Shank3 Modulates Sleep and Expression of Circadian Transcription Factors

  1. Ashley Ingiosi
  2. Hannah Schoch
  3. Taylor P Wintler
  4. Kristan G Singletary
  5. Dario Righelli
  6. Leandro Roser
  7. Elizabeth Medina
  8. Davide Risso
  9. Marcos G Frank  Is a corresponding author
  10. Lucia Peixoto  Is a corresponding author
  1. Washington State University, United States
  2. National Research Council (CNR), Italy
  3. University of Padova, Italy

Abstract

Autism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States and often co-presents with sleep problems. Sleep problems in ASD predict the severity of ASD core diagnostic symptoms and have a considerable impact on the quality of life of caregivers. Little is known, however, about the underlying molecular mechanisms of sleep problems in ASD. We investigated the role of Shank3, a high confidence ASD gene candidate, in sleep architecture and regulation. We show that mice lacking exon 21 of Shank3 have problems falling asleep even when sleepy. Using RNA-seq we show that sleep deprivation increases the differences in prefrontal cortex gene expression between mutants and wild types, downregulating circadian transcription factors Per3, Bhlhe41, Hlf, Tef, and Nr1d1. Shank3 mutants also have trouble regulating wheel-running activity in constant darkness. Overall, our study shows that Shank3 is an important modulator of sleep and clock gene expression.

Data availability

Sequencing data have been deposited in GEO under accession code GSE113754. Source data files have been provided for Figures 1-4, Tables 1 and 2 and Supplementary Files 1 and 2. The R code used in this article is available on GitHub (github.com/drighelli/peixoto). The R code used for the statistical analysis of RNA-seq and circadian wheel running data is also available in Source Code file 1.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ashley Ingiosi

    Department of Biomedical Science, Washington State University, Spokane, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3035-3010
  2. Hannah Schoch

    Department of Biomedical Science, Washington State University, Spokane, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Taylor P Wintler

    Department of Biomedical Science, Washington State University, Spokane, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kristan G Singletary

    Department of Biomedical Science, Washington State University, Spokane, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Dario Righelli

    Instituto per le Applicazioni del Calcolo, National Research Council (CNR), Napoli, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1504-3583
  6. Leandro Roser

    Department of Biomedical Science, Washington State University, Spokane, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Elizabeth Medina

    Department of Biomedical Science, Washington State University, Spokane, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Davide Risso

    Department of Statistical Sciences, University of Padova, Padova, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8508-5012
  9. Marcos G Frank

    Department of Biomedical Science, Washington State University, Spokane, United States
    For correspondence
    marcos.frank@wsu.edu
    Competing interests
    The authors declare that no competing interests exist.
  10. Lucia Peixoto

    Department of Biomedical Science, Washington State University, Spokane, United States
    For correspondence
    lucia.peixoto@wsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8444-9600

Funding

National Institute of Neurological Disorders and Stroke (K01NS104172)

  • Lucia Peixoto

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

Reviewing Editor

  1. Eunjoon Kim, Institute for Basic Science, Korea Advanced Institute of Science and Technology, Korea (South), Republic of

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 of Washington State University. Protocol numbers: 04705-001 and 04704-001IACUC 6155-Peixoto BreedingIACUC 4705-Peixoto experimentalIACUC 4581-Frank experimental

Human subjects: PMSIR patient data was obtained de-identified under IRB exemption 15005-Peixoto

Version history

  1. Received: October 14, 2018
  2. Accepted: April 10, 2019
  3. Accepted Manuscript published: April 11, 2019 (version 1)
  4. Version of Record published: April 29, 2019 (version 2)

Copyright

© 2019, Ingiosi 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. Ashley Ingiosi
  2. Hannah Schoch
  3. Taylor P Wintler
  4. Kristan G Singletary
  5. Dario Righelli
  6. Leandro Roser
  7. Elizabeth Medina
  8. Davide Risso
  9. Marcos G Frank
  10. Lucia Peixoto
(2019)
Shank3 Modulates Sleep and Expression of Circadian Transcription Factors
eLife 8:e42819.
https://doi.org/10.7554/eLife.42819

Share this article

https://doi.org/10.7554/eLife.42819

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