Contribution of oligodendrocytes to ASD pathology: role of CHD8

“Autism spectrum disorder” (ASD) is a new name that recognizes four previously separated disorders (autistic disorder, Asperger’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified) as one single condition with different levels of symptom severity across a spectrum. This disease is associated with both genetic and environmental causal factors, as explainable by the high but not overwhelming heritability. ASD is also characterized by certain neurobiological features, such as region-specific volumetric changes, connectivity issues and fine micro-structural changes in the central nervous system. These alterations have been linked to functional disruption in several CNS cell types, including oligodendrocytes. Oligodendrocytes’ main function is the formation of myelin sheaths which wrap around neuronal axons and provide electric insulation, thus accelerating the transmission of electrical signals. Oligodendrocytes are a peculiar cell population, as they are capable of self-renewal thanks to the maintenance of a pool of progenitors, called Oligodendrocyte Precursor Cells (OPCs). The aim of this thesis is to explore the contribution of the previously under-represented oligodendrocytes to ASD pathology. By performing large-scale exome sequencing, Satterstrom et al. (2020) identified 102 ASD-associated genes, whose expression has been studied in an existing single-gene RNA-seq dataset. The authors identified 25 cell type clusters, and 62 out of the 102 genes have been found enriched in the cluster associated with astrocytes and oligodendrocytes (cluster C4), the only non-neuronal cluster with significant enrichment. Within the 62 C4-associated genes, CHD8 has been extensively associated with ASD in the past. The studies carried out by Kawamura et al. (2020) and Zhao et al. (2018) investigated the role of CHD8 in oligodendroglia, showing that a disruption in the expression of CHD8 in mice models is linked to disruption in myelination and to defects in OPC proliferation and differentiation. Kawamura et al. also showed that a defect in CHD8 expression gives rise to anxiety-like behaviour in mice, thus partially recapitulating ASD-linked behavioural phenotype. These findings show that CHD8 is crucial in the progression of the oligodendroglial lineage and in the correct formation and distribution of myelin. Thus, its disfunctions could underlie subsets of ASD which are linked to myelin reduction. Even if CHD8 deficiency in oligodendrocytes is not sufficient to strongly recapitulate ASD behavioural features, we can speculate that the contribution of oligodendrocytes to ASD pathology could be carried out by the interaction between CHD8 and other genes. Further research needs to be carried out in order to expand the knowledge on this protein’s contribution to oligodendrocyte’s functioning and to ASD.