellular sequencing of single neurons reveals the dendritic transcriptome of GABAergic interneurons

    Julio D Perez et al.
    Tools and Resources Updated

    Although mRNAs are localized in the processes of excitatory neurons, it is still unclear whether interneurons also localize a large population of mRNAs. In addition, the variability in the localized mRNA population within and between cell types is unknown. Here we describe the unbiased transcriptomic characterization of the subcellular compartments of hundreds of single neurons. We separately profiled the dendritic and somatic transcriptomes of individual rat hippocampal neurons and investigated mRNA abundances in the soma and dendrites of single glutamatergic and GABAergic neurons. We found that, like their excitatory counterparts, interneurons contain a rich repertoire of ~4000 mRNAs. We observed more cell type-specific features among somatic transcriptomes than their associated dendritic transcriptomes. Finally, using celltype-specific metabolic labeling of isolated neurites, we demonstrated that the processes of glutamatergic and, notably, GABAergic neurons were capable of local translation, suggesting mRNA localization and local translation are general properties of neurons.

    1. Neuroscience

    Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength

    Yunbo Li et al.
    Research Article

    The conserved MAP3K Dual leucine zipper kinases can activate JNK via MKK4 or MKK7. Vertebrate DLK and LZK share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of Map2k7, strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

    1. Neuroscience
    2. Stem Cells and Regenerative Medicine

    Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

    Laura J Wagstaff et al.
    Research Article

    After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems. In mice, we find that repair cells express reduced c-Jun protein as regenerative support provided by these cells declines during aging and chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to control levels. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, suggesting molecular pathways that can be targeted to promote repair in the PNS.