Using a novel developmental approach, embryogenesis of the substantia nigra (SN) and postnatal degeneration in both the SN and striatum of the weaver mutant mouse will be studied as an animal model of human nigrostriatal degeneration and Parkinson disease. Postnatal studies will focus on cell loss in the nigrostriatal system between days 8 and 360. Long survival [3H] thymidine autoradiography will be combined with immunocytochemistry in the same tissue section. The questions to be addressed are: Do the postnatal deficits in the SN appear in a systematic order that can be linked to the time of origin of neurons and their neurochemical characteristics? Immunocytochemistry against tyrosine hydroxylase (TH), cholecystokinin (CCK), and 28-kDa calcium binding protein (CaBP) will be used to subdivide the SN population. The data will be analyzed to see which neurogenetic/neurochemical subgroups are most vulnerable and which are most resistant to the action(s) of the weaver gene. Does cell loss in the SN produce secondary cell loss in the striatum? Immunocytochemistry against gamma-aminobutyric acid, Substance P, enkephalin, choline acetyltransferase and CaBP neurons will be used to subdivide the striatal cells. The data will be analyzed to see which neurogenetic/neurochemical subsets are most resistant to SN deafferentation. Embryonic studies will focus on differences between normals and weavers to address the question: Does the SN develop normally in weaver embryos? The large dopamine (DA) population in the SN (as seen with TH immunocytochemistry) will be combined with short-survival [3H] thymidine autoradiography to differentiate SN-DA cells from other monoamine neurons in the mesencephalon. SN neurons will be characterized as to their germinal source, migratory pathway and settling patterns. Taken together, the proposed experiments in the weaver mutant will provide quantitative observations on the underlying developmental mechanisms involved in the degeneration of the nigrostriatal system.
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