Cerebellar associative sensory learning defects in five mouse autism models. Author Alexander Kloth, Aleksandra Badura, Amy Li, Adriana Cherskov, Sara Connolly, Andrea Giovannucci, M Ali Bangash, Giorgio Grasselli, Olga Peñagarikano, Claire Piochon, Peter Tsai, Daniel Geschwind, Christian Hansel, Mustafa Sahin, Toru Takumi, Paul Worley, Samuel Wang Publication Year 2015 Type Journal Article 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 Animals, Association Learning, Autistic Disorder, Cerebellum, Conditioning, Eyelid, Disease Models, Animal, Mice, Purkinje Cells Journal Elife Volume 4 Pages e06085 Date Published 2015 Jul 09 ISSN Number 2050-084X DOI 10.7554/eLife.06085 Alternate Journal Elife PMCID PMC4512177 PMID 26158416 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML