This proposal outlines the continuation (years 7-12) of the study of a mutation that discriminates in its effects between the nigrostriatal and mesolimbic dopamine-containing pathways suggesting separable genetic control of these two systems that may account for their differential vulnerability to a variety of agents. The genetic mutation to be examined is weaver, an autosomal recessive mutation in mice in which the dorsal striatum suffers reduction in dopamine content and tyrosine hydroxylase activity in a pattern with strict and reproducible boundaries. The mesolimbic system escapes most but not all the effects of the gene and suffers little or no cell death. The pattern of cell death seen in weaver is remarkably similar to that seen in Parkinson's disease and in humans and animals made parkinsonian through exposure to the neurotoxin MPTP. Evidence gathered in the last grant period point to defects in axonal and dendritic processes as being close to the primary cellular action of the mutant gene. Although cell death in the midbrain is restricted to subpopulations, """"""""spared"""""""" groups of cells are not wholly invulnerable for they show pathology as measured by deficits in high affinity uptake of 3H dopamine in target regions. Experiments are planned to examine the hypothesis that differentiated properties of neuronal processes are targets of weaver and that a single dose of the gene will affect uptake without causing cell death. Experiments are also planned to explore the possibility that the gene affects many more neurons than it kills. Gradients in the distribution of dopamine uptake sites in the striatum will be mapped and examined for convergence with the pattern of dopamine loss. Such a gradient may underlie the pattern of cell populations vulnerable to cell death in weaver and in parkinsonian disorders and may be a key to understanding a number of diseases of the basal ganglia including Huntington's disease and parkinsonism. A main aim of the new grant period will be to identify intrinsic and extrinsic effects of the weaver gene in the nigrostriatal system. Chimeric mice of normal and weaver parentage will be used to provide an unambiguous answer as to whether the dopamine-containing cells are a primary cellular target of the gene. 3H thymidine birthdating and studies of fluorogold accumulation will be employed to determine the fate of striatal island cells. The search for the gene has been initiated and will be continued using genetic linkage studies.
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