GRAFT FUNCTION

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The fragmentary understanding of the biological sequelae of neural transplantation is reflected in the variable success of attempts to reverse parkinsonism in human and non-human primates using intrastriatal fetal tissue grafts. This project will investigate the basis of functional recovery employing neurochemical and morphological measures and relating them to behavioral recovery following grafting in a primate model of parkinson's disease. This knowledge will facilitate refinement of the transplantation technique. The model used in these studies is allograft of fetal ventral mesencephalon transplanted into the caudate nucleus of the MPTP-treated parkinsonian monkey. The proposed experiments will address the controversy that the improvement in parkinsonism observed following transplantation of fetal ventral mesencephalon is due to the presence of the graft and that the graft- induced recovery is dependent on the presence of dopamine derived from the graft. These issues will be examined in a study that involves immunological rejection of the grafted tissue, once the improvement has occurred. If the recovery is found to be significantly dependent on the presence of the graft, we will investigate the dopamine-dependence of the improvement by destruction of the dopamine neurons in the graft. Other studies will investigate a) whether athe extent of improvement is dependent on the degree of dopaminergic restoration of the caudate nucleus, and how much reinnervation is necessary, b) whether the dopaminergic reinnervation changes with time and if this change is paralleled by alterations in parkinsonism, and c) whether the dopaminergic reinnervation can be enhanced by the presence of co-grafts of fetal striatum or adult peripheral nerve-derived Schwann cells, and if so, if it corresponds to decreased parkinsonian behavior. These experiments will utilize quantitative dopamine transporter autoradiography, dopamine concentrations, homovanillic acid to dopamine ratios and tyrosine hydroxylase immunohistochemistry. Further experiments will determine whether the grafted dopamine neurons establish normal synaptic connections with GABAergic and cholinergic neurons in the host caudate nucleus. This will be addressed using correlated light and electron microscopy of double-immunostained sections from a defined region of the caudate nucleus in close proximity to the grafts. These studies will provide further insight into the basis of transplant- induced behavioral recovery from parkinsonism. The outcome of these investigations will have an important impact in tailoring research and future treatments of neurodegenerative disorders.