ABSTRACT
Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. To investigate how Chd8 haploinsufficiency disrupts brain development and predisposes individuals to ASD, we generated and characterised a Chd8 heterozygous mouse model. In line with clinical observations of humans with CHD8 mutations, Chd8 heterozygous mice display subtle brain hyperplasia, hypertelorism and anomalous behaviours, although autism-like social deficits, repetitive and restricted behaviours are not present. Few gene expression changes were observed in the mid-gestation embryonic neocortex, whilst over 600 genes were differentially expressed in the neocortex five days after birth. These genes included several known autism candidate genes. Amongst the down-regulated transcripts, genes involved in cell adhesion and axon guidance were particularly prominent, implicating altered connectivity as a potential mechanism underlying the behavioural phenotypes. Accordingly, resting state functional MRI identified increased synchronised activity in cortico-hippocampal and auditory-parietal networks, previously implicated in ASD. Together, these data show that Chd8 heterozygous mice recapitulate key clinical features found in patients with CHD8 mutations and suggest that distinctive anomalies in brain connectivity underlie the neuropsychiatric phenotypes associated with CHD8 haploinsufficiency.
Footnotes
↵* First co-authors