Mechanisms of Sympathetic Axon Pruning

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DESCRIPTION (provided by applicant): Remodeling of mature neural pathways involves both axonal outgrowth to establish new connections and axonal degeneration whereby terminations are eliminated. Mechanisms by which axon terminations are eliminated, or pruned, in the absence of cell death are poorly understood. Peripheral sympathetic innervation presents an especially tractable model for studying axon pruning under normal physiological and pathophysiological conditions. Sympathetic axon density in the virgin rodent uterus fluctuates rapidly during the estrous cycle, with terminal axons degenerating when estrogen levels rise and regenerating when they decline. We have shown that estrogen elevates uterine brain derived neurotrophic factor, and hypothesize that this contributes to sympathetic axon degeneration. We hypothesize that brain derived neurotrophic factor activates the p75 neurotrophin receptor, which stimulates intra-axonal ceramide formation. This promotes terminal axon degeneration through abnormal increases in membrane permeability and actin depolymerization. The present study investigates mechanisms whereby targets elicit selective terminal axon pruning. The first aim evaluates the hypothesis that p75NTR activation is responsible for inducing sympathetic axon degeneration under physiological conditions. In aim 2, we explore the hypothesis that p75NTR activation produces axon degeneration by increasing permeability of axonal membranes, and by promoting destabilization of the actin cytoskeleton. In aim 3, we investigate the nature of ligands produced by the target that incur axon degeneration. Specifically, the roles of BDNF, pro-NGF and neurotrimin will be assessed. These studies use tractable in vivo and in vitro approaches to explore relationships among target- derived ligands, neural receptors, and signal transduction pathways, and will provide novel information on how selective terminal axon degeneration is accomplished under physiological and pathophysiological conditions. Findings will be pertinent to understanding both organizing principles related to normal nervous system plasticity, and to disturbances in innervation in certain disease states.