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 the treatment of DS, we screened a chemical library of ∼1000 compounds and identified 4 compounds that rescued the behavioral seizure component, including 1 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 that 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.
Highlights
Dravet syndrome (DS) is a devastating genetic epileptic encephalopathy that has been linked to more than Ͼ300 de novo mutations in a neuronal voltage-gated sodium channel (SCN)
Larval zebrafish clutches were bred from wild-type (WT; TL strain) or scn1Lab heterozygous animals that had been backcrossed to TL wild-type for at least 10 generations
We performed a phenotype-based screen to identify compounds that significantly reduce mutant swim behavior to levels associated with Stage 0 or Stage I
Summary
Dravet syndrome (DS) is a devastating genetic epileptic encephalopathy that has been linked to more than Ͼ300 de novo mutations in a neuronal voltage-gated sodium channel (SCN). Children with DS are at a higher risk for sudden unexplained death in epilepsy and episodes of Received June 18, 2015; accepted August 4, 2015; First published August 20, 2015. S.C.B. performed research; M.T.D. and S.C.B. analyzed data; S.C.B. wrote the paper Children with DS are at a higher risk for sudden unexplained death in epilepsy and episodes of Received June 18, 2015; accepted August 4, 2015; First published August 20, 2015. 1The authors declare no competing financial interests. 2Author contributions: M.T.D. and S.C.B. designed research; M.T.D. and
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