Department of Neurobiology, University of Chicago, Chicago, United States
Olga Peñagarikano
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Center for Autism Research, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Claire Piochon
Department of Neurobiology, University of Chicago, Chicago, United States
Peter T Tsai
The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, United States
Daniel H Geschwind
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Center for Autism Research, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
Christian Hansel
Department of Neurobiology, University of Chicago, Chicago, United States
Mustafa Sahin
The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, United States
Toru Takumi
RIKEN Brain Science Institute, Wako, Japan
Paul F Worley
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
Samuel S-H Wang
Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States
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/+, which are 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.
