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Cerebellar associative sensory learning defects in five mouse autism models

  1. Alexander D Kloth
  2. Aleksandra Badura
  3. Amy Li
  4. Adriana Cherskov
  5. Sara G Connolly
  6. Andrea Giovannucci
  7. M Ali Bangash
  8. Giorgio Grasselli
  9. Olga Peñagarikano
  10. Claire Piochon
  11. Peter T Tsai
  12. Daniel H Geschwind
  13. Christian Hansel
  14. Mustafa Sahin
  15. Toru Takumi
  16. Paul F Worley
  17. Samuel S H Wang  Is a corresponding author
  1. Princeton University, United States
  2. Johns Hopkins University School of Medicine, United States
  3. University of Chicago, United States
  4. University of California, Los Angeles, United States
  5. Harvard Medical School, United States
  6. RIKEN Brain Science Institute, Japan
Research Article
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Cite this article as: eLife 2015;4:e06085 doi: 10.7554/eLife.06085

Abstract

Sensory integration difficulties have been reported in autism, but their underlying brain-circuit mechanisms are underexplored. Using five autism-related mouse models, Shank3+/ΔC, Mecp2R308/Y, Cntnap2-/-, L7-Tsc1 (L7/Pcp2Cre::Tsc1flox/+) and patDp(15q11-13)/+, we report specific perturbations in delay eyeblink conditioning, a form of associative sensory learning requiring cerebellar plasticity. By distinguishing perturbations in the probability and characteristics of learned responses, we found that probability was reduced in Cntnap2-/-, patDp(15q11-13)/+, and L7/Pcp2Cre::Tsc1flox/+, all associated with Purkinje-cell/deep-nuclear gene expression, along with Shank3+/ΔC. Amplitudes were smaller in L7/Pcp2Cre::Tsc1flox/+ as well as Shank3+/ΔC and Mecp2R308/Y, which are associated with granule-cell pathway expression. Shank3+/ΔC and Mecp2R308/Y also showed aberrant response timing and reduced Purkinje-cell dendritic spine density. Overall, our observations are potentially accounted for by defects in instructed learning in the olivocerebellar loop and response representation in the granule cell pathway. Our findings indicate that defects in associative temporal binding of sensory events are widespread in autism mouse models.

Article and author information

Author details

  1. Alexander D Kloth

    Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Aleksandra Badura

    Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Amy Li

    Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Adriana Cherskov

    Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sara G Connolly

    Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Andrea Giovannucci

    Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. M Ali Bangash

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Giorgio Grasselli

    Department of Neurobiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Olga Peñagarikano

    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Claire Piochon

    Department of Neurobiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Peter T Tsai

    The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Daniel H Geschwind

    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Christian Hansel

    Department of Neurobiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Mustafa Sahin

    The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Toru Takumi

    RIKEN Brain Science Institute, Wako, Japan
    Competing interests
    The authors declare that no competing interests exist.
  16. Paul F Worley

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Samuel S H Wang

    Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States
    For correspondence
    sswang@princeton.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experiments were performed according to protocols (#1943-13) approved by the Princeton University Institutional Animal Care and Use Committee. All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Michael Häusser, University College London, United Kingdom

Publication history

  1. Received: December 13, 2014
  2. Accepted: July 3, 2015
  3. Accepted Manuscript published: July 9, 2015 (version 1)
  4. Version of Record published: July 24, 2015 (version 2)

Copyright

© 2015, Kloth 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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