The goal of this research is to gain a better understanding of the basic mechanisms of epilepsy. Several neuroplastic structural changes occur in the hippocampal dentate granule cells of rodents after chemical (kainate or pilocarpine) or electrical (perforant path stimulation) induction of status epilepticus (SE). These include axonal (mossy fiber) sprouting, increased granule cell neurogenesis, formation of hilar basal dendrites (HBDs) and ectopic migration of granule cells into the hilus. These changes are associated with the formation of additional recurrent excitatory circuits and may underlie the development of spontaneous seizures in rodents after SE. Our work has focused on two of these changes, HBDs and hilar ectopic granule cells (EGCs). During the prior grant cycle, we analyzed the neural circuitry engaged by these two structures and uncovered factors that may influence their formation after SE. Our preliminary studies with doublecortin, a marker for newly born granule cells up to 3 weeks after birth, have revealed new features of the dendrites of newborn granule cells in adult rats, including growth cones and recurrent basal dendrites. The proposed studies in this renewal application will utilize this method to determine whether granule cells with HBDs and hilar EGCs are newly generated cells.
For Specific Aim 1, we will determine whether markers for newly-generated neurons are found in granule cells with HBDs, and to determine whether HBDs form in the absence of neurogenesis. The electron microscopic analysis of growth cones on dendrites of newborn neurons will determine the developmental pattern for the formation of recurrent basal dendrites and HBDs in epileptic rats.
Specific Aim 2 examines granule cells and their processes during postnatal ages corresponding with the end of developmental neurogenesis of the granule cells. This will allow for comparison of newborn granule cells between the developing and adult SE rat.
In Specific Aim 3, hilar EGCs will be examined at the ultrastructural level to determine the types and number of somal and dendritic synapses after pilocarpine-induced SE. In addition, pilocarpine-induced hilar EGCs will be analyzed with neuronal markers for newly-generated neurons following gamma irradiation. Together, these planned studies will determine whether granule cells with HBDs and hilar EGCs arise from newly-generated granule cells and whether newly-generated granule cells in the adult follow a stereotypical developmental pattern. Furthermore we will determine the effects of irradiation on the populations of granule cells with HBDs and hilar EGCs. This knowledge may in turn be used to develop rational therapeutics to block spontaneous seizure development.
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