This proposal is designed to address the fundamental question of whether target characteristics such as cell position and number are critical in determining the development and/or maintenance of the normal distribution and terminal pattern of an afferent to that target. The climbing fiber projection from the inferior olivary complex to the cerebellum is ideal for this type of analysis since it is a highly specific projection system. In addition, there exists an excellent tool, namely, mutant strains of mice in which a genetically determined defect has either primarily or secondarily caused a failure in the development of normal cerebellar cytoarchitectonic organization. Included in this group are some (weaver, staggerer, reeler, lurcher) in which the Purkinje cell population, the main target of climbing fiber terminations is severely affected. By analyzing the organization of this projection system in these mutant and control mice we expect to determine what effects, if any, target cell position and deletion play in the organization of an afferent system to that target. To explore this question we will, in each of the mutant and control mice (1) analyze the qualitative and quantitative organization of the inferior olivary complex, (2) determine the number of Purkinje cells in cerebellum and thereby calculate the Purkinje cell/inferior olive cell ratio and (3) with the use of anterograde techniques analyze the distribution and terminal pattern of the olivocerebellar projection using light and electron microscopic techniques. These studies should provide us with new and important information concerning whether variables such as target cell position and number which are critical in determining the relationship between a single afferent source and its target. More generally, these studies speak to basic issues in the development of the nervous system such as axonal distribution, target selection and synapse formation. A better understanding of the critical developmental processes which contribute to the formation of the central nervous system will eventually lead to a more complete analysis of abnormal development of the CNS and perhaps lead to ways in which such abnormal development may be beneficially manipulated.
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