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

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Abstract

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.

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.

References (55)

  • P.O. Fernagut et al.

    A simple method to measure stride length as an index of nigrostriatal dysfunction in mice

    J. Neurosci. Methods

    (2002)
  • K.L. Gabrielson et al.

    Mitochondrial toxin 3-nitropropionic acid induces cardiac and neurotoxicity differentially in mice

    Am. J. Pathol.

    (2001)
  • N. Georgiou-Karistianis et al.

    Future directions in research with presymptomatic individuals carrying the gene for Huntington's disease

    Brain Res. Bull.

    (2003)
  • I. Ghorayeb et al.

    Simultaneous intrastriatal 6-hydroxydopamine and quinolinic acid injection: a model of early-stage striatonigral degeneration

    Exp. Neurol.

    (2001)
  • M. Glass et al.

    The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease

    Neuroscience

    (2000)
  • J.G. Greene et al.

    Bioenergetics and excitotoxicity: the weak excitotoxic hypothesis

  • G.W. Kim et al.

    Oxidative stress and neuronal DNA fragmentation mediate age-dependent vulnerability to the mitochondrial toxin, 3-nitropropionic acid, in the mouse striatum

    Neurobiol. Dis.

    (2001)
  • K. Matsuura et al.

    Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion

    J. Neurosci. Methods

    (1997)
  • A.J. Morton et al.

    Mice transgenic for the human Huntington's disease mutation have reduced sensitivity to kainic acid toxicity

    Brain Res. Bull.

    (2000)
  • M. Nakai et al.

    NMDA and non-NMDA receptor-stimulated IkappaB-alpha degradation: differential effects of the caspase-3 inhibitor DEVD.CHO, ethanol and free radical scavenger OPC-14117

    Brain Res.

    (2000)
  • R.C. Roberts et al.

    Intrastriatal injections of quinolinic acid or kainic acid: differential patterns of cell survival and the effects of data analysis on outcome

    Exp. Neurol.

    (1993)
  • G. Rozas et al.

    The overall rod performance test in the MPTP-treated-mouse model of Parkinsonism

    J. Neurosci. Methods

    (1998)
  • M. Sedelis et al.

    Behavioral phenotyping of the MPTP mouse model of Parkinson's disease

    Behav. Brain Res.

    (2001)
  • F. Squitieri et al.

    Onset and pre-onset studies to define the Huntington's disease natural history

    Brain Res. Bull.

    (2001)
  • E.M. Urbanska et al.

    AMPA/kainate-related mechanisms contribute to convulsant and proconvulsant effects of 3-nitropropionic acid

    Eur. J. Pharmacol.

    (1999)
  • R.L. Albin et al.

    Alternative excitotoxic hypotheses

    Neurology

    (1992)
  • T. Alexi et al.

    3-Nitropropionic acid's lethal triplet: cooperative pathways of neurodegeneration

    NeuroReport

    (1998)
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