While the onset and extent of epilepsy increases in the aged population, the reasons for this increased incidence remain unexplored. The present study used two inbred strains of mice (C57BL/6J and FVB/NJ) to address the genetic control of age-dependent neurodegeneration by building upon previous experiments that have identified phenotypic differences in susceptibility to hippocampal seizure-induced cell death. We determined if seizure induction and seizure-induced cell death are affected differentially in young adult, mature, and aged male C57BL/6J and FVB/NJ mice administered the excitotoxin, kainic acid. Dose response testing was performed in three-four groups of male mice from each strain. Following kainate injections, mice were scored for seizure activity and brains from mice in each age group were processed for light microscopic histopathologic evaluation seven days following kainate administration to evaluate the severity of seizure-induced brain damage. Irrespective of the dose of kainate administered or the age group examined, resistant strains of mice (C57BL/6J) continued to be resistant to seizure-induced cell death. In contrast, aged animals of the FVB/NJ strain were more vulnerable to the induction of behavioral seizures and associated neuropathology after systemic injection of kainic acid than young or middle-aged mice.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, similar to previous observations in young adult mice. Keywords mouse strain; excitotoxicity; kainic acid; epilepsy; cell death; aging Knowledge about the influence of aging on the susceptibility of the brain to seizure disorders is of critical importance in geriatric medicine and public health. Epilepsy is the most common neurological disorder after stroke, affecting more than 50 million persons worldwide and with a 2-3% life time risk of being given a diagnosis of epilepsy (Browne and Holmes, 2001). Currently it is well known that there is a significant incidence of epilepsy in children. However, less clearly recognized but of increasing importance is the significant incidence of epilepsy in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the elderly population. Recent studies in the United States and Europe indicate that the agespecific incidence of epilepsy is higher in those over the age of 65 years than in those in the first decade of life (Talli...

C57BL/6J (B6) and FVB/NJ (FVB) mice are phenotypically distinct in their susceptibility to seizure-induced cell death after kainate administration. Previous studies using quantitative trait loci (QTLs) mapping established that the distal region of mouse chromosome 18 contains a gene(s) that is probably responsible for the difference in seizure-induced cell death susceptibility between two inbred strains, B6 and FVB, that are relatively resistant and susceptible, respectively, to seizure-induced cell death. The genetic locus has been mapped to a approximately 12-centimorgan region of chromosome 18, designated as seizure-induced cell death 1 (Sicd1). In order to confirm the Sicd1 QTL, we have developed congenic mouse strains containing the relevant donor segment from the resistant B6 strain on the susceptible FVB background, also referred to as the FVB.B6-Sicd1 congenic strain. Congenic and FVB littermate controls were tested in a seizure-induced cell death paradigm. The presence of B6 chromosome 18 alleles on an FVB genetic background conferred protection against seizure-induced cell death, as compared with FVB littermate controls. To further localize the Sicd1 QTL, new congenic lines carrying overlapping intervals of the B6 segment were created [interval-specific congenic lines (ISCLs)-1-4] and assessed for seizure-induced cell death phenotype. All of the ISCLs exhibited reduced cell death associated with the B6 phenotype, as compared with the parental FVB strain. The most dramatic of these, ISCL-4, showed a nearly four-fold reduction in the extent of seizure-induced cell death. This suggests that ISCL-4 contains the putative gene(s) of the Sicd1 QTL.