Mus musculus Raw sequence reads

ASD has a strong genetic basis, and the gene encoding a chromatin remodeler CHD8 is the most frequently mutated in individuals with ASD. CHD8 haploinsufficiency causes macrocephaly and autistic phenotypes in humans and mice, although the mechanisms and cell types responsible for these phenotypes have remained largely unknown. Here we show that reduced expression of CHD8 in oligodendrocytes significantly contributes to ASD pathogenesis. Gene set enrichment analysis for cell types revealed that expression of genes that are specifically expressed in oligodendrocytes were most down-regulated in Chd8 heterozygous mutant mice (Chd8+/?L) compared with other cell types in the brain. Consistently, down-regulation of these genes was also observed in the brain of human ASD patients. Chd8+/?L mice displayed thinner myelin sheath in association with the structural changes in the node of Ranvier and reduced conduction velocity, which were also found in oligodendrocyte lineage-specific Chd8 heterozygous mutant mice. Furthermore, CHD8 was shown to regulate many myelination-associated genes and required for oligodendrocyte maturation and myelination. Oligodendrocyte lineage-specific Chd8 heterozygous mutant mice displayed some ASD-like behavioural characteristics including increased anxiety and altered social behaviour. Our results thus indicate that CHD8 is essential for myelination and that dysfunction of oligodendrocytes as a result of CHD8 haploinsufficiency is responsible for altered neuronal functions and core ASD-like phenotypes.