A systematic study of the environmental etiology of autism spectrum disorder using high-throughput behavioral screening

ABSTRACT Both genetic and environmental factors influence the risk of developing autism spectrum disorder. Environmental contributions in particular, are estimated to account for ~40% of autism risk, yet we know very little about the identities of these environmental risk factors for autism. To bridge this gap in knowledge through an experimental approach, I developed a zebrafish-based high-throughput behavioral assay of sociality during my postdoctoral training. Social deficit is one of the two core symptoms of autism and a hallmark of this disease, so I hypothesized that environmental inhibitors of sociality are also likely risk factors for autism. Using this assay, I conducted a large-scale screening of 1120 compounds and discovered topoisomerase II (Top2) inhibitors as a class of environmental chemicals that inhibit the development of sociality and likely contribute to autism risk. The main objective of this proposal is to characterize the role of Top2 in the development of social behavior. During the K99 award period, I demonstrated that between the two isoforms of Top2, Top2a but not Top2b is required for the normal development of sociality. In addition, I discovered that Top2a likely functions by interacting with the polycomb repressive complex 2 (PRC2) and regulating H3K27 trimethylation (H3K27me3) in specific genomic loci. I also gained skills and knowledge in mouse genetics, mouse behavioral science, genomics, and bioinformatics. With the new training and mechanistic insights acquired in the K99 phase, I will extend the scope of my research in the R00 phase to: 1) establish and characterize a genetic mouse model of Top2a depletion through conditional knockout; 2) examine genome-wide changes in H3K27me3 distribution following Top2a inhibition; and 3) systematically discover environmental factors that affect the development of social behavior by screening the ToxCast library. Together, the proposed research will greatly facilitate environmental risk factor discovery for autism and may reveal novel therapeutic targets to prevent or treat autism. The support that the R00 award provides will help me achieve my long-term goal of establishing a successful independent research program to investigate environmental impacts on mental illnesses.