Aging as a risk factor for seizure-induced cell death

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DESCRIPTION (provided by applicant): The focus of this proposal is Research Objective 17. While previous studies in the applicants' laboratory have established that there are genetic differences in susceptibility to seizure-induced cell death among inbred strains of mice, the present proposal represents entry into a new area for the investigator: The effects of aging on seizure and seizure-induced cell death susceptibility. Knowledge about the influence of aging on the susceptibility of the brain to chemical injury is of critical importance in geriatric medicine and public health. While the onset and extent of epilepsy increases in both healthy aged and diseased aged populations, the reasons for this increased incidence remain unexplored. Among the different experimental models used to study neurotoxicity, the kainic acid chemoconvulsant rodent model is well known for its ability to act as an epileptogenic agent. Kainic acid is known to produce substantial lesions in the hippocampus, the amygdala and related limbic pathways, and is associated with lasting neurological deficits including seizures. Thus, we are interested in determining whether age-related differences in either functional sensitivity to kainic acid or tolerance might account for the apparent age-related supersensitivity to excitotoxins. The proposed research will explore the possibility that aged mice are more susceptible to kainate neurotoxicity than their adult counterparts. As a first step to addressing the pharmacological mechanisms regulating susceptibility differences, we will determine whether variability in the response to excitotoxic cell death results from differences in the pharmacological sensitivity to kainate. We have proposed 2 Aims to address these issues. In Aim 1, we will determine whether aging can modulate sensitivity to kainate-induced seizures and seizure-induced cell death. In Aim 2, we will initiate pilot studies to determine the pharmacological mechanism that contributes to variability in the response to excitotoxic cell death. Specifically, we will characterize whether variability in the response to excitotoxic cell death results from strain-or age-dependent differences in kainate delivery to the brain, and secondly, whether the neurotoxic effects of kainate administration can be prevented by administration of glutamate antagonists. The results of these experiments will help determine if the aging brain has the same sensitivity to neurotoxic insults as that of younger animals, and will begin to evaluate the mechanistic basis for differential.