Convergence of genetic and gestational immune mechanisms in CHD8-related ASD

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 DESCRIPTION (provided by applicant): Genetic studies indicate that Autism and Autism spectrum disorders (ASD) result from a complex genetic predisposition that acts with non-genetic factors to alter brain development. Common genetic variation may account for up to 50% of ASD risk with remaining causes attributed to other factors 2,3. Even penetrant single gene mutations are not alone sufficient to cause autism in all individuals who carry the alteration and it is clear that non-genetic or "environmental" factors must interact with genetics to modify risk of ASD. With diagnoses at 1 in 68 in the United States8, it has become vital to develop animal models that reflect gene-environment interactions that contribute to the development of ASDs. One of the strongest environmental associations with ASD is a maternal immune event during early pregnancy9-11. Infections of the fetus are not required for these effects and simple activation of a maternal inflammatory response is associated with increased risk9. Despite strong evidence that that both genetic and immune factors contribute to ASD, there are very few reports confirming that specific genetic alterations interact with a gestational immune events to cause or worsen the severity of ASD. Animal models confirm that activation of an innate maternal immune event is alone sufficient to cause alterations in neurodevelopment and behavior 15. It is also known that immune-induced placental damage14,16 or alterations in placental function 17 contribute to these effects. Some ASD risk genes are involved in placentation and we propose that certain types of illness or immune-activating exposures during early pregnancy will synergistically converge with genetic risk to endanger the placenta and developing fetus. Here we provide evidence that the ASD risk gene chromodomain helicase DNA binding 8 (CHD8) mechanistically converges with immune-related mechanisms in both the placenta and developing brain. In this proposal, experiments in mice and with human pluripotent stem cells will determine whether environmental and CHD8-related genetic risks synergize to more severely impact neurodevelopment and function in ASD.