Abstracts

Rationale: Previous studies have suggested that there is an aging effect on susceptibility to seizure-induced cell death within the hippocampus in rats. However, the links between perturbations in aging and neurodegeneration are unclear. Knowledge of such differences may provide insight into the role of aging as a putative risk factor for neuronal degeneration. The present study used two inbred strains of mice (C57BL/6J and FVB/NJ) to address the genetic control of age-dependent neurodegeneration. In the present study, we determined if seizure induction and seizure-induced cell death are affected in aged animals administered the excitotoxin, kainic acid (KA).Methods: Young (2 mo.), middle-aged (12 mo.) and old (18 mo.) male C57BL/6J (B6) and FVB/NJ (FVB) mice obtained from the NIA aging colony (B6) or aged in-house (FVB) received one subcutaneous injection of KA. Dose response testing was performed in three-four groups of male mice (n=7 mice/group) from each strain. Following KA injections, mice were monitored continuously for 4 h and scored for seizure activity. Brains from animals in each age group were processed for histopathologic evaluation seven days following KA administration to evaluate the severity of seizure-induced brain damage.Results: Previously, we had discovered that although B6 and FVB mouse strains exhibit comparable seizure activity, resistant strains of mice (B6) show essentially no cell death within the hippocampus. Our results in the 2 mo. group replicate these findings, irrespective of the dose of kainate administered. Among the 12 mo.-old mice, we saw a significant strain-dependent difference in the extent of cell death at the 20-mg/kg kainate dose, yet no significant differences in seizure sensitivity. In 18 mo. mice, we saw a number of strain differences in seizure susceptibility that were dose-dependent. As predicted aged FVB mice were more vulnerable to the induction of behavioral seizures as compared to the B6 strain. In contrast, we continued to see no hippocampal cell death in B6 mice irrespective of the dose of kainate administered and the age group.Conclusions: Results from these studies suggest that the age-related increased susceptibility to the neurotoxic effects of seizure induction and seizure-induced injury is regulated in a strain-dependent manner. In particular, while we did not observe any significant strain-dependent differences in seizure susceptibility among young-adult, middle-aged, and aged mice of these two strains, as originally hypothesized, aged animals of the FVB strain were more vulnerable to the induction of behavioral seizures and associated neuropathology after systemic injection of KA than young or middle-aged mice. In contrast, no age-dependent differences were observed in the induction of behavioral seizures or susceptibility to seizure-induced cell damage after systemic injection of KA in B6 mice. These results suggest that significant strain-dependent differences in the extent of seizure-induced cell death continue to exist across the lifespan.