Grant: CIHR Fellowship

The global prevalence of autism spectrum disorder (ASD) has increased by 243% since 2000. ASD is characterized by deficits in social interaction, communication, and repetitive behaviours. CHD8 (Chd8 in non-primates), which encodes chromodomain-helicase-DNA-binding protein 8, is the highest confidence risk gene for ASD. About 85% of individuals with CHD8 mutations present with ASD-related behavioural deficits and macrocephaly. Animal models using global Chd8 knockdown have recapitulated these phenotypes and implicated increased numbers of either neurons or oligodendrocytes in these outcomes. However, global Chd8 suppression lacks the cellular resolution necessary to understand cell-type-specific contributions to Chd8-associated ASD. The proposed research program will provide a preclinical understanding of the roles of neurons, oligodendrocytes, microglia, and astrocytes in the predominant outcomes of Chd8 mutation: ASD-like behavioural deficits and macrocephaly. We will achieve this by leveraging well-established genetic techniques to create novel cell-type-specific mouse lines. First, I will validate and perform a behavioural battery at critical periods to comprehensively understand the contributions of each cell type on ASD-relevant behaviours in male and female mice. Second, I will assess contributions to brain volumetric enlargement using an advanced magnetic resonance imaging murine scanner to study whole-brain and region-specific macrocephaly, ending with a quantification of cell numbers in critical regions using histological techniques. This innovative research is necessary as it will provide the missing cellular insights into the pathogenesis of CHD8-associated ASD. Further, the findings of this study will guide future molecular, functional, and post-mortem experiments, as well as human neuroimaging studies to ultimately support therapeutic strategies for CHD8-linked ASD and related conditions.