title: Cerebellar associative sensory learning defects in five mouse autism models.
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.
authors.affiliation: Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States.
authors.forename: Alexander D
authors.identifier: http://orcid.org/0000-0001-8119-1213
authors.initials: AD
authors.lastname: Kloth
authors.affiliation: Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Badura
authors.affiliation: Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States.
authors.forename: Adriana
authors.initials: A
authors.lastname: Cherskov
authors.affiliation: Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States.
authors.forename: Sara G
authors.initials: SG
authors.lastname: Connolly
authors.affiliation: Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Giovannucci
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: M Ali
authors.initials: MA
authors.lastname: Bangash
authors.affiliation: Department of Neurobiology, University of Chicago, Chicago, United States.
authors.forename: Giorgio
authors.identifier: http://orcid.org/0000-0002-2942-9615
authors.initials: G
authors.lastname: Grasselli
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Olga
authors.initials: O
authors.lastname: Peñagarikano
authors.affiliation: Department of Neurobiology, University of Chicago, Chicago, United States.
authors.forename: Claire
authors.initials: C
authors.lastname: Piochon
authors.affiliation: The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, United States.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Tsai
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Department of Neurobiology, University of Chicago, Chicago, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Hansel
authors.affiliation: The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, United States.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
authors.affiliation: RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.affiliation: Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University, Princeton, United States.
authors.forename: Samuel S-H
authors.initials: SS
authors.lastname: Wang
mesh_terms: D000818:Animals; D001245:Association Learning; D001321:Autistic Disorder / Q000473:pathology*; D002531:Cerebellum / Q000503:physiopathology*; D003215:Conditioning, Eyelid; D004195:Disease Models, Animal; D051379:Mice; D011689:Purkinje Cells / Q000502:physiology
keywords: associative learning; autism spectrum disorder; cerebellum; mouse; neuroscience