Epilepsy frequently develops in association with structural lesions in the central nervous system, but the cellular mechanisms that generate recurrent seizures in association with brain lesions are not well understood. There is now considerable evidence that pathways in the central nervous system undergo rearrangements of synaptic connections in response to structural lesions, and recent work from this laboratory has also demonstrated that brief seizures induced neuronal loss and synaptic rearrangements in pathways of the hippocampal formation. If these rearrangements in circuitry increase excitability, synaptic reorganization induced by lesions or seizures could play a role in the development of epilepsy. The major goal of this research is to contribute to understanding of the role of synaptic reorganization and other forms of activity-induced plasticity in the generation of seizures and development of epilepsy. This proposal specifically investigates the hypothesis that axon sprouting in hippocampal circuitry contributes to the development of epilepsy by formation of recurrent excitatory circuits. The major aims of the proposal are: 1) to assess the roles of enhanced NMDA dependent synaptic transmission and synaptic reorganization in the generation of excitation in the dentate gyrus during the development and permanence of the kindled state, 2) to determine if mossy fiber sprouting increases excitatory synaptic coupling between granule cells in the dentate gyrus, 3) to identify anatomical features of sprouted mossy fiber collaterals that could play a role in the generation of recurrent positive feedback in the dentate gyrus, 4) to determine if repeated seizures induce neuronal loss in other pathways. The investigations will utilize in vitro intracellular and in vivo chronic recording methods, histochemistry, immunocytochemistry, and stereological counting techniques. The proposed experiments will provide insight into structural and functional aspects of hippocampal organization and plasticity, and identify cellular alterations in hippocampal circuitry that play a role in the development of epilepsy after brain injury.
