MOLECULAR BASES OF NEURONAL CONNECTIVITY

点击翻译按钮获取中文摘要

The proposed research will investigate the role of specific proteins in the development, regeneration, and modulation of connections in the visual system. One major focus on this research is a presynaptic membrane phosphoprotein (GAP-43 or - 48, B-50, pp46, F1) that is expressed at high levels and conveyed to the nerve endings during axonal outgrowth and the organization of synaptic relationships; in most neurons its synthesis declines precipitously with maturation, but rises again during axonal regeneration. We have developed monospecific antibodies to this protein as well as a cDNA probe, which we will use to investigate further the development and functional modulation of connections in the visual system. We will examine the temporal relationship between the regeneration of the optic nerve of goldfish and the expression of the GAP/B-50 gene, using Northern blot analysis and in situ hybridization with the cDNA probe; of particular interest will be the question of whether its expression correlates with the "sensitive period, "during which synaptic organization can be modulated by activity-dependent mechanisms. We will also examine whether the regeneration of the mammalian optic nerve, which can occur through a grafted segment of peripheral nerve, likewise depends upon reinduction of the GAP/B-50 gene. Another line of research will investigate the normal time course of the expression of GAP/B-50 in various visual processing areas, and will be done in both the human and rodent brains. This will help define when different areas are forming and reorganizing connections, and will also allow us to identify areas that continue to express the gene throughout life, and which thus may be capable of modifying their synaptic relationships continuously. Other studies will examine the biosynthesis and possible functions of the GAP/B-50 protein. A second general area of research will isolate and characterize macromolecules, secreted by the non-neuronal cells of the goldfish optic nerve, that regulate the growth of axons. Preliminary results indicate that the glial sheath cells secrete both a neurite-promoting protein and another molecule that is inhibitory to growth, suggesting that the balance between these may determine whether axons will regenerate or not. The identification of these factors may provide insights valuable for ultimately effecting growth of neurons after damage in the mammalian visual system.