Zebrafish reveal drug candidates linked to autism risk genes.

Yale researchers screened 774 FDA‑approved drugs in larval zebrafish and used behavioral fingerprints to identify candidates that reverse dysregulated behaviors tied to autism risk genes, notably finding levocarnitine as a top rescue for SCN2A and DYRK1A and reporting rescue in human neuron models; they also published an open, searchable database of the screened drugs.

Yale researchers used zebrafish behavioral fingerprints to predict and test drugs that might reverse dysfunctions linked to autism risk genes. More than 100 genes are associated with autism and affect core developmental brain processes such as neuronal communication and gene regulation. The team built on earlier work mapping how disrupting 10 autism risk genes changed basic sleep and sensory behaviors in larval zebrafish. Zebrafish offer experimental advantages for this approach because they are genetically similar to humans, breed prolifically, and are amenable to large automated pharmacological screens. Key findings: - The researchers screened 774 U.S. FDA‑approved drugs using automated assays of sleep and sensory processing in wild‑type larval zebrafish. - Statistical models produced a database of 520 drugs that were non‑toxic and produced significant effects on zebrafish behavior. - The team applied pharmaco‑behavioral profiling to match drug behavioral fingerprints to zebrafish carrying mutations in autism risk genes, focusing follow-up tests on SCN2A and DYRK1A. - Levocarnitine was identified as a top rescue candidate for SCN2A and DYRK1A; it reversed dysregulated behaviors, affected lipid metabolic pathways and regional baseline brain activity in zebrafish, and rescued network activity deficits in human pluripotent stem cell‑derived excitatory neurons with these mutations. - The investigators created an open‑source, searchable website with behavioral profiles for all 774 screened drugs to support further research. Summary: The study links specific drug behavioral profiles to genetic models of autism and supplies a searchable resource for researchers. Investigators reported levocarnitine as a repeated rescue for mutations in SCN2A and DYRK1A and described the database as a tool to identify candidates relevant to other autism risk genes. Further experimental work in additional systems was described as the next stage for investigating these drug mechanisms.