A Large‐scale Mutagenesis Screen to Identify Seizure‐resistant Zebrafish

Methods: Seizures were induced with pentylenetetrazole (PTZ). Zebrafish were analyzed between 3 and 7 days postfertilization (dpf). Genome mutations were induced in founders by using N‐ethyl‐nitrosourea (ENU). Seizure behavior was monitored by using a high‐speed camera and quantified by locomotion‐tracking software. Electrographic activity was monitored by using a field‐recording electrode placed in the optic tectum of agar‐immobilized zebrafish. Results: Short‐term PTZ exposure elicited a burst‐suppression seizure pattern in 3‐dpf zebrafish and more complex activity consisting of interictal‐ and ictal‐like discharges at 7 dpf. Prolonged exposure to PTZ induced status epilepticus–like seizure activity and fatality in wild‐type zebrafish larvae. With a PTZ survival assay at 6–7 dpf, we identified six zebrafish mutants in a forward‐genetic screen covering nearly 2,000 F2 families. One mutant (s334) also was shown to exhibit reduced behavioral activity on short‐term PTZ exposure and an inability to generate long‐duration ictal‐like discharge. Conclusions: Zebrafish offers a powerful tool for the identification and study of a genetic basis for seizure resistance.