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

Abstract

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.

Germline Chd8 haploinsufficiency alters brain development in mouse

“…The obvious differences in biological consequences and mechanisms between in utero knockdown 15 and our germline heterozygous model likely explain many differences and make cross-approach comparisons a challenge. Our data on the absence of repetitive behaviors agree with those reported in Katayama et al 2016 13 and Platt et al 2017 14 ; however, these studies also report specific social phenotypes in heterozygous Chd8 mice. We focus our comparison on the Katayama et al 13 study as we were able to directly compare neurodevelopmental gene expression changes to our model.…”

“…Durak et al 2016 15 reported an in utero knockdown of Chd8 expression, including restricted knockdown of Chd8 in upper cortical layer neurons. Katayama et al 2016 13 generated two lines of Chd8 mutant mice via embryonic stem cell targeting, while Platt et al 2017 14 used CRISPR/Cas9 targeting to generate indel mutations in Chd8 . The obvious differences in biological consequences and mechanisms between in utero knockdown 15 and our germline heterozygous model likely explain many differences and make cross-approach comparisons a challenge.…”

“…Chd8 knockdown in zebrafish recapitulates macrocephaly and gastrointestinal phenotypes 9,11 , suggesting a high degree of evolutionary conservation of CHD8 function in development. It has been proposed that CHD8 achieves this regulatory function in brain development by binding to relevant gene promoters and enhancers 11-14 . Although recent mouse studies indicate that Chd8 is required in neurogenesis and that mutations to Chd8 cause behavioral phenotypes 13,15 , important questions remain regarding the role of Chd8 in regulating neurodevelopment, brain structure, and behavior via direct and indirect transcriptional regulation.…”

Autism spectrum disorder: neuropathology and animal models

“…Knock-down of the CHD8 ortholog results in macrocephaly in zebrafish [32, 343] and increased brain weight and volume [187, 287] in mice, phenotypes that reflect clinical observations in subjects with loss-of-function mutations in the gene [32]. CHD8 knockdown in human neural progenitor cells results in downregulation of neuronal development and cell adhesion genes, several of which have been associated with ASD [343].…”

“…In utero knockdown of CHD8 in layers II and III neurons of mice at embryonic day 13 results in reduced neural proliferation, dendritic arborization and spine density [91]. Germline Chd8 knockdown mice have normal cortical lamination in the somatosensory cortex [287]. …”