Large-scale phenotype-based antiepileptic drug screening in a zebrafish model of Dravet syndrome

Abstract

Mutations in a voltage-gated sodium channel (SCN1A) result in Dravet Syndrome (DS), a catastrophic childhood epilepsy. Zebrafish with a mutation in scn1Lab recapitulate salient phenotypes associated with DS including seizures, early fatality and resistance to antiepileptic drugs. To discover new drug candidates for DS, we screened a chemical library of ∼1,000 compounds and identified four compounds that rescued the behavioral seizure component, including one compound (dimethadione) that suppressed associated electrographic seizure activity. Fenfluramine, but not Huperzine A, also showed antiepileptic activity in our zebrafish assays. The effectiveness of compounds that block neuronal calcium current (dimethadione) or enhance serotonin signaling (fenfluramine) in our zebrafish model suggests these may be important therapeutic targets in patients with DS. Over 150 compounds resulting in fatality were also identified. We conclude that the combination of behavioral and electrophysiological assays provide a convenient, sensitive and rapid basis for phenotype-based drug screening in zebrafish mimicking a genetic form of epilepsy.

Significance Statement: Dravet syndrome is a catastrophic childhood epilepsy resistant to available medications. Current animal models for this disease are not amenable to high-throughput drug screening. We used a zebrafish model for Dravet syndrome and screened over 1000 compounds. We report the identification of compounds with the ability to suppress seizure behavior and electrographic seizure activity. This approach provides an example of precision medicine directed to pediatric epilepsy.