Manipulating Brain Manganese and Behavior in Huntington's Disease
Wilcox, Jordyn Michelle
Manganese (Mn) is an essential micronutrient required for diverse biological processes but is neurotoxic in excess and thus maintaining appropriate homeostatic balance of Mn is crucial. Several factors, including exposure route, biological sex, age, and genetic mutations in metal transporters or other proteins can influence brain Mn concentrations. In 2010, a multi-faceted disease-neurotoxicant interaction was discovered between the inherited neurodegenerative disorder Huntington’s Disease (HD) and Mn, whereby the HD genotype offers neuroprotection against Mn toxicity and Mn exposure is capable of rescuing select HD phenotypes. This work further explored the HD-Mn interaction using the YAC128 mouse model of HD, several Mn exposure routes and doses, both sexes, various ages, and with a primary focus on behavioral outcome measures. Chapter 2 examined global changes at the level of the transcriptome and metabolome following both acute (1-week) and chronic (20-week) subcutaneous Mn exposures of 50 mg/kg MnCl2•4(H2O) or vehicle. The impact of chronic Mn exposure (up to 40 weeks; 0, 5, 15, or 50 mg/kg MnCl2•4(H2O)) on behavioral outcome measures and striatal neuron counts (0 or 5 mg/kg MnCl2•4(H2O) only) in YAC128 and WT mice was investigated in Chapter 3. Changes in behavior and in expression of dopaminergic pathway proteins following eight weeks of excess dietary Mn (2400 ppm, compared to 70 ppm in control diet) in young (3 months) and aged (14 months) WT and YAC128 mice were explored in Chapter 4. Finally, in Chapter 5, dynamic changes in dopamine release and clearance as well as neurotransmitter metabolites were measured following acute Mn (50 mg/kg MnCl2•4(H2O)) exposure in middle-aged (8 month) YAC128 and WT mice. In each of these experimental chapters, two remarkably consistent themes emerged. YAC128 mice were repeatedly less sensitive to adverse Mn-induced changes experienced by WT (with some HD-related phenotypes corrected by Mn) and WT Mn-exposed mice frequently resembled YAC128 vehicle-treated mice. With these findings, this body of work contributes to our knowledge of Mn neurobiology and provides additional insight on the pathophysiology of HD.