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 b a potential link between exposure to Mn early in life and heightened susceptibility to neurotoxic injury and 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 NF-kB-dependent intercellular signaling between microglia and astrocytes, resulting in ongoing neuroinflammation that enhances susceptibility to neurological dysfunction during aging. This hypothesis will be tested by three Specific Aims that will examine: the role of glial- specific NF-kB activation in promoting Mn-induced neurotoxicity during development and aging (Specific Aim 1), critical cell-cell interactions between astrocytes and microglia necessary for amplifying inflammatory activation and neuronal injury (Specific Aim 2), and transcriptional regulatory mechanisms in astrocytes mediating NF-kB-dependent induction of neuroinflammatory genes (Specific Aim 3). We will use a two-hit model in NF-kB-EGFP reporter mice and astrocyte-specific NF-kB knockout mice generated in our laboratory that expose animals to Mn from pre-weaning through puberty and then examine their susceptibility to the dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We except to identify temporal patterns of NF-kB activation in astrocytes and microglia that correlate with onset of neuroinflammation and that astrocyte-specific loss of function of NF-kB 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 previous work from our laboratory to address key mechanistic questions regarding critical cellular interactions between astrocytes and microglia that potentiate neuronal dysfunction caused by developmental exposure to Mn.
The long term health effects of exposure to Manganese (Mn) are a concern to public health in general and to children's health, in particular, due to widespread exposure through air, drinking water, and diet. Recent epidemiological evidence now links elevated Mn in drinking water to behavioral and learning deficits in children and additional scientific data suggest that the developing brain may be more sensitive to Mn and other heavy metals than the adult brain. Persistent inflammation within the non- neuronal cells of the brain, collectively termed glial cells, is linked with the progression of neurological injur due to Mn toxicity but the mechanisms by which this inflammatory state initiates and progresses are poorly understood, particularly during juvenile development. The proposed studies will therefore longitudinally examine neuroinflammatory responses to Mn in developing and aging mice using novel transgenic models in order to determine the basis for the sensitivity of children to the neurogical effects of Mn and to improve our understanding of how excessive exposure to Mn early in life may increase susceptibility to neurotoxic injury and neurodegenerative diseases during aging.
|Lee, Syng-Ook; Li, Xi; Hedrick, Erik et al. (2014) Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells. Mol Endocrinol 28:1729-39|
|Miller, James A; Kirkley, Kelly A; Padmanabhan, Rachel et al. (2014) Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-?B) prior to seizure in transgenic NF-?B/EGFP reporter mice. Neurotoxicology 44:39-47|
|Streifel, Karin M; Miller, James; Mouneimne, Rola et al. (2013) Manganese inhibits ATP-induced calcium entry through the transient receptor potential channel TRPC3 in astrocytes. Neurotoxicology 34:160-6|