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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022093-09
Application #
2264377
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1986-02-01
Project End
1996-01-31
Budget Start
1994-02-01
Budget End
1996-01-31
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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
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
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
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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