Large-Scale Phenotype-Based Antiepileptic Drug Screening in a Zebrafish Model of Dravet Syndrome

Positive hits identified in the locomotion assay. a, Heat map showing the results of individual zebrafish trials (1-6) for compounds tested at a concentration of 100 µm in the locomotion-tracking assay. Raw data values for individual fish are shown within the color-coded boxes for one sample trial. Mean velocity data are shown at right for “trial 1” and “trial 2”; six fish per trial. Note: only drugs highlighted in bold type were classified as positive nontoxic hits in two independent trials and moved on to further testing. b, Representative raw locomotion data plots for six individual scn1Lab mutant larvae at baseline (top) and following the addition of a compound resulting in fatality (bottom, gemfibrozil) or hyperactivity (bottom, mepivacaine). Movement is color coded, with low-velocity movements shown in yellow, and high velocity movements shown in red.

Electrophysiology assay to identify drugs that rescue the scn1Lab mutant epilepsy phenotype. a, Representative field electrode recording epochs (5 min in duration) are shown for the “positive” compounds identified in the locomotion assay. All recordings were obtained with an electrode placed in the forebrain of agar-immobilized scn1Lab larvae that was previously tested in the locomotion assay. A suppression of epileptiform electrographic discharge activity was noted in mutants exposed to dimethadione. b, Bar plot showing the mean number of epileptiform events in a 10 min recording epoch for scn1Lab larvae exposed to cytarabine (N = 6), dimethadione (N = 6), theobromine (N = 6), and norfloxacin (N = 6). The mean ± SEM is shown. The fish shown were tested in the locomotion assay first. c, Bar plot showing the total distance traveled before (black bars) and after (white bars) exposure to a test compound; 10 min recording epoch and six fish per drug. The mean ± SEM is shown.