Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity

Huntington's disease (HD) is a hereditary neurodegenerative disorder presen ting with chorea, dementia, and extensive striatal neuronal death. The mech anism through which the widely expressed mutant HD gene mediates a slowly p rogressing striatal neurotoxicity is unknown. Glutamate receptor-mediated e xcitotoxicity has been hypothesized to contribute to the pathogenesis of HD , Here we show that transgenic HD mice expressing exon 1 of a human HD gene with an expanded number of CAG repeats (line R6/1) are strongly protected from acute striatal excitotoxic lesions, Intrastriatal infusions of the N-m ethyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive st riatal neuronal death in wild-type mice, but no damage in transgenic KD lit termates, The remarkable neuroprotection in transgenic HD mice occurred at a stage when they had not developed any neurological symptoms caused by the mutant HD gene. At this stage there was no change in the number of striata l neurons and astrocytes in untreated R6/1 mice, although the striatal volu me,vas decreased by 17%. Moreover, transgenic HD mice had normal striatal l evels of NMDA receptors, calbindin D28k (calcium buffer), superoxide dismut ase activity (antioxidant enzyme), Bcl-2 (anti-apoptotic protein), heat sho ck protein 70 (stress-induced anti-apoptotic protein), and citrate synthase activity (mitochondrial enzyme). We propose that the presence of exon 1 of the mutant HD gene induces profound changes in striatal neurons that rende r these cells resistant to excessive NMDA receptor activation.