The Zebrafish Pannexin1a and Pannexin1b Ohnologs Contribute Differentially to Seizure Propagation In Vivo

Seizures are a hallmark of epilepsy and are associated with many other diseases. However, their molecular determinants are not well understood. A membrane glycoprotein, Pannexin1, has been implicated in seizures for its overexpression in epileptic tissue and the channels function of extracellular ATP release. Here, we investigated the mechanistic role of ohnologs panx1a and panx1b in-vivo, in a chemically induced zebrafish seizure model. Panx1a and panx1b knockout zebrafish lines, and treatment with a Panx1 channel blocker were evaluated for seizure phenotypes across behavioral, molecular, computational, and electrophysiological analyses. Pharmacologically blocking the channel suppressed seizures, while genetic targeting showed both pro- and anti-seizure properties. We propose the involvement of ATP and purinoceptor P2rx7 that drive the two Panx1 channels differential effects on seizures. By identifying the critical players and their associated molecular processes, we present the Panx1 zebrafish model as a robust platform for seizure investigation in antiepileptic drug discovery.