Disease-Toxicant Interactions in Manganese Exposed Huntington Disease Mice: Early Changes in Striatal Neuron Morphology and Dopamine Metabolism

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 MnCl2-4H2O (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

Transmitter receptors and functional anatomy of the cerebral cortex

The currently available architectonic maps of the human cerebral cortex do not match the high degree of cortical segregation as shown by functional imaging. Such functional imaging studies have demonstrated a considerable number of functionally specialized areas not displayed in the architectonic maps. We therefore analysed the regional and laminar distribution of various transmitter receptors in the human cerebral cortex, because these signalling molecules play a crucial role in cortical functions. They may provide a novel and functionally more relevant insight into the regional organization of the cortex, which cannot be achieved by architectonic observations in cell body- or myelin-stained sections. Serial cryostat sections through whole human hemispheres were used for quantitative receptor autoradiography. The regional and laminar densities of numerous receptors of classic transmitter systems were analysed. Alternating sections were stained for comparisons based on cyto- or myeloarchitectonic criteria. Our results demonstrate that the regional distribution of transmitter receptors reflects well-established cyto- and myeloarchitectonically defined borders of cortical areas, but in addition enables the identification of more cortical areas than previously demonstrated. Moreover, the laminar distribution patterns of a given receptor type in different cortical areas as well as those of different receptor types in the same cortical area reveal novel and functionally relevant data concerning the intracortical organization in the human cerebral cortex