Electrophysiological screen reveals 8 genes in zebrafish model of catastrophic childhood epilepsies

Catastrophic childhood epilepsies are characterized by persistent seizures and are frequently associated with cognitive and developmental impairments. Many, approximately 30%, of these epilepsies are rare genetic disorders that do not have effective therapeutic options. The bench to drug process is lengthy and expensive, and thus it is critical to find more affordable drug screening options. Zebrafish are an ideal model organism for screening studies as they share considerable (70%) genetic similarities with humans and are cheap to maintain with efficient breeding capabilities. In the present study, 37 zebrafish lines were screened for epileptic brain activity to identify high priority genes for future pharmacology studies. Each zebrafish line, generated by CRISPR-Cas9 represents a single gene loss of function mutation associated with 3 epilepsy based on genome wide association studies. Larval zebrafish were screened for spontaneous seizure activity using electrophysiological assays. The following 8 genes were significantly associated with spontaneous seizure activity in zebrafish: EEF1A, ARX, GRIN1, GABRB3, PNPO, STRADA, SCN1A, and STXBP1. There is now an open-source database for all 37 zebrafish lines, which contains sequencing information, survival curves, behavioral profiles, and electrophysiological data. The findings reveal novel target genes for future drug development and discovery. Future work is needed to explore whether zebrafish also model co-morbidities commonly seen in human patients with epilepsy