One of the most critical challenges in the identification of new medications to treat autism spectrum disorders (ASDs) is our limited understanding of the biological mechanisms underlying these disorders. In recent years, there have been considerable advances in the genetics of ASD, with a resulting rapidly accumulating pool of reliable ASD risk genes. Currently, we need systems that will allow us to progress from gene discovery to the illumination of relevant biological pathways and novel therapeutics.

Ellen Hoffman and her colleagues at Yale University have developed an innovative strategy to advance the discovery of biologically based treatments for ASD. They utilize zebrafish as a model system, an amenable model due to large progenies that allow for the screening of hundreds of psychoactive molecules simultaneously. Using a high-throughput in vivo approach, Hoffman and her team previously identified dysfunction of excitatory and inhibitory systems in zebrafish lacking a functional autism risk gene, CNTNAP2. Through an unbiased screen, they identified a novel role for compounds with estrogenic activity in the rescue of an autism gene-associated mutant behavioral phenotype.

Hoffman’s team aims to extend this work by investigating zebrafish with mutations in nine strong ASD candidate genes, previously identified from whole-exome sequencing of the Simons Simplex Collection (SSC). Because the regulation of gene expression has been found to be a common mechanism underlying ASD, the team will analyze gene expression patterns in the brains of mutants. To assess and quantify specific behavioral paradigms, the group plans to utilize an automated assay that tracks the locomotor activity of hundreds of larval zebrafish. Behavioral profiles arising after exposure to psychoactive compounds will be compared in zebrafish containing mutations in ASD genes and in wildtype zebrafish.

Results of these comparisons will elucidate biological pathways that are likely to be disrupted by the ASD risk genes, and will identify compounds with the potential to selectively suppress specific behavioral phenotypes arising from these mutations. Finally, by searching for enrichment of specific neurochemical pathways in the pharmacological and gene expression studies, the team aims to identify common biological mechanisms and promising pharmacological candidates for the treatment of ASD.