TY - JOUR
T1 - Disease-toxicant interactions in manganese exposed Huntington disease mice
T2 - Early changes in striatal neuron morphology and dopamine metabolism
AU - Madison, Jennifer L.
AU - Wegrzynowicz, Michal
AU - Aschner, Michael
AU - Bowman, Aaron B.
N1 - Funding Information:
The authors would like to thank Ms. Rosanne Delapp and Dr. David Kosson in the Department of Civil and Environmental Engineering at Vanderbilt University for performing the ICP-MS analysis of striatal Mn levels and Mr. Christopher Jetter for technical assistance. The authors are grateful for instruction and advice on the Golgi staining technique from Dr. Ariel Deutch and members of his laboratory. HPLC determinations were performed by the CMN/KC Neurochemistry Core Lab at Vanderbilt University. The CMN/KC Neurochemistry Core Lab is supported by Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt Conte Center for Neuroscience Research and The Vanderbilt Center for Molecular Neuroscience. We also thank Terry Jo Bichell and Dr. Diana Neely for helpful comments on the manuscript.
PY - 2012/2/17
Y1 - 2012/2/17
N2 - YAC128 Huntington's disease (HD) transgenic mice accumulate less manganese (Mn) in the striatum relative to wild-type (WT) littermates. We hypothesized that Mn and mutant Huntingtin (HTT) would exhibit gene-environment interactions at the level of neurochemistry and neuronal morphology. Twelve-week-old WT and YAC128 mice were exposed to MnCl 2-4H 2O (50 mg/kg) on days 0, 3 and 6. Striatal medium spiny neuron (MSN) morphology, as well as levels of dopamine (DA) and its metabolites (which are known to be sensitive to Mn-exposure), were analyzed at 13 weeks (7 days from initial exposure) and 16 weeks (28 days from initial exposure). No genotype-dependent differences in MSN morphology were apparent at 13 weeks. But at 16 weeks, a genotype effect was observed in YAC128 mice, manifested by an absence of the wild-type age-dependent increase in dendritic length and branching complexity. In addition, genotype-exposure interaction effects were observed for dendritic complexity measures as a function of distance from the soma, where only YAC128 mice were sensitive to Mn exposure. Furthermore, striatal DA levels were unaltered at 13 weeks by genotype or Mn exposure, but at 16 weeks, both Mn exposure and the HD genotype were associated with quantitatively similar reductions in DA and its metabolites. Interestingly, Mn exposure of YAC128 mice did not further decrease DA or its metabolites versus YAC128 vehicle exposed or Mn exposed WT mice. Taken together, these results demonstrate Mn-HD disease-toxicant interactions at the onset of striatal dendritic neuropathology in YAC128 mice. Our results identify the earliest pathological change in striatum of YAC128 mice as being between 13 to 16 weeks. Finally, we show that mutant HTT suppresses some Mn-dependent changes, such as decreased DA levels, while it exacerbates others, such as dendritic pathology.
AB - YAC128 Huntington's disease (HD) transgenic mice accumulate less manganese (Mn) in the striatum relative to wild-type (WT) littermates. We hypothesized that Mn and mutant Huntingtin (HTT) would exhibit gene-environment interactions at the level of neurochemistry and neuronal morphology. Twelve-week-old WT and YAC128 mice were exposed to MnCl 2-4H 2O (50 mg/kg) on days 0, 3 and 6. Striatal medium spiny neuron (MSN) morphology, as well as levels of dopamine (DA) and its metabolites (which are known to be sensitive to Mn-exposure), were analyzed at 13 weeks (7 days from initial exposure) and 16 weeks (28 days from initial exposure). No genotype-dependent differences in MSN morphology were apparent at 13 weeks. But at 16 weeks, a genotype effect was observed in YAC128 mice, manifested by an absence of the wild-type age-dependent increase in dendritic length and branching complexity. In addition, genotype-exposure interaction effects were observed for dendritic complexity measures as a function of distance from the soma, where only YAC128 mice were sensitive to Mn exposure. Furthermore, striatal DA levels were unaltered at 13 weeks by genotype or Mn exposure, but at 16 weeks, both Mn exposure and the HD genotype were associated with quantitatively similar reductions in DA and its metabolites. Interestingly, Mn exposure of YAC128 mice did not further decrease DA or its metabolites versus YAC128 vehicle exposed or Mn exposed WT mice. Taken together, these results demonstrate Mn-HD disease-toxicant interactions at the onset of striatal dendritic neuropathology in YAC128 mice. Our results identify the earliest pathological change in striatum of YAC128 mice as being between 13 to 16 weeks. Finally, we show that mutant HTT suppresses some Mn-dependent changes, such as decreased DA levels, while it exacerbates others, such as dendritic pathology.
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U2 - 10.1371/journal.pone.0031024
DO - 10.1371/journal.pone.0031024
M3 - Article
C2 - 22363539
AN - SCOPUS:84857182455
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 2
M1 - e31024
ER -