During brain development and again following injury, glial cells produce a variety of molecules that affect the positioning and growth of neurons and their processes. Recently, glial and glycoconjugate (glycoproteins, glycolipids, and glycosaminoglycans) boundaries have been discovered during brain pattern formation, and these structures cordon off developing groups of functionally distinct neurons and their neurites. In the developing caudate-putamen (neostriatum), these boundaries surround different compartments of a neostriatal mosaic, the patch and matrix, and most likely serve to separate growing processes of cells in the two different compartments during a critical period of their formation. The following proposal will test possible roles for astrocytes and glycoconjugates during normal and abnormal development of a clinically important area of the brain, the nigrostriatal circuit.
In Aim 1, the time course of appearance and disappearance of astrocyte- derived extracellular matrix (ECM) molecules will be determined in this circuit.
Specific Aim 2 will focus on the potential reappearance of boundaries following different lesions within the nigrostriatal circuit during development and in the adult, and antibody perturbation experiments versus studies on a tenascin-knockout mouse will provide complementary data on possible functions of particular ECM boundary molecules on neuritic growth. A third set of experiments will exploit two in vitro bioassays to affect the functions of certain boundary molecules during cell-boundary interactions in the developing nigrostriatal circuit, as well as in the lesioned adult circuit that results in the appearance of another type of glial/glycoconjugate boundary - the astroglial scar. These studies will be performed in normal as well as tenascin-deficient animals where other ECM molecules (e.g. DSD-1) can now be studied and manipulated in a nigrostriatal circuit that, e.g., has always lacked tenascin. In Specific 4, the potential roles of astrocytes and ECM in neurodegenerative diseases that affect the human basal ganglia will be explored in an extensive collection of Huntington's, Parkinson's, and other disease and control specimens that allow a thorough correlation of boundary elements in relation to neuronal loss that occurs in nigrostriatal circuit in these diseases. In all, the studies proposed here will establish functional roles for astrocytes and associated, developmentally-regulated molecules in shaping normal basal circuitry during development, and perhaps how they adversely affect neurons and possible neurite regeneration following traumatic injury or chronic disease. The normal developing and injured nigrostriatal circuit is amenable to studies of functions of glial/glycoconjugate boundary elements. Glia and glycoconjugates may play important roles during brain pattern formation, but the recapitulation of cell and molecular interactions that might occur during normal development may have deleterious effects on neuron survival and neuritic regrowth in the compromised, mature brain.
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