Employing zebrafish to understand genetic drivers of epilepsy-related comorbid behaviors

Children with epilepsy frequently experience a range of significant comorbidities beyond seizures, such as motor dysfunction, cognitive impairment, and neurodevelopmental delays. In some cases, these comorbidities contribute more significantly to overall disease burden than the seizures themselves. To improve quality-of-life (QOL) for these children, treatment options should be selected that control seizures and ameliorate comorbidities. Unfortunately, such therapeutics remain largely elusive. Addressing this issue requires suitable preclinical models. Here we used CRISPR-generated zebrafish with single-gene mutations linked to pediatric epilepsy and applied clinically-relevant behavioral assays to study the effects of these mutations. Using high-throughput locomotion-based assays, we uncovered errors in sensorimotor integration in larval scn1lab, stxbp1b , arxa and gabrb3 zebrafish mutants at 6 days post-fertilization (dpf) compared to wild-type sibling controls. Strikingly abnormal exploratory and preference responses were also observed in scn1lab and stxbp1b zebrafish mutants. Pharmacological testing revealed that, compared to stiripentol and valproic acid, clemizole produced the most extensive rescue of deficits in scn1lab mutants. Within the broader epilepsy research landscape, this study further supports the use of zebrafish as a robust, dual platform to understand and discover novel therapeutics for epilepsy and its associated behavioral comorbidities.