The genetic and epigenetic mechanisms involved in the premature loss of specific nerve cells in the central nervous system are for the most part unknown. In the proposed studies an effort is made to determine whether gene-dose-dependent mechanisms operate in the degeneration of neurons of the substantia nigra in the weaver and of the Purkinje cells in the pcd mutant mouse. Weaver and pcd are recessive mutations. Neuronal losses are known to take place in the homozygotes; the demonstration of losses in heterozygotes would support the hypothesis that a gene- dose-dependent mechanism regulates losses either of nigral neurons or of Purkinje cells in the respective mutants. In weaver mutants loss of dopamine neurons of the substantia nigra will be used as a natural model of nigrostriatal degeneration to analyze the neurochemical dysfunction of the cholinergic and GABAergic neurons possibly resulting from loss of presvnaptic cells. Finally, strategies of neural tissue grafting in the cerebellum and in the striatum will be applied in order to obtain a restoration of structure and neurotransmitter function. The comprehension of both the biological phenomena related to nerve cell degeneration and its sequelae as well as of the mechanisms related to the structural and neurochemical interaction between neural elements of host and grafted tissue is a fundamental step in designing strategies for the repair of neural circuitries in degenerative conditions of the central nervous system and in aging. The proposed goals will be achieved by bringing together techniques of genetic crossing and neural grafting as well as methodologies of immunocytochemistry, electron microscopy and computerized morphometry that will be correlated with sophisticated neurochemical and neuropharmacological methods and with behavioral analysis.
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