Cell Reports
Volume 19, Issue 2, 11 April 2017, Pages 335-350
Journal home page for Cell Reports

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

https://doi.org/10.1016/j.celrep.2017.03.052Get rights and content
Under a Creative Commons license
open access

Highlights

  • Chd8+/− mice display macrocephaly and ASD-like behaviors

  • Major insult to genome regulation and cellular processes in Chd8+/– mice

  • LOF Chd8 mutations cause synaptic dysfunction in the nucleus accumbens

  • NAc-specific perturbation of Chd8 in adult Cas9 mice recapitulates behavior

Summary

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.

Keywords

CRISPR
autism spectrum disorder
MRI
behavior
RNA-seq
ChIP-seq
physiology
neocortical development
adeno-associated virus
Cas9 knockin mouse

Cited by (0)

14

Co-first author

15

Lead Contact