Experimental basis for the putative role of GluR6/kainate glutamate receptor subunit in Huntington's disease natural history
Introduction
Huntington's disease (HD) is a completely penetrant autosomal dominant disease caused by abnormal expansion of CAG repeats in the IT15 gene Brouillet et al., 1999, Squitieri et al., 2001. This multiple system degenerative disorder predominantly affects subcortical motor systems, particularly the striatum. Age at onset of HD is known to be statistically correlated with the length of expanded CAG repeats. It is however known that considerable individual variations in the age at onset may occur for the same repeat length range Georgiou et al., 1999, Squitieri et al., 2001. Environmental factors, gender, or interacting genes besides IT15 may exert subtle to marked differences in the course of the disease (Kehoe et al., 1999). Among such interacting genes, two independent groups found that part of the variance in the age at onset of HD may be attributable to a polymorphism in the 3′ untranslated region of GluR6/kainate receptor (Grik2) subtype gene MacDonald et al., 1999, Rubinsztein et al., 1997. Although it is obvious that the GluR6 subunit is heavily expressed in the striatum Bahn et al., 1994, Bischoff et al., 1997 and indirectly involved in striatal synaptic transmission (Chergui et al., 2000), it is not known whether such GluR6 variant induces receptor functional changes that may be pathogenic (Barbon et al., 2001). To further investigate this issue, we studied the susceptibility of GluR6 knockout mice (GluR6−/−) to 3-nitropropionic acid (3-NP) compared to their wild-type littermates (GluR6+/+). 3-NP is an irreversible inhibitor of succinate dehydrogenase (SDH, mitochondrial complex II) used in rodents and primates to induce a profound striatal metabolic failure and secondary excitotoxic damage similar to that observed in HD Beal et al., 1993, Brouillet et al., 1999. We recently demonstrated that a phenotypic model of HD, similar to that proposed in the rat, can be obtained in C57Bl/6 mice using subacute/chronic 3-NP systemic injections (Fernagut et al., 2002a).
Section snippets
Animals
Experiments were carried out in adult homozygous GluR6−/− and GluR6+/+ mice of two age groups: 6 months (GluR6−/−, n = 7 and GluR6+/+, n = 16) and 1 year (GluR6−/−, n = 9 and GluR6+/+, n = 9). Eight additional mice (four GluR6−/− and four GluR6+/+) were used to assess 3-NP-induced SDH inhibition. All mice included in this study were obtained by mating hybrid C57BL/6 × 129Sv GluR6 +/− mice (Mulle et al., 1998). Genotypes were determined by Southern blot analysis (Mulle et al., 1998). All
Mortality during 3-NP administration
In mice aged 6 months, 3 out of 7 GluR6+/+ (43%) died during 3-NP administration at day 13 from a full blown severe motor disorder with profound akinesia (last motor score = 5, 7, 8/10); while 12 out of 16 GluR6−/− (75%) died at day 10 (n = 1, last motor score = 8/10), day 11 (n = 3, last motor score = 3, 5, 7/10), day 12 (n = 3, last motor score = 5, 5, 7/10), and day 13 (n = 5, last motor score = 4, 5, 6, 7, 7/10). Thus, excepting “unexpected” death (likely acute systemic, i.e., cardiac) of
Discussion
The aim of the present study was to analyze, from a behavioral and histopathological point of view, the susceptibility of GluR6 knockout mice to systemic 3-NP striatal metabolic compromise compared to their wild-type littermates. Functional kainate receptors containing the GluR6 subunit (GluR6/KARs) are expressed in the striatum (Bischoff et al., 1997); however, their function in synaptic transmission remains unclear Chergui et al., 2000, Mulle et al., 1998. Functional GluR6/KARs are present in
Acknowledgements
This work was supported by CNRS and Université Victor Segalen Bordeaux2. Elsa Diguet is a recipient of a France Parkinson grant.
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