Autism spectrum disorders (ADs) are a group of neurodevelopmental

disorders characterized by marked deficits in social communication and

repetitive, restrictive behaviors. Recent large-scale whole-exome sequencing

studies have led to the identification of a growing number of genes that are

strongly associated with AD. However, the mechanisms by which the loss of

AD risk gene function affects specific cellular and molecular pathways

remain incompletely understood, which limits our ability to develop targeted

pharmacological treatments. The goal of our research is to identify potential

points of convergence across AD risk genes in the developing vertebrate

brain as a path towards uncovering pharmacological candidates. To

accomplish this, we use zebrafish as a model system, given their optical

transparency, high tractability, and amenability to high-throughput screens.

Using CRISPR/Cas9, we generated zebrafish mutants disrupting 10 high

confidence AD risk genes. We performed pharmaco-behavioral profiling to

identify pharmacological compounds that might reverse abnormal sensory

processing and arousal behaviors in mutants. To identify alterations in brain

circuitry, we are performing whole-brain activity mapping. We characterized

the behavioral "fingerprints" of zebrafish AD risk gene mutants and

identified points of convergence and divergence across mutant behavioral

profiles. We screened 775 FDA-approved drugs in wild-type fish and are

currently using these behavioral profiles to predict and test potential

suppressors of mutant behavioral phenotypes. These studies highlight the

strength of high-throughput functional screens in zebrafish to identify

potential convergent pathways underlying AD risk genes.

Location: Virtual Talk