Phenotypic screening is a powerful approach for discovering the therapeutic and toxic effects of small molecules.  Although cellular phenotypes are frequently used for screening, they are relatively limited in their utility for modeling nervous system function.  We have therefore focused on zebrafish behaviors as readouts for phenotypic screening, including such diverse behaviors as threat responses, light-evoked responses, opioid self-administration, and response to social stimuli.  Sociality is broadly conserved across the animal kingdom, facilitating cooperation, reproduction, and protection from predation. In humans, social dysfunction is a hallmark of several neurodevelopmental disorders, including autism spectrum disorder.  To systematically identify environmental factors that influence development of sociality, we established an automated screening system named Fishbook to search for chemicals that disrupt development of social behavior in zebrafish (Danio rerio). A screen of 1120 drugs revealed that the α isoform of topoisomerase II (Top2a) is required for zebrafish social behavior development. In mice, prenatal exposure to the Top2 inhibitor ICRF-193 caused lasting behavioral deficits related to core symptoms of autism without affecting other major behavioral categories. Top2a depletion in zebrafish selectively altered expression level and epigenetic status of autism related genes, and a custom upstream analysis pipeline unveiled Ezh2 and H3K27me3 as the key mediators of this effect. Together, these findings identify Top2a as a key component of an evolutionarily conserved molecular mechanism that regulates the development of social behavior.

Scaling up:  Zebrafish behaviors as scalable phenotypes for small molecule screening

ACS Fall 2021

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