Cerebellar associative sensory learning defects in five mouse autism models

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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, Mecp2^R308/Y, Cntnap2-/-, L7-Tsc1 (L7/Pcp2^Cre::Tsc1^flox/+) 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/Pcp2^Cre::Tsc1^flox/+, all associated with Purkinje-cell/deep-nuclear gene expression, along with Shank3+/ΔC. Amplitudes were smaller in L7/Pcp2^Cre::Tsc1^flox/+ as well as Shank3+/ΔC and Mecp2^R308/Y, which are associated with granule-cell pathway expression. Shank3+/ΔC and Mecp2^R308/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.

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Alexander D Kloth

Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States

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Aleksandra Badura

Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States

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Amy Li

Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States

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Adriana Cherskov

Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States

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Sara G Connolly

Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States

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Andrea Giovannucci

Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States

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M Ali Bangash

Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States

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Giorgio Grasselli

Department of Neurobiology, University of Chicago, Chicago, United States

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Olga Peñagarikano

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

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Claire Piochon

Department of Neurobiology, University of Chicago, Chicago, United States

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Peter T Tsai

The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, United States

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Daniel H Geschwind

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

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Christian Hansel

Department of Neurobiology, University of Chicago, Chicago, United States

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Mustafa Sahin

The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, United States

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Toru Takumi

RIKEN Brain Science Institute, Wako, Japan

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Paul F Worley

Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States

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Samuel S H Wang

Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States

For correspondence
sswang@princeton.edu

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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.

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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.