Cerebellar associative sensory learning defects in five mouse autism models
- Princeton University, United States
- Johns Hopkins University School of Medicine, United States
- University of Chicago, United States
- University of California, Los Angeles, United States
- Harvard Medical School, United States
- RIKEN Brain Science Institute, Japan
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.
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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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© 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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Cerebellar associative sensory learning defects in five mouse autism models
eLife 4:e06085.
https://doi.org/10.7554/eLife.06085
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