Inhibition of TRPC3 channels suppresses seizure susceptibility in the genetically-epilepsy prone rats

Transient receptor potential canonical 3 (TRPC3) channels are important in regulating Ca2+ homeostasis and have been implicated in the pathophysiology of chemically induced seizures. Inherited seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s) has been linked to increased voltage-gated Ca2+ channel currents in the inferior colliculus neurons, which can affect intraneuronal Ca2+ homeostasis. However, whether TRPC3 channels also contribute to inherited seizure susceptibility in GEPR-3s is unclear. This study investigated the effects of JW-65, a potent and selective inhibitor of TRPC3 channels, on acoustically evoked seizure susceptibility in adult male and female GEPR-3s. These seizures consisted of wild running seizures (WRSs) that evolved into generalized tonic-clonic seizures (GTCSs). The results showed that acute administration of low doses of JW-65 significantly decreased by 55-89% the occurrence of WRSs and GTCSs and the seizure severity in both male and female GEPR-3s. This antiseizure effect was accompanied by increased seizure latency and decreased seizure duration. Additionally, female GEPR-3s were more responsive to JW-65's antiseizure effects than males. Moreover, JW-65 treatment for five consecutive days completely suppressed acoustically evoked seizures in male and female GEPR-3s. These findings suggest that inhibiting TRPC3 channels could be a promising antiseizure strategy targeting Ca2+ signaling mechanisms in inherited generalized tonic-clonic epilepsy.