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.
Highlights
Twenty-four-hour monitoring revealed that administration of EACT at the tested doses did not alter the gross behavior of the genetically epilepsy-prone rats (GEPRs)-3s
The analysis showed that EACT significantly reduced the incidence of the occurrence of generalized tonic-clonic seizures (GTCSs) in male GEPR-3s by 56% (p < 0.029) at 2 h but not 0.5, 1, and 24 h posttreatment time points compared with the control testing conditions (Figure 1C)
We evaluated the role of activating transmembrane protein 16A (TMEM16A) channels as a putative novel mechanism for seizure suppression in the GEPR-3s
Summary
Epilepsy is one of the most common chronic neurological disorders characterized by recurrent seizures, which result from hypersynchronous discharges of neurons in specific brain networks. Systemic administration of inhibitors of voltage-gated Ca2 + channels (VGCCs) and activator of small conductance Ca2+ -activated K+ channels markedly suppressed acoustically evoked seizures in the genetically epilepsy-prone rats (GEPRs) and DBA/2 mice [11,12,13,14,15]. These findings suggested a functional and molecular remodeling of these channels, at least in the inferior
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