There is an urgent need to leverage the rapidly expanding list of autism spectrum disorder (ASD) risk genes to gain an actionable understanding of the biology of ASD and to develop mechanism-based pharmacotherapies.

Ellen Hoffman’s laboratory has developed a high-throughput in vivo system for screening hundreds of small molecules in zebrafish models of high-confidence ASD (hcASD) risk genes. They have successfully utilized this approach in zebrafish containing mutations in the ASD risk gene CNTNAP2, uncovering GABAergic and glutamatergic dysfunction and a novel role for estrogenic compounds as suppressors of an ASD-associated behavioral phenotype in these animals¹.

Funded in part by a SFARI Pilot Award, her laboratory has begun assessing additional zebrafish models of other hcASD risk genes. However, although zebrafish offer unique advantages for large-scale, high-throughput screening, the extent to which compounds identified in zebrafish screens target related mechanisms in mammals remains unclear. Yet this level of high-throughput screening is also impractical in rodents.

To address these issues, Hoffman has established a collaboration with the laboratory of Ted Abel to leverage her expertise in high-throughput drug screens in zebrafish models of hcASD risk genes with Abel’s expertise in mouse behavioral phenotyping. The objective of the current research project is to directly translate findings from zebrafish behavior-based screens to mouse behavioral assays, elucidating the cellular and circuit-level effects of ASD drug candidates in both systems. These studies will provide a critical path forward in the discovery of novel targeted pharmacotherapies with relevance to ASDs.

The central hypothesis of this proposal is that pharmacological suppressors identified in Hoffman’s behavior-based screens in zebrafish genetic models will reverse related behavioral phenotypes in mouse models and reveal conserved mechanisms. This hypothesis is based on multiple lines of evidence for the deep conservation of neurodevelopmental, pharmacological and circuit-level pathways in zebrafish and mice.

The results of this combined screening approach are expected to bridge a critical gap in translational drug discovery, leading to the identification of novel pharmacological targets for further evaluation in ASD.