Abstracts

Rationale: Animal models of epilepsy have provided a wealth of information about mechanisms related to epileptogenesis; however, each model has its own limitations. This has necessitated the need for the development of new models to address limitations. In the repeated flurothyl model (RFM), C57BL/6J (B6) mice received daily exposures to a 10% flurothyl solution over eight days (induction phase). These exposures resulted in the expression of only generalized clonic-forebrain seizures. Following the eight induction phase trials, mice were allowed to rest for 28-days (incubation phase). When the mice were retested with flurothyl, after this 28-day rest period, 75% of the B6 mice displayed a change in the behavioral seizure phenotype expressed, from a generalized clonic-forebrain seizure (as observed in the induction-phase) to a generalized clonic-forebrain seizure that rapidly progressed into a generalized brainstem seizure (referred to as a forebrain-->brainstem seizure). These experiments indicate the occurrence of epileptogenic processes in mice exposed to the RFM. However, spontaneous seizures have not been examined yet in the RFM model; a necessary requisite for a new model of epileptogenesis. The current study uses long-term electroencephalographic (EEG) recordings to determine whether mice exposed to the RFM have spontaneous seizures. Methods: Two groups of B6 mice, exposed to the RFM, were utilized for these experiments, group 1: cerebral cortical electrodes were implanted and EEG was monitored pre-induction, and during the induction and incubation phases; group 2: cortical electrodes were implanted 1 day after the 8th trial of the seizure induction and EEG was monitored during the incubation phase. Results: To date, 75% of the B6 mice observed, displayed spontaneous seizures during the incubation phase. No spontaneous seizures were observed during the pre-induction or induction phases. On average, spontaneous seizures occurred at a rate of 1 seizure every other day or every 2 days. All EEG events were also characterized by video monitoring. The spontaneous behavioral seizures observed were virtually identical to the generalized forebrain-clonic seizures observed during the induction phase. No generalized tonic-brainstem seizures were observed. Seizures typically lasted 30-60 seconds, followed by a prolonged period of slow and relatively flattened EEG (post-ictal period) with concomitant behavioral hypoactivity. Conclusions: Overall, our data indicate that mice exposed to 8 repeated flurothyl trials develop spontaneous seizures. Interestingly, the presence of spontaneous seizures in 75% of the mice tested, matches the percentage of animals that change their seizure phenotype following exposure to the RFM. This suggests the possibility that the spontaneous seizures are inducing a reorganizational event(s) in the brain to account for the change in behavioral seizure expression. These results suggest that the RFM may serve as a new model of epileptogenesis that does not have some of the limitations of other epilepsy models.