Cell cycle reentry and cell proliferation as candidates for the seizure predispositions in the hippocampus of EL mouse brain.

ABSTRACT

We have recently found that there was DNA fragmentation without cell loss in the hippocampus in EL mice, an epileptic mutant. Neurotrophic factors are also expressed at high levels during the early developmental stages. In the present study, we used EL mice to examine how altered cyclin and the corresponding cyclin dependent kinase (CDK) family are related to cell proliferation during development and during epileptogenesis. Developmental changes of cyclin family and corresponding CDK family (cyclin D/CDK-4, cyclin E/CDK-2, cyclin A/CDK-2, cyclin A/CDK-1, cyclin B/CDK-1) were examined by Western blotting in the hippocampus of EL mice and in nonepileptic control animals (DDY mice). In addition, we attempted to quantify cell proliferation during this period. The developmental changes in cell proliferation were determined by using systemic injections of Bromo-deoxyUridine (BrdU) to label dividing cells. As compared with the control DDY mice, EL mice show an upregulation of cell cycle specific Cyclins/CDKs during early developmental stages suggesting that reentry into the cell cycle is enhanced prior to the onset of seizure activity, possibly due to the abundance of neurotrophic factors. These results show that Cyclins/CDKs are activated during early stages of development in an epileptic animal, before the mouse exhibits seizures. These results suggest that reentry of cells into the cell cycle, with consequent cell proliferation in the hippocampus, contribute to the seizure predispositions of EL mice.