Post-traumatic epilepsy in zebrafish is drug-resistant and impairs cognitive function.

Abstract

Post-traumatic epilepsy (PTE) is acquired epilepsy after traumatic brain injury (TBI). Despite the availability of more than 20 anti-seizure medications (ASMs), there is no way at present to prevent epileptogenesis in TBI survivors, and many cases of PTE become drug-resistant. Importantly, the adverse effects of ASMs can significantly affect patients quality of life. Mammalian models are commonly used for studying refractory PTE, but are expensive and laborious. Zebrafish models have become popular for studying epilepsy, but most focus on larvae and there have been no reports to date of pharmacological screening in an adult zebrafish model of acquired epilepsy. Valid animal models are critical for understanding PTE and for developing novel therapeutics. The aim of the present study was to characterize the cognitive impairments of a zebrafish model of TBI that leads to the development of PTE. Using combined behavioural and electrophysiological approaches, we also characterized the pharmacological effects of the most commonly used ASMs to treat PTE (valproate, carbamazepine, and phenytoin). Zebrafish with PTE exhibited impairments in learning and memory, difficulty in decision making, and reduced social preference. Valproate and carbamazepine had a limited protective effect against behavioural seizures, and all three drugs failed to significantly reduce electrographic seizures. The negative impacts of TBI and ASMs in zebrafish parallel those observed in other animals, making the zebrafish model of PTE a promising high-throughput model of refractory and drug-resistant epilepsy.