Increased mitotic activity in the dentate gyrus of the hippocampus of adult C57BL/6J mice exposed to the flurothyl kindling model of epileptogenesis.

Repeated flurothyl-induced generalized forebrain seizures result in a progressive and permanent lowering of the generalized seizure threshold in mice and an increase in the percentage of animals expressing forebrain-brainstem seizures, when rechallenged with flurothyl, after a stimulation-free period. Since this seizure paradigm serves as an excellent model for examining changes in seizure threshold and seizure propagation, we were interested in examining mitotic activity in hippocampal progenitors following flurothyl-induced epileptogenesis. In the present studies, we investigated (1). the effect of one or eight flurothyl-induced seizures on mitotic activity in the hippocampal dentate gyrus of adult mice measured by 5-bromo-2'-deoxyuridine incorporation, (2). the time course of change in hippocampal mitotic activity, (3). the cellular phenotype of these mitotically active cells, and (4). the relationship of changes in mitotic activity to changes in seizure threshold and phenotype. Significant increases in hippocampal mitotic activity were observed in mice exposed to either one or eight flurothyl-induced seizures. Increases were observed at 1 and 3 days following one seizure, and at 0, 1, 3, and 7 days following eight seizures. Confocal analyses, using neuronal and glial markers, suggest that the majority of these mitotic cells are neurons. In addition, no correlation was observed between hippocampal mitotic activity and the final seizure type that animals expressed following incubation and flurothyl retest. A significant correlation was observed between hippocampal mitotic activity and seizure threshold in flurothyl-kindled mice. Overall, these results indicate that both one and eight flurothyl-induced seizures are potent inducers of hippocampal neurogenesis in adult mice. Results further suggest that the increases in hippocampal neurogenesis are not directly related to the processes that underlie the shift in behavioral seizure phenotype, but may be involved in either the establishment or the maintenance of seizure threshold in this flurothyl model of epileptogenesis.