Reconstitution of the damaged neural circuitry in the adult central nervous system (CNS) using fetal neural grafts has considerable promise for treating neurodegenerative diseases. However, this strategy affects only moderate recovery in patients with advanced neurodegenerative diseases, consistent with poor survival of grafts and diminished graft-host integration observed in animal models of chronic brain injury. Thus, evaluation of the efficacy of neural grafting strategies that have potential to enhance both graft integration and graft-mediated functional recovery in the chronically injured brain is of profound importance. The major goal of this project is to develop an ideal neural grafting strategy that facilitates both structural and functional repair of the kainic acid lesioned adult rat hippocampus when applied at 4-months post-lesion, a model of temporal lobe epilepsy (TLE). This paradigm is equivalent to the human application of grafting for chronic TLE. The 1st hypothesis is that pre-treatment and grafting of gestation day (GD) 19 hippocampal CA3 cells with caspase inhibitor and/or specific neurotrophic factors enhances both structural repair and functional recovery mediated by grafts in the chronically injured adult hippocampus. The 2nd hypothesis is that grafts of both younger fetal (i.e. GD17) hippocampal CA3 cells and immature hippocampal CA3 region stem cells are also competent for exhibiting enhanced integration and facilitating functional recovery in the chronically injured adult hippocampus. These hypotheses will be tested with a comprehensive set of quantitative parameters. This will include the following measurements. (1) Graft cell survival. (2) Efferent graft projections to local host sites and appropriate distant sites. (3) Afferent mossy fiber projections to grafts. (4) The extent of graft-mediated: (i) retraction of host aberrant mossy fiber sprouting; (ii) restoration in the number of host GABA-ergic interneurons; (iii) normalization of calbindin protein expression in the host hippocampus; and (iv) the degree of suppression of spontaneous recurrent motor seizures. Identification of strategies that enhance both graft integration and appropriate functional repair of the chronically injured adult hippocampus is of significant relevance for developing graft-mediated therapy for chronic temporal lobe epilepsy. These studies also have implications for the treatment of other neurodegenerative conditions such as stroke and head injury. ? ?
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