Dissociation of spontaneous seizures and brainstem seizure thresholds in mice exposed to eight flurothyl-induced generalized seizures

Abstract

Objective: C57BL/6J mice exposed to eight flurothyl-induced generalized clonic seizures exhibit a change in seizure phenotype following a 28-day incubation period and subsequent flurothyl rechallenge. Mice now develop a complex seizure semiology originating in the forebrain and propagating into the brainstem seizure network (a forebrain→brainstem seizure). In contrast, this phenotype change does not occur in seizure-sensitive DBA/2J mice. The underlying mechanism was the focus of this study. Methods: DBA/2J mice were exposed to eight flurothyl-induced seizures (1/day) followed by 24-h video-electroencephalographic recordings for 28 days. Forebrain and brainstem seizure thresholds were determined in C57BL/6J and DBA/2J mice following one or eight flurothyl-induced seizures, or after eight flurothyl-induced seizures, a 28-day incubation period, and final flurothyl rechallenge. Results: Similar to C57BL/6J mice, DBA/2J mice expressed spontaneous seizures. However, unlike C57BL/6J mice, DBA/2J mice continued to have spontaneous seizures without remission. Because DBA/2J mice did not express forebrain→brainstem seizures following flurothyl rechallenge after a 28-day incubation period, this indicated that spontaneous seizures were not sufficient for the evolution of forebrain→brainstem seizures. Therefore, we determined whether brainstem seizure thresholds were changing during this repeated-flurothyl model and whether this could account for the expression of forebrain→brainstem seizures. Brainstem seizure thresholds were not different between C57BL/6J and DBA/2J mice on day 1 or on the last induction seizure trial (day 8). However, brainstem seizure thresholds did differ significantly on flurothyl rechallenge (day 28), with DBA/2J mice showing no lowering of their brainstem seizure thresholds. Significance: These results demonstrate that DBA/2J mice exposed to the repeated-flurothyl model develop spontaneous seizures without evidence of seizure remission and provide a new model of epileptogenesis. Moreover, these findings indicated that the transition of forebrain ictal discharge into the brainstem seizure network occurs as a result of changes in brainstem seizure thresholds that are independent of spontaneous seizure expression.