Some very intriguing results and observations from experiments concerning the organization of the olivocerebellar projection in mutant mice (see Progress Report) have led to the experiments in this continuation. These new experiments, we believe, are logical and exciting extensions of the study of afferent organization in neurological mouse mutants. They specifically address questions concerning proper generation of target cells (reeler), nerve fiber- target cell recognition (lurcher) and synaptogenesis (staggerer), all of which are important characteristics of a normally organized afferent system. (1) In reeler, a mutant in which migration is considered to be the primary defect, we have discovered that, in the adult there is a 50% reduction in the number of Purkinje cells while the organization and topography of the olivocerebellar projection is generally preserved. This proposal will examine the cause (cell death) and/or decreased cell generation) of decreased Purkinje cell number. In doing so we address the question of whether proper numerical generation or survival of a target cell population is necessary for proper migration and placement of that population (2) In lurcher, a mutant in which all Purkinje cells die postnatally during the second to twelfth weeks, the olivocerebellar projection appears to terminate in plexuses at the border of the molecular and granular layers. The topographic and parasagittal zonal organization appears to be generally preserved. The new experiments in this proposal are designed to determine whether during development (a) these afferents ever enter the molecular layer and associate with Purkinje cell dentrites and (b) if they do not, to determine buy immunological and biochemical analyses what molecular deficiency exists in these dentrites to preclude recognition and """"""""climbing"""""""" by olivocerebellar fibers. (3) In staggerer, a mutant characterized by the death of cerebellar granule cells, the failure to develop tertiary spines on Purkinje cells and the death of the majority of Purkinje cells, there still exists a patchy, parasagittal and topographically appropriate (in general) organization of the olivocerebellar projection. In this continuation we plan to explore the defect in synaptogenesis between the parallel fiber-Purkinje cells by examining via immunological and biochemical approaches, the molecular differences in the staggerer and normal mice. The considered use of neurological mutants will enable us to address basic questions concerning the organization and development of an afferent system.

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National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology B Subcommittee 2 (NEUB)
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Thomas Jefferson University
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Eisenman, L M; Gallagher, E; Hawkes, R (1998) Regionalization defects in the weaver mouse cerebellum. J Comp Neurol 394:431-44
Hawkes, R; Eisenman, L M (1997) Stripes and zones: the origins of regionalization of the adult cerebellum. Perspect Dev Neurobiol 5:95-105
Napieralski, J A; Eisenman, L M (1993) Developmental analysis of the external granular layer in the meander tail mutant mouse: do cerebellar microneurons have independent progenitors? Dev Dyn 197:244-54
Grunwald, G B; Eisenman, L M (1993) Analysis of protein variations in adult and postnatal day 11 staggerer and lurcher mutant mice. Brain Res Dev Brain Res 73:146-50
Eisenman, L M; Pruett Jr, J R (1992) Expression of the Purkinje cell specific zebrin antigens in the cerebellum of the meander tail mutant mouse. Brain Res 589:135-8
Tano, D; Napieralski, J A; Eisenman, L M et al. (1992) Novel developmental boundary in the cerebellum revealed by zebrin expression in the lurcher (Lc/+) mutant mouse. J Comp Neurol 323:128-36
Heckroth, J A; Eisenman, L M (1991) Olivary morphology and olivocerebellar topography in adult lurcher mutant mice. J Comp Neurol 312:641-51
Heckroth, J A; Goldowitz, D; Eisenman, L M (1990) Olivocerebellar fiber maturation in normal and lurcher mutant mice: defective development in lurcher. J Comp Neurol 291:415-30
Heckroth, J A; Goldowitz, D; Eisenman, L M (1989) Purkinje cell reduction in the reeler mutant mouse: a quantitative immunohistochemical study. J Comp Neurol 279:546-55
Blatt, G J; Eisenman, L M (1989) Regional and topographic organization of the olivocerebellar projection in homozygous staggerer (sg/sg) mutant mice: an anterograde and retrograde tracing study. Neuroscience 30:703-15

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