Increased cortical volume without increased neuron number in heterozygous Chd8 mutant mouse cortex

De novo mutations in the chromatin-remodeling factor CHD8 (Chromodomain-Helicase DNA-binding protein 8) have emerged as a key genetic risk factor for Autism Spectrum Disorder (ASD) and, more generally, neurodevelopmental disorders. Individuals with heterozygous mutations in CHD8 typically present hallmarks of ASD with comorbid cognitive disability and macrocephaly. Knockdown or haploinsufficiency of Chd8 in animal models has recapitulated phenotypes observed in patients, including increased head circumference and brain size. Here, we aimed to determine whether increased neuron numbers or soma size drives increased cortical volume. We performed design-based stereological analyses of cortical structure in adult male and female heterozygous Chd8 mice and wild-type littermate controls. Chd8 haploinsufficient male mice displayed a ~8-12% increase in cortical volume, no differences in cortical neuron number and comparable neuronal soma size. Our study reproduced previous reports of increased brain size associated with CHD8 mutation in humans and mice and are consistent with reported sex-specific impacts of Chd8 mutations in mice and increased burden of CHD8 mutations in human males with ASD. These findings suggest that the nature of the cortical enlargement due to Chd8 haploinsufficiency is complex and appears to be due to a factor other than an increased neuron number or soma size. Lay SummaryWe measured the size and neuron number in the neocortex in mice with heterozygous Chd8 mutation, a model relevant to Autism Spectrum Disorder. We found an increased cortical volume in male mutants, which was not accompanied by increased neuron number or soma size. Our results indicate that the enlarged brain in Chd8 mutant mice is complex, more evident here in males, and is due to factors other than increased neuron number.