The analysis of afferent organization in neurological mutants has illuminated interesting and potentially revealing model systems which, with further exploration, will undoubtedly provide us with an understanding of important mechanisms in the development of afferent-target relationships. In analyzing the developmental process of afferent organization and afferent-target relationships in the olivocerebellar system of the lurcher mutant mouse, we have demonstrated a specific defect in the transposition of the olivocerebellar fiber from somal synaptic contacts to dendritic synapses. This defect is both afferent specific, since parallel fiber synapses form normal contacts, and membrane specific, as normal synaptic contacts are formed by olivocerebellar fibers onto the Purkinje cell soma, but not its dendrite. Another mutant, the staggerer, exhibits a somewhat complementary defect to lurcher, in that the other major synaptic input to the Purkinje cell, namely the parallel fiber, does not develop. Thus in lurcher and staggerer there are specific, but different, alterations of the two major afferents to the Purkinje cell. Another mutant, meander tail, is characterized by a cerebellum which is partially normal cytoarcbitectually and partly abnormal. It therefore provides an unusual opportunity to analyze normal an abnormal processes of afferent organization and afferent-target relationship in the same animal; an internal control, if you will. This proposal contains experiments to further analyze afferent systems in these mutants. These new experiments are designed to: 1) determine in the lurcher the molecular basis of the specific defect in the synaptogenesis of olivocerebellar fibers and their Purkinje cell target, 2) determine if there is a relationship between the temporal vulnerability of Purkinje cells in the lurcher and their biochemical or positional heterogeneities, 3) determine the molecular basis of the synaptogeneic defect between parallel fibers and Purkinje cells in the staggerer, and 4) examine the organization and synaptic relationship of the spino and olivocerebellar systems in the meander tail mutant mouse to determine the afferent target characteristics which are under target control. The considered use of neurological mutants will enable us to address basic questions concerning the organization and development of afferent systems.
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