Behavioral Comorbidities and Drug Treatments in a Zebrafish scn1 lab Model of Dravet Syndrome.

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(Grone B, et al. 2017). Anti-epileptic drug (AED) screening in zebrafish has proven efficient in models of Dravet syndrome due to the lower cost of maintaining fish compared with mouse colonies and rapid reproduction rates. The zebrafish used to study Dravet syndrome carry mutations in scn1lab (a zebrafish version of the human SCN1A gene) and are studied as larvae rather than adult fish. Several aspects of these models have been validated through tests of traditional AEDs and and some other assessments, suggesting the syndrome presents similarly in these zebrafish and humans. Other aspects of the zebrafish models, such as sleep and behavior are not as well validated.

In this study, the authors monitored a specific strain of scn1lab mutant larvae during sleep and found they were more active during dark (night phase) than their healthy controls. This suggests the mutant larvae have sleep and diurnal (light/dark or day/night) rhythm disturbances, resembling what is found in human Dravet patients with SCN1A mutations and mouse models of the syndrome. Clemizole and diazepam (brand name Diastat), but not trazodone or valproic acid (Depakote), decreased the distance moved at night.

To examine behavior and, potentially, anxiety, the authors monitored larvae in an \”open arena,\” or unfamiliar setting. One larvae was placed in the middle of each of several small flat-bottom wells and movement was tracked for 5 minutes. In the first 30 seconds of monitoring, the mutants and healthy controls had the same level of total movement, but the mutants moved to the edge of the well sooner.  As the 5 minutes passed, the mutants\’ level of movement decreased steadily, unlike the healthy controls\’ movement.  The mutants spent more time near the edge of the arena than their healthy controls and showed decreased mobility overall. Clemizole and diazepam but not trazodone or valproic acid decreased the distance moved and increased the time spent in the center of the arena. No differences in numbers of inhibitory neurons (as shown in imaging data) were seen between mutants and healthy controls.

The sleep activity and open arena movement results further confirm the similarities between humans with SCN1A mutations and their scn1lab-mutated zebrafish counterparts, suggesting zebrafish may be an appropriate model for studying these comorbidities. They also show that scn1lab deficiency, and not seizures or medication side effects, are likely responsible for the sleep and behavioral abnormalities observed in the larvae.

Grone BP, Qu T, Baraban SC. Behavioral Comorbidities and Drug Treatments in a Zebrafish scn1lab Model of Dravet Syndrome. eNeuro. 2017 Aug 14;4(4). pii: ENEURO.0066-17.2017. doi: 10.1523/ENEURO.0066-17.2017. eCollection 2017 Jul-Aug. PubMed PMID: 28812061; PubMed Central PMCID: PMC5555352.
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