Behavioral Comorbidities and Drug Treatments in a Zebrafishscn1labModel of Dravet Syndrome

Loss-of-function mutations inSCN1Acause Dravet syndrome (DS), a catastrophic childhood epilepsy in which patients experience comorbid behavioral conditions, including movement disorders, sleep abnormalities, anxiety, and intellectual disability. To study the functional consequences of voltage-gated sodium channel mutations, we use zebrafish with a loss-of-function mutation inscn1lab, a zebrafish homolog of humanSCN1A. Homozygousscn1labs552/s552mutants exhibit early-life seizures, metabolic deficits, and early death. Here, we developedin vivoassays usingscn1labs552mutants between 3 and 6 d postfertilization (dpf). To evaluate sleep disturbances, we monitored larvae for 24 h with locomotion tracking software. Locomotor activity during dark (night phase) was significantly higher in mutants than in controls. Among anticonvulsant drugs, clemizole and diazepam, but not trazodone or valproic acid, decreased distance moved at night forscn1labs552mutant larvae. To monitor exploratory behavior in an open field, we tracked larvae in a novel arena. Mutant larvae exhibited impaired exploratory behavior, with increased time spent near the edge of the arena and decreased mobility, suggesting greater anxiety. Both clemizole and diazepam, but not trazodone or valproic acid, decreased distance moved and increased time spent in the center of the arena. Counting inhibitory neuronsin vivorevealed no differences betweenscn1labs552mutants and siblings. Taken together, our results demonstrate conserved features of sleep, anxiety, and movement disorders inscn1labmutant zebrafish, and provide evidence that a zebrafish model allows effective tests of treatments for behavioral comorbidities associated with DS.