Experimental basis for the putative role of GluR6/kainate glutamate receptor subunit in Huntington's disease natural history.

Age of onset of Huntington's disease (HD) statistically correlates with the length of expanded CAG repeats in the IT15 gene. However, other factors such as polymorphism in the 3' untranslated region of the GluR6 kainate receptor gene subunit may contribute to variability in the age at onset. To investigate this issue, we studied the motor disorder and related striatal damage induced by 3-nitropropionic acid (3-NP) subacute administration in GluR6 knockout mice (GluR6(-/-)) as compared to wild-type mice. In two different age groups (6 months and 1 year), we observed that GluR6(-/-) mice did not display more motor impairment nor more striatal histopathological damage than GluR6(+/+) mice, although 1-year-old GluR6(-/-) mice displayed reduced activity parameters either at baseline or after 3-NP administration compared to GluR6(+/+). In both age groups, GluR6(-/-) mice died earlier and displayed earlier motor symptoms during 3-NP-induced metabolic compromise, suggesting that GluR6-containing kainate receptors may be implicated during neurodegeneration, such as in HD, rather than in the final outcome.