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Cell Rep DOI:10.1016/j.celrep.2017.03.052

Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits.

Publication TypeJournal Article
Year of Publication2017
AuthorsPlatt, RJ, Zhou, Y, Slaymaker, IM, Shetty, AS, Weisbach, NR, Kim, J-A, Sharma, J, Desai, M, Sood, S, Kempton, HR, Crabtree, GR, Feng, G, Zhang, F
JournalCell Rep
Volume19
Issue2
Pages335-350
Date Published2017 Apr 11
ISSN2211-1247
KeywordsAnimals, Autism Spectrum Disorder, Chromatin, Corpus Striatum, Disease Models, Animal, DNA-Binding Proteins, Gene Expression Regulation, Developmental, Germ-Line Mutation, Histones, Humans, Megalencephaly, Mice, Wnt Signaling Pathway
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. Chd8mice 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 Chd8animals, 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.

DOI10.1016/j.celrep.2017.03.052
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28402856?dopt=Abstract

Alternate JournalCell Rep
PubMed ID28402856
PubMed Central IDPMC5455342
Grant ListDP1 MH100706 / MH / NIMH NIH HHS / United States
F31 MH111157 / MH / NIMH NIH HHS / United States
R01 MH110049 / MH / NIMH NIH HHS / United States