EPILEPTOGENESIS IN THE AGED CNS

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DESCRIPTION: (Adapted from the application) Although epidemiological studies have demonstrated an increased incidence and prevalence of seizure disorders in the elderly, the underlying mechanisms are not known. The goal of this project is to investigate physiological mechanisms that could contribute to this epileptogenicity. Aged rodents will be used as the model system since several studies suggest a similar increase in seizure susceptibility during aging. The applicant s preliminary studies corroborate these findings and demonstrate that an increased propensity to generate epileptiform activity can also be seen in neuronal tissue in isolation following exposure to a GABA-A receptor antagonist. This suggests that alterations may occur in the CNS during aging that could underlie an increased seizure susceptibility. The dentate gyrus will be examined since it is believed to play a critical role in some forms of epilepsy and anatomical changes have been described in the aged dentate gyrus that could be epileptogenic in nature. Their primary hypothesis is that changes in recurrent excitation and/or inhibition underlie the increased seizure susceptibility in the aged CNS. They will also examine whether alterations in nonsynaptic mechanisms may be involved. Several electrophysiological techniques will be used to test these two hypotheses in aged rats. Intra- and extracellular recordings will be made from granule cells to test for the presence of new recurrent excitatory circuits and to examine the strength of synaptic inhibition. Extracellular recordings will be made in low [Ca2+]o and elevated [K+]o media containing amino acid receptor antagonists to determine if there is an increased susceptibility to generate nonsynaptic seizures in the dentate of aged rats. Anatomical studies will be performed to evaluate changes in axonal elaboration. These experiments should begin to address whether synaptic reorganization and/or altered nonsynaptic interactions underlie the increased seizure susceptibility in the elderly. One of the long-term objectives is to understand the mechanisms of epileptogenesis in the elderly so that patients can be diagnosed and treated more effectively. Additionally, synaptic reorganization may also affect other hippocampal processes such as learning and memory. Thus, by examining synaptic reorganization within the aged CNS they may also provide insight into the basic mechanisms of epilepsy and learning and memory within the overall population.