Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats

Abstract

Inherited seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s) is associated with increased voltage-gated calcium channel currents suggesting a massive calcium influx resulting in increased levels of intraneuronal calcium. Cytosolic calcium, in turn, activates many processes, including chloride channels, to restore normal membrane excitability and limit repetitive firing of the neurons. Here we used EACT and T16Ainh-A01, potent activator and inhibitor of calcium-activated channels transmembrane protein 16A (TMEM16A), respectively, to probe the role of these channels in the pathophysiology of acoustically evoked seizures in the GEPR-3s. We used adult male and female GEPR-3s. Acoustically evoked seizures consisted of wild running seizures (WRSs) that evolved into generalized tonic-clonic seizures (GTCSs) and eventually culminated into forelimb extension (partial tonic seizures). We found that acute EACT treatment at relatively higher tested doses significantly reduced the incidences of WRSs and GTCSs, and the seizure severity in male GEPR-3s. Furthermore, these antiseizure effects were associated with delayed seizure onset and reduced seizure duration. Interestingly, the inhibition of TMEM16A channels reversed EACT’s antiseizure effects on seizure latency and seizure duration. No notable antiseizure effects were observed in female GEPR-3s. Together, these findings suggest that activation of TMEM16A channels may represent a putative novel cellular mechanism for suppressing GTCSs.