Cerebral mGluR5 availability contributes to elevated sleep need and behavioral adjustment after sleep deprivation

  1. Sebastian C Holst
  2. Alexandra Sousek
  3. Katharina Hefti
  4. Sohrab Saberi-Moghadam
  5. Alfred Buck
  6. Simon M Ametamey
  7. Milan Scheidegger
  8. Paul Franken
  9. Anke Henning
  10. Erich Seifritz
  11. Mehdi Tafti
  12. Hans-Peter Landolt  Is a corresponding author
  1. University of Zürich, Switzerland
  2. University of Lausanne, Switzerland
  3. University Hospital Zürich, Switzerland
  4. Swiss Federal Institute of Technology, Switzerland

Abstract

Increased sleep time and intensity quantified as low-frequency brain electrical activity after sleep loss demonstrate that sleep need is homeostatically regulated, yet the underlying molecular mechanisms remain elusive. We here demonstrate that metabotropic glutamate receptors of subtype 5 (mGluR5) contribute to the molecular machinery governing sleep-wake homeostasis. Using positron emission tomography, magnetic resonance spectroscopy, and electroencephalography in humans, we find that increased mGluR5 availability after sleep loss tightly correlates with behavioral and electroencephalographic biomarkers of elevated sleep need. These changes are associated with altered cortical myo-inositol and glycine levels, suggesting sleep loss-induced modifications downstream of mGluR5 signaling. Knock-out mice without functional mGluR5 exhibit severe dysregulation of sleep-wake homeostasis, including lack of recovery sleep and impaired behavioral adjustment to a novel task after sleep deprivation. The data suggest that mGluR5 contribute to the brain's coping mechanisms with sleep deprivation and point to a novel target to improve disturbed wakefulness and sleep.

Article and author information

Author details

  1. Sebastian C Holst

    Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3657-4535
  2. Alexandra Sousek

    Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Katharina Hefti

    Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Sohrab Saberi-Moghadam

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Alfred Buck

    Division of Nuclear Medicine, University Hospital Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Simon M Ametamey

    Center for Radiopharmaceutical Sciences, Swiss Federal Institute of Technology, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  7. Milan Scheidegger

    Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  8. Paul Franken

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2500-2921
  9. Anke Henning

    Center for Radiopharmaceutical Sciences, Swiss Federal Institute of Technology, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  10. Erich Seifritz

    Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  11. Mehdi Tafti

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6997-3914
  12. Hans-Peter Landolt

    Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland
    For correspondence
    landolt@pharma.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0887-9403

Funding

Swiss National Science Foundation (320030_135414)

  • Hans-Peter Landolt

Universität Zürich (Sleep & Health)

  • Hans-Peter Landolt

NCCR Neural Plasticity and Repair

  • Erich Seifritz
  • Hans-Peter Landolt

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

Ethics

Animal experimentation: All animal experiments were carried out in accordance with the regulations of the Swiss Federal and State of Vaud Veterinary Offices (No. 2699.0).

Human subjects: All experimental procedures were conducted in accordance with the declaration of Helsinki (1964) and approved by the cantonal (ethics committee for research on human subjects of the canon of Zurich [Reference Nr. EK-Nr. 786] and Swiss federal authorities for research on human (Swiss Federal Institute of Public Health, Reference Nr. 464-0002-6/08.005701) subjects.

Reviewing Editor

  1. Louis J Ptáček, University of California, San Francisco, United States

Publication history

  1. Received: May 17, 2017
  2. Accepted: October 4, 2017
  3. Accepted Manuscript published: October 5, 2017 (version 1)
  4. Version of Record published: October 17, 2017 (version 2)

Copyright

© 2017, Holst 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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  1. Sebastian C Holst
  2. Alexandra Sousek
  3. Katharina Hefti
  4. Sohrab Saberi-Moghadam
  5. Alfred Buck
  6. Simon M Ametamey
  7. Milan Scheidegger
  8. Paul Franken
  9. Anke Henning
  10. Erich Seifritz
  11. Mehdi Tafti
  12. Hans-Peter Landolt
(2017)
Cerebral mGluR5 availability contributes to elevated sleep need and behavioral adjustment after sleep deprivation
eLife 6:e28751.
https://doi.org/10.7554/eLife.28751
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