Role and mechanisms of excretion in manganese neurotoxicity

摘要

ABSTRACT Work on this diversity supplement will (1) test the impact of early-life inhibition of manganese excretion on dopamine metabolism in the brain using microdialysis; and (2) provide career development opportunities for Stephanie Grant. Our specific rationale is below. In the parent grant, we had proposed to interrogate the neurotoxic effects of Mn in the liver or intestine- specific Slc30a10 knockout or knockin strains using 4 approaches: (1) neurobehavioral assays to assess Mn- induced changes in skilled motor function and locomotor/exploratory activity; (2) inductively-coupled plasma mass spectrometry (ICP-MS) metal analyses to quantify brain Mn levels; (3) microscopy to assess neuronal degeneration, neuroinflammation, and apoptosis; and (4) tissue neurochemistry to assess striatal levels of catecholamines. To increase the impact and significance of our studies, we now propose to add one more approach to quantify Mn neurotoxicity in a selected group of animals through this diversity supplement – in vivo microdialysis to quantify evoked dopamine release. Inclusion of the microdialysis study through this diversity supplement will (1) substantially increase the significance of the findings of the parent proposal; and (2) provide Stephanie with a high-impact, independent project that fosters her scientific and career development.