Escape behaviors are transiently modulated after acutely induced epileptic seizures in larval zebrafish

Abstract Epilepsy is a common neurological disorder giving rise to both recurrent and spontaneous seizures as well as additional neurological comorbidities. In approximately 30% of patients, seizures are not ameliorated by existing anti-seizure drugs. To bridge this treatment gap, the larval zebrafish has emerged as a powerful model for high-throughput drug-screening, based on changes in swimming behavior during seizures. However, such screening has low specificity and thus requires subsequent, low-throughput validation of drug candidates. We found that behavioral escape responses to startling stimuli are strongly reduced for a few hours after seizures, suggesting this behavioral change could serve as a useful assay to identify drugs ameliorating seizures with higher specificity. Moreover, we found that the extent of behavior change and the rate of recovery are dependent on convulsant concentration which determines seizure strength. Finally, we demonstrated that an anti-epileptic drug, Valproic acid, reduced swimming behavior during seizures as well as mitigated the reduction in post-seizure escape behaviors. Nevertheless, it also reduced escape behaviors in the absence of seizures. These data argue that monitoring escape behavior after drug treatment and after seizures provides an improved high throughput assay to identify new anti-epileptic drugs as well as reveal non-specific effects of drugs on neural circuit function, which may predict side-effects in humans.