The overall goal of this research plan is to study the relationship of dentate granule cell (DGC) neurogenesis in the adult dentate gyrus to seizure-induced hippocampal synaptic plasticity. Network reorganization in the hippocampal formation is thought to be a critical element in the pathogenesis of temporal lobe epilepsy, one of the most common and intractable forms of epilepsy. Nonetheless, the cellular and molecular mechanisms underlying this process are unknown. Reorganization of DGC axons (mossy fibers) is the most conspicuous example of seizure induced network plasticity, and the DGC population also possesses the distinctive features of neurogenesis that continues into adulthood in certain mammalian species. We have recently discovered that chemoconvulsant- induced seizure activity and electrical stimulation of the perforant path markedly increase neurogenesis of putative granule cells in the dentate gyrus of adult rats. Some of these newly born neurons appear to project to aberrant locations characteristic of seizure-induced mossy fiber """"""""sprouting."""""""" Furthermore, seizure-induced injury to mature granule neurons suggests that increased cell birth leads to significant turnover of the detente granule cell layer. Based on these findings, the primary hypothesis of the proposed research is that seizure-induced mossy fiber reorganization is a consequence of aberrant axon outgrowth from newly generated DGCs in the adult hippocampal function. The secondary hypothesis is that seizure-induced death of mature DGCs stimulates neurogenesis in the dentate gyrus of adult rats.
The specific aims of the proposed investigations are: 1) to characterize the identity, long-term fate and anatomic integration of newly born neurons in the normal and epileptic adult hippocampal formation.;2) to determine the structural and functional effects of inhibiting DGC neurogenesis in adult rats following seizure- induced hippocampal injury. Experimental design and methods to accomplish the first two aims include the use of mitotic labeling, retroviral lineage analysis, and degeneration stains to determine the fate of newly born and mature DGCs following chemoconvulsant-or electrical stimulation-induced seizures.
The final aim consists of studies using brain irradiation to inhibit neurogenesis after seizures to determine the consequent effects on hippocampal structural reorganization and electrophysiology. Progress in these aims will advance our knowledge of the cellular basis of neuronal network plasticity and its role in temporal lobe epilepsy, and may provide insight into mechanisms of neuronal development and regeneration of the mature brain following injury.