Drosophila prickle mutants display comorbid neurological phenotypes and present with autism spectrum disorder-associated phenotypes.

Epilepsy affects approximately 30% of individuals with autism spectrum disorder (ASD). Consistent with these observations, while PRICKLE mutations are primarily linked with epilepsy, there is an enrichment of pathogenic DNA sequence variants in PRICKLE genes carried by individuals with ASD. Nonetheless, a connection between PRICKLE function and ASD warrants further investigation. Here, we show that a seizure-prone Drosophila prickle mutant (prickle-spiny-legs, or pksple) exhibits learning and memory deficits, increased pain sensitivity, both communication and social interaction difficulties, and restrictive repetitive grooming behaviors, all of which are strongly correlated with ASD, while a non-seizure prone prickle mutant (prickle-prickle, or pkpk) does not, thereby associating epilepsy and ASD through prickle. Comparing headed versus headless pksple mutants, we also show that the excessive grooming requires higher level cognitive processing from the brain. Finally, both pksple and pkpk mutants exhibit circadian rhythm defects, another feature correlated with ASD, as well as distinct yet overlapping neurological anomalies in processes that include innate immune response, oxidative stress response, neuronal cell death, neurodegeneration, motor dysfunction and reduced lifespan, likely reflecting the unique isoform expression patterns observed in the developing CNS. Collectively, this study highlights the broadscale effects of PRICKLE mutations that extend beyond the primary clinical features of epilepsy to include several of the core features of ASD.