The basal ganglia are at the very heart of the central nervous system. Derangements of their function lead to numerous movement disorders from Parkinsonism to tardive dyskinesia. Furthermore, analogous neural structures in the limbic system are the substrate for our most basic behavioral repetoires. Increased understanding of the basal ganglia development should illuminate disorders of movement and of emotions. The study of the biochemical architecture of the basal ganglia has recently received a great impetus from the discovery of basal ganglia specific phosphoproteins which are found only in certain cell types. Antibodies to these proteins can be used to map out the location of specific neural types that contain them. The prototype is DARPP-32 -- a phosphoprotein localized in the medium spiny neurons which receive dopaminergic input via D1 receptors. One part of this research will trace the sequential appearance of DARPP-32 in the embryonic development of the rodent brain. This will be done with fluorescence labeled antibodies to DARPP-32. The biochemical ontogeny of other basal ganglia specific phosphoproteins will be similarly examined. A central tenet of developmental neurobiology is that the development of neural structures is guided by communication between the neurons in interconnected embryonic structures. The experimental problem that derives from this is identification of the molecules which are agents of this communication. The second part of this project addresses this problem in a recently developed system for co-culturing mouse embryonic neurons from the mesencephalon with their targets in the corpus striatum. This is a set of dopaminergic-dopaminoceptive neurons that develop a connection at a D1-synapse. The in vitro expression of DARPP-32 in the corpus striatum neurons is stimulated by the presence of the co-cultured mesencephalic cells. The appearance of DARPP-32 will be quantitated by radioimmunoassay and used to assay for a stimulating factor from the mesencephalic cells which exerts this trophic influence. Correlation with the in vivo developmental studies should provide essential validation by the in vitro work.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Neurological Disorders Program Project Review B Committee (NSPB)
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Rockefeller University
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New York
United States
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Ehrlich, M E; Rosen, N L; Kurihara, T et al. (1990) DARPP-32 development in the caudate nucleus is independent of afferent input from the substantia nigra. Brain Res Dev Brain Res 54:257-63
Girault, J A; Shalaby, I A; Rosen, N L et al. (1988) Regulation by cAMP and vasoactive intestinal peptide of phosphorylation of specific proteins in striatal cells in culture. Proc Natl Acad Sci U S A 85:7790-4