Manganese & Basal Ganglia Dysfunction: Role of NO

Colorado State University, Fort Collins CO

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Abstract

DESCRIPTION (provided by applicant): Neurotoxic injury to the developing CNS is linked to neurological disease in humans but mechanisms that may predispose to such conditions remain very poorly understood. Exposure to elevated levels of the essential element manganese (Mn) causes a spectrum of neurochemical and neuropathologic changes that can culminate in irreversible neuronal injury in subcortical and cortical structures. Children appear to be more vulnerable to Mn than adults and recent epidemiological evidence links high Mn in drinking water to cognitive and behavioral impairment in children but the basis for the apparent greater sensitivity of young individuals is not clear. Persistent inflammatory changes in glial cells may be a potential link between exposure to Mn early in life and heightened susceptibility to neurological dysfunction during aging because neuroinflammation is now recognized as a central feature in the progression of manganism and other neurological disorders of the basal ganglia. It is the central hypothesis of this proposal that Mn exposure during development stimulates intercellular signaling between microglia and astrocytes that results in a persistent inflammatory phenotype and enhances neurological dysfunction during aging. This hypothesis will be tested by the following Specific Aims that will examine: cell-specific activation of NF-:B in microglia and astrocytes in vivo resulting from developmental exposure to Mn (Specific Aim 1), the effect of astrocyte-specific gene deletion of NF-?B on neuroinflammatory signaling and neurological dysfunction in developing and aging mice (Specific Aim 2), the role of cell-cell signaling between microglia and astrocytes in mediating neuronal dysfunction from Mn (Specific Aim 3), and transcriptional regulatory mechanisms in astrocytes required for NF-?B- dependent induction of neuroinflammatory genes (Specific Aim 4). We anticipate that these studies will uncover molecular interactions between glial cells that will help to explain the sensitivity of the developing brain to Mn-induced neuroinflammatory injury. Specifically, we except to identify temporal patterns of NF-?B activation in astrocytes and microglia that correlate with onset of neuroinflammation and that astrocyte-specific loss of function of NF-?B activity will mitigate the neurotoxic effects of Mn, both in developing mice and during aging. We also expect that exposure to Mn during juvenile development will lead to greater neurological dysfunction during aging due to persistent neuroinflammation that increases neuronal dysfunction, relative to mice without prior exposure to Mn. Collectively, the proposed Specific Aims will build upon the work published during the initial period of funding to address key mechanistic questions regarding critical cellular interactions between astrocytes and microglia that potentiate neuronal dysfunction from developmental exposure to Mn.