Susceptibility to excitotoxic and metabolic striatal neurodegeneration in the mouse is genotype dependent

Previously, we had reported that hippocampal susceptibility to the neurotoxic effects of excitotoxin administration is strain dependent [Schauwecker and Steward, Proc. Natl. Acad. Sci. U.S.A. 94 (1997) 4103]. However, it has been unclear whether strain-related gene products may play a similar role in providing protection against drugs that produce striatal lesions. The present series of experiments sought to elucidate whether genetic background alters neuronal viability within the striatum following metabolic or excitotoxic injury. Thus, we have examined the effect of mouse strain on susceptibility to striatal injury using well-characterized animal models of Huntington's disease by examining whether C57BL/6 mice, previously identified as resistant to excitotoxin-induced hippocampal cell death, are resistant to quinolinate, malonate, and 3-nitropropionic acid (3-NP). Intrastriatal injection of either malonate or quinolinate and systemic administration of 3-NP resulted in significantly smaller striatal lesions in C57BL/6 mice as compared to FVB/N mice, previously identified as susceptible to hippocampal excitotoxic injury. The existence of an animal strain with decreased resistance to striatal lesions suggests that there are mediating factors involved in the preferential vulnerability of the striatum to neurotoxic lesioning. The identification of these factors could provide strategies for therapeutic intervention in Huntington's disease.