Differential susceptibility to striatal neurodegeneration induced by quinolinic acid and kainate in inbred, outbred and hybrid mouse strains

Abstract

In mice, the genetic background determines susceptibility to hippocampal neurodegeneration induced by the excitotoxin kainic acid (KA). If genetic background plays as significant a role in the striatum, the area most affected in Huntington's disease (HD), it is important to characterize intrinsic differences in neuronal susceptibility in mouse strains used in HD models. This study was performed to investigate whether strain differences of different HD mouse models are determinants of striatal resistance to excitotoxicity. We conducted a survey of the susceptibility of striatal neurons to neurodegeneration induced by quinolinic acid and KA in six inbred, two outbred and two F1 hybrid (resistant*vulnerable) strains. These are the same strains in which we have assessed vulnerability to KA-induced hippocampal neurodegeneration. We found significant strain differences in response to both excitotoxins and, for the most part, the strain-dependent patterns of susceptibility to quinolinic acid and KA were similar and comparable to those previously found with KA-induced hippocampal neurodegeneration. There were some incongruities, suggesting that the genetic determinants may be different for the two forms of excitotoxicity or that there are important interacting factors. For example, the F1 hybrid strains exhibited neurodegeneration similar to their vulnerable parent, indicating that the vulnerable phenotype is dominant. This is in contrast to KA-induced hippocampal neurodegeneration, where F1 hybrids exhibit the resistant phenotype. These results are also of significance with regard to the issue of region-specific vulnerability in the context of different diseases in which genetic modifiers affect age of onset and/or disease progression.