A Zebrafish Platform to Model Human SCN2A and SCN8A Epilepsy and Evaluate Anti-Seizure Medications

Abstract

Many patients with epilepsy have inadequate seizure control using current anti-seizure medications (ASMs), illustrating the need for new treatments. Genetic epilepsy syndromes like pathogenic variants in voltage gated sodium channel SCN2A and SCN8A are often poorly controlled by current medications, highlighting the need for better models. Voltage gated sodium channel pathogenic variants that induce epilepsy are often gain-of-function, producing hyperexcitability. We established a fast and precise zebrafish seizure assay using mRNA overexpression of SCN2A and SCN8A variants, which allows rapid screening of both variants and ASMs. These short-term genetic seizure models are assayed in 3 days postfertilization (dpf) larvae. Pathogenic variants of SCN2A and SCN8A produced sporadic seizure behavior. We tested human SCN2A R1882Q, SCN2A R853Q and SCN8A R1872Q pathogenic variants that were identified in epilepsy syndrome patients. These models were used to evaluate the efficacy of 3 ASMs: Topiramate, GS967 and PF-04856264. All 3 epilepsy-associated variants increased seizure activity, and the ASMs significantly decreased this seizure activity. This mRNA overexpression assay successfully evaluates seizure activity induced by variants in voltage gated sodium channel genes and examines ASM efficacy in patient specific pathogenic variants. SummaryGenetic epilepsy syndromes have devastating consequences for patients. A zebrafish method is presented that analyzes pathogenic epilepsy variants in human voltage gated sodium channels (Nav1.2 and Nav1.6) and tests efficacy of anti-seizure medications (ASMs). This method provides a rapid platform for evaluating variants and medications.