Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life

Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown.

We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months).

Chd8^V986*/+ mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8^V986*/+ mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8^V986*/+ crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8^V986*/+ mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8^V986*/+ mice, whereas genes associated with the c-MET signaling pathway were increased in expression.

It is unclear whether the transcriptional changes observed with age in Chd8^V986*/+ mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities.

Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8^V986*/+ mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8^V986*/+ mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice.