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Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1

  1. Robbert Havekes  Is a corresponding author
  2. Alan J Park
  3. Jennifer C Tudor
  4. Vincent G Luczak
  5. Rolf T Hansen
  6. Sarah L Ferri
  7. Vibeke M Bruinenberg
  8. Shane G Poplawski
  9. Jonathan P Day
  10. Sara J Aton
  11. Kasia Radwańska
  12. Peter Meerlo
  13. Miles D Houslay
  14. George S Baillie
  15. Ted Abel  Is a corresponding author
  1. University of Pennsylvania, United States
  2. Columbia University, United States
  3. University of Groningen, Netherlands
  4. University of Glasgow, United Kingdom
  5. University of Michigan, United States
  6. Nencki Institute of Experimental Biology, Poland
  7. King's College London, United Kingdom
Research Article
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Cite this article as: eLife 2016;5:e13424 doi: 10.7554/eLife.13424

Abstract

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density.

Article and author information

Author details

  1. Robbert Havekes

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    For correspondence
    r.havekes@rug.nl
    Competing interests
    The authors declare that no competing interests exist.
  2. Alan J Park

    Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jennifer C Tudor

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3826-3012
  4. Vincent G Luczak

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rolf T Hansen

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sarah L Ferri

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Vibeke M Bruinenberg

    Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Shane G Poplawski

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jonathan P Day

    Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Sara J Aton

    LSA Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Kasia Radwańska

    Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  12. Peter Meerlo

    Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  13. Miles D Houslay

    Institute of Pharmaceutical Science, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. George S Baillie

    Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Ted Abel

    Department of Biology, University of Pennsylvania, Philadelphia, United States
    For correspondence
    abele@sas.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2423-4592

Funding

National Institutes of Health (1RO1MH086415)

  • Ted Abel

National Institutes of Health (RO1, AG017628)

  • Ted Abel

Netherlands organization for Scientific Research (postdoctoral fellowship 825.07.029)

  • Robbert Havekes

University of Pennsylvania (UPENN rsearch foundation grant)

  • Robbert Havekes
  • Ted Abel

National Institutes of Health (postdoctoral fellowship, 5K12GM081529)

  • Jennifer C Tudor

National Institutes of Health (postdoctoral fellowship, T32 NS077413)

  • Sarah L Ferri

European Commission (FP7-PEOPLE-2009-RG-Alco_CaMK)

  • Kasia Radwańska

NCN grant Harmonia 2013/08/m/NZ3/00861 (Research grant)

  • Kasia Radwańska

Medical Research Council (Grant MR/J007412/1)

  • George S Baillie

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 of the animals were handled according to approved institutional animal care and use committee (IACUC protocols 804240, 804407, 802784) of the University of Pennsylvania and Head Necki Institute of Experimental Biology, Warsaw.

Reviewing Editor

  1. Joseph S Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: December 1, 2015
  2. Accepted: July 29, 2016
  3. Accepted Manuscript published: August 23, 2016 (version 1)
  4. Version of Record published: August 24, 2016 (version 2)
  5. Version of Record updated: August 26, 2016 (version 3)

Copyright

© 2016, Havekes 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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