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Elife. 2015 Jul 9;4:e06085. doi: 10.7554/eLife.06085.

Cerebellar associative sensory learning defects in five mouse autism models.

Author information

  • 1Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States.
  • 2Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States.
  • 3Department of Neurobiology, University of Chicago, Chicago, United States.
  • 4Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
  • 5The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, United States.
  • 6RIKEN Brain Science Institute, Wako, 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, 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/+), which are 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.

KEYWORDS:

associative learning; autism spectrum disorder; cerebellum; mouse; neuroscience

PMID:
26158416
PMCID:
PMC4512177
DOI:
10.7554/eLife.06085
[PubMed - indexed for MEDLINE]
Free PMC Article
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