Hippocampal lesions inflicted by acute seizures or head injury initially lead to epileptogenic changes, and then to hippocampal dysfunction exemplified by chronic epilepsy, and learning and memory impairments. More than two-million Americans suffer from epilepsy, and many people with epilepsy have chronic seizures that are resistant to antiepileptic drugs, and learning and memory dysfunction. Thus, therapeutic interventions capable of blocking both chronic epilepsy development and learning and memory dysfunction, after the hippocampal injury, are needed. The central focus of this project is on the development of ideal cell transplantation strategies that prevent the progression of initial precipitating injury (IPI) in the hippocampus into chronic epilepsy and long-term impairments in learning and memory function and dentate neurogenesis. We will analyze the efficacy of grafts of three different donor cell types: fetal post-mitotic hippocampal cells, neural stem/progenitor cells (NSCs) from the fetal hippocampus, and NSCs from the anterior subventricular zone. The 1st hypothesis is that transplantation of fetal post-mitotic hippocampal cells or immature NSCs into the hippocampus shortly after the injury averts the progression of the IPI into chronic epilepsy characterized by spontaneous recurrent motor seizures (SRMS). The 2nd hypothesis is that grafting of fetal hippocampal cells or NSCs into the hippocampus shortly after the injury is efficacious for preventing the injury-induced deficits in learning and memory function and dentate neurogenesis. These hypotheses will be tested with wide-ranging immunohistochemical, video-electroencephalographic (video-EEC), and learning and memory analyses in young adult F344 rats undergoing intraperitoneal kainic acid induced acute seizures and hippocampal injury, a model of temporal lobe epilepsy. The 1st Specific Aim will rigorously analyze the efficacy of grafting of fetal hippocampal cells and NSCs into the hippocampus at 4 days after the seizure-induced injury for replacing the lost neurons, and blocking both epileptogenic changes and the occurrence of SRMS. The 2nd Specific Aim will quantify the effectiveness of transplantation of fetal hippocampal cells and NSCs into the hippocampus at 4 days after the seizure induced injury for preventing or minimizing long-term deficits in hippocampal-dependent learning and memory function and dentate neurogenesis. It is envisioned that bilateral grafting of fetal hippocampal cells or NSCs as above suppresses multiple epileptogenic changes that occur during the early post-injury phase, reconstruct the disrupted hippocampal circuitry and thereby prevent or minimize the hippocampal injury- induced chronic epilepsy development and deficits in learning and memory function. Collectively, the proposed experiments have immense value for the development of apt treatment strategy that prevents both chronic epilepsy and learning and memory impairments after hippocampal injury in adults.
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