Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits
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Platt-2017-Chd8 Mutation Leads to Autistic-lik.pdf
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Author(s)
Shetty, Ashwin S.
Weisbach, Niels R.
Crabtree, Gerald R.
Platt, Randall Jeffrey
Zhou, Yang
Slaymaker, Ian
Kim, Jinah
Sharma, Jitendra
Desai, Mitul
Sood, Sabina
Date Issued
April 2017
Journal
Cell Reports
Publisher
Elsevier
Citation
Platt, Randall J.; Zhou, Yang; Slaymaker, Ian M.; Shetty, Ashwin S.; Weisbach, Niels R.; Kim, Jin-Ah; Sharma, Jitendra et al. “Chd8 Mutation Leads to Autistic-Like Behaviors and Impaired Striatal Circuits.” Cell Reports 19, no. 2 (April 2017): 335–350 © 2017 The Authors
Version
Final published version
Abstract
Autism spectrum disorder (ASD) is a heterogeneous disease, but genetically defined models can provide an entry point to studying the molecular underpinnings of this disorder. We generated germline mutant mice with loss-of-function mutations in Chd8, a de novo mutation strongly associated with ASD, and demonstrate that these mice display hallmark ASD behaviors, macrocephaly, and craniofacial abnormalities similar to patient phenotypes. Chd8[superscript +/–] mice display a broad, brain-region-specific dysregulation of major regulatory and cellular processes, most notably histone and chromatin modification, mRNA and protein processing, Wnt signaling, and cell-cycle regulation. We also find altered synaptic physiology in medium spiny neurons of the nucleus accumbens. Perturbation of Chd8 in adult mice recapitulates improved acquired motor learning behavior found in Chd8[superscript +/–] animals, suggesting a role for CHD8 in adult striatal circuits. These results support a mechanism linking chromatin modification to striatal dysfunction and the molecular pathology of ASD.
MIT Department
Broad Institute of MIT and Harvard
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.celrep.2017.03.052
