Pharmaco-Behavioral Screens Identify Novel Suppressors in Zebrafish Mutants of Neuropsychiatric Disorder Genes

There are currently >100 genes associated with autism spectrum disorders. Similarly, a 2024 study reported there are >90 risk loci associated with post-traumatic stress disorder. Although, advancing from multiple-genetic causes to identifying relevant pharmacological targets in neuropsychiatric disorders remains a central challenge. Zebrafish present a scalable system that is increasingly being used for pharmacological screens. In this study, we use large-scale zebrafish larval behavioural assays to screen US. FDA-approved drugs and develop a database of the behavioural fingerprints of 520 drugs in wild-type fish. In a previous functional screen of 10 genes that are strongly associated with autism, we showed that the behavioural phenotypes of these mutants clustered in three distinct subgroups. Here, we utilise our drug screening database to identify targets that significantly correlate and anticorrelate with each subgroup. Further, by screening select drugs that anti-correlate with specific mutant behavioural phenotypes, we identify top rescue drugs. As a next step, we have created stress paradigms in larval zebrafish that model post-stress behaviours in humans. Combining the post-stress behavioural fingerprints with the behavioural phenotype in zebrafish mutants of PTSD driver genes, we will leverage our pharmaco-behavioural database to identify suppressors of specific post-stress behaviours.