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Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits
Randall J Platt1, Yang Zhou2, Ian M Slaymaker3
1Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biosystems Science and Engineering, ETH Zurich, Basel 4058, Switzerland; Department of Chemistry, University of Basel, Basel 4056, Switzerland.
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+/- 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+/- 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.