This application for renewal of an R01 grant proposes to expand on promising leads developed during previous years of support. One set of questions followed from an hypothesis that AMPA/kainate-type glutamate receptor activation might contribute to the selective neurodegeneration that occurs in Alzheimer's disease (AD), or global ischemia. Indeed, recent findings indicate that populations of neurons that degenerate in these conditions, including basal forebrain cholinergic neurons and pyramidal neurons, may often express AMPA/kainate channels that are directly permeable to Ca2+ ions (Ca-A/K channels), a factor that may predispose to Ca2+ dependent excitotoxic injury. Over the past 3 years (since the present grant was awarded), considerable further progress has been made at examining the distribution of Ca-A/K channels on central neurons and elucidating ways in which these channels may contribute to neuronal Injury. Specifically these channels are highly permeable to the endogenous synaptically released cation, Zn2+ as well as to Ca2+, and that rapid entry of either cation can interfere with mitochondrial function and trigger injurious free radical production. Planned experiments seek to further elucidate pathophysiologic mechanisms of selective injury, progressively moving from simple culture models to more complex culture and slice models mimicking the in vivo situation. Initial studies will primarily use imaging approaches to determine whether Ca-A/K channels are expressed on postsynaptic membranes of pyramidal neurons (where they would be of greatest physiologic importance) and compare their Ca2+ and Zn2+ permeabilities. Subsequent studies will compare downstream mechanisms through which Zn2+ and Ca2+ entry through these channels may mediate neuronal injury, and test ways of blocking the injury pathway. Further studies will address ways in which these injury mechanisms may come into play in disease, by examining ways in which environmental factors of likely importance in disease (trophic factors, beta-amyloid peptide, metabolism stress) interact with the Ca2+ or Zn2+ dependent injury. Finally studies in slice preparations will examine the role of Ca2+ and Zn2+ flux through Ca-A/K channels in hippocampal pyramidal neuronal injury in situ.
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