Cerebellar associative sensory learning defects in five mouse autism models.

TitleCerebellar associative sensory learning defects in five mouse autism models.
Publication TypeJournal Article
Year of Publication2015
AuthorsKloth, AD, Badura, A, Li, A, Cherskov, A, Connolly, SG, Giovannucci, A, M Bangash, A, Grasselli, G, Peñagarikano, O, Piochon, C, Tsai, PT, Geschwind, DH, Hansel, C, Sahin, M, Takumi, T, Worley, PF, Wang, SS-H
JournalElife
Volume4
Paginatione06085
Date Published2015 Jul 09
ISSN2050-084X
KeywordsAnimals, Association Learning, Autistic Disorder, Cerebellum, Conditioning, Eyelid, Disease Models, Animal, Mice, Purkinje Cells
Abstract

<p>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. </p>

DOI10.7554/eLife.06085
Alternate JournalElife
PubMed ID26158416
PubMed Central IDPMC4512177
Grant ListF31 MH098651 / MH / NIMH NIH HHS / United States
R01 NS045193 / NS / NINDS NIH HHS / United States
R01 NS070301 / NS / NINDS NIH HHS / United States