(Investigator s Abstract). This project is designed to study in vivo molecular mechanisms in the hippocampus which initiate and guide new, aberrant synaptic connections that may lead to chronic seizure in human epilepsy by inducing and following the time course of cell loss and sprouting in a rat model. The neurobiology of aberrant synaptic reorganization in hippocampal sclerosis will be compared to similar molecular mechanism of axon growth and synaptogenesis seen during development. This proposal will answer two biologically significant questions: 1) Do the cellular, molecular, and axon growth patterns after damage follow the developmental programs or retain other mature programs? 2) Does chronic hippocampal rat epilepsy model true human hippocampal epilepsy in its interictal EEG spikes, focal EEG seizures, synaptic reorganizations, and molecular expressions? These experiments will test for molecular mechanisms that correlate with several unexplained phenomena in epilepsy: 1) What is the developmentalcritical period for susceptibility to damaged-induced epilepsy?2) What causes the long latent period between acute injury/acute seizures and eventual chronic seizures? 3) Are neurotrophic factors upregulated to maintain epileptic neoinnervation and/or to maintain synaptic hyperexcitability? Temporal lobe epilepsy is the most frequent form of human epilepsy, and in surgical series 65% of patients have hippocampal sclerosis. There is a pattern of cell loss and sprouting characterized by an aberrant monosynaptic feedback of mossy fibers on granule cells of the dentate gyrus which apparently contributes to intractable seizures.Little is known about the mechanisms causing the synaptic reorganization.The proposed research will map the molecular signals in the postnatal to adult developmental sequence in rats using modern in vivo probes for: 1) axonal growth patterns, 2) extrinsic tropic and trophic factors, and 3) target neurotrophic factors. In situ hybridization of messenger ribonucleic acids (mRNA) will be used to further confirm significant changes in the developmental expressions of these growth promoting molecules and synaptogenesis. These studies will be compared to true human epileptic neurons and circuits, an opportunity underway in our lab and critical next step for understanding human epileptogenesis. To compare with normally-developed connections in the rat dentate gyrus, aberrant reactive synaptogenesis will be induced by intrahippocampal damage in rats which will cause hyperexcitability and seizures that often develop into chronic seizures. Simultaneous studies with identical molecular probes will be used in epileptic rats from early postnatal to adult ages to compare the eventual chronic EEG patterns between epileptic rat and man and relate these epileptic changes to alterations or expression of critical proteins involved in different reorganizations. These results may suggest antecedent mechanisms involved in progressive damage in human sclerotic epileptic hippocampus.
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