The purpose of this research program is to study compensation and recovery of function that occurs following experimentally induced neurodegeneration in the central nervous system. Stereotaxic infusion of colchicine into the hippocampus of rats preferentially destroys dentate gyrus granule cells and mossy fibers and elicits reactive synaptogenesis from the cholinergic septohippocampal pathway. Intradentate colchicine causes specific changes in in vivo sensitivity to muscarinic cholinergic receptor agonists, increases in cholineacetyltransferase (ACHE) and cholineacetyltransferase (CHAT), two presynaptic markers for acetylcholine, and a decrease in the number, but not affinity, of muscarinic cholinergic receptors in the hippocampus. Agonist- mediated turnover of phosphoinositol was significantly increased in colchicine-treated animals suggesting hypersensitivity of the muscarinic receptor. Future studies will determine the specificity of this change in phosphoinositol turnover and attempt to examine possible colchicine-induced changes in the receptor-GTP coupling mechanism. The intrahippocampal colchicine model has been used to study the role of trophic factors in mediating recovery of function. Hyperactivity and deficits in working memory produced by intradentate colchicine were ameliorated by injection of a suspension of undifferentiated fetal cells into the hippocampus. Subsequent studies found that Timm-stained (for zinc) and enkephalin (ENK) immunoreactive (IR) fibers clustered around presumptive pyramidal cells 4 weeks after implant while ENK-IR and dynorphin-IR were present in grafted mossy fibers 6-12 weeks after implant. In situ hybridization histochemistry is being used to identify dentate granule cells in the grafts. Other experiments found that hippocampal fetal cell suspensions also ameliorated the cognitive deficits produced by N-methyl-D-aspartate. Future studies will characterize the conditions leading to the facilitative effects of the fetal implants.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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U.S. National Inst of Environ Hlth Scis
United States
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