Disease-toxicant interactions in manganese exposed Huntington disease mice: Early changes in striatal neuron morphology and dopamine metabolism

Jennifer L. Madison, Michal Wegrzynowicz, Michael Aschner, Aaron B. Bowman

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere31024
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 17 2012
Externally publishedYes

Fingerprint

Corpus Striatum
Dopaminergic Neurons
Huntington Disease
Manganese
dopamine
toxic substances
Metabolism
Neurons
manganese
Dopamine
neurons
metabolism
mice
Genotype
Metabolites
genotype
metabolites
neuropathology
Neurochemistry
Gene-Environment Interaction

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Disease-toxicant interactions in manganese exposed Huntington disease mice : Early changes in striatal neuron morphology and dopamine metabolism. / Madison, Jennifer L.; Wegrzynowicz, Michal; Aschner, Michael; Bowman, Aaron B.

In: PLoS One, Vol. 7, No. 2, e31024, 17.02.2012.

Research output: Contribution to journalArticle

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