Dopaminergic neurons of system xc- deficient mice are protected against 6-OHDA induced toxicity

System xc- or the cystine/glutamate antiporter exchanges extracellular cystine for intracellular glutamate. Intracellularly cystine is reduced to cysteine, the rate-limiting substrate in the synthesis of glutathione. Increased activity of system xc- can thus protect cells against oxidative stress. Yet, at the same time, an increased release of glutamate via this antiporter can induce excitotoxicity. We used mice lacking xCT, the specific subunit of system xc-, to investigate the possible involvement of system xc- in the pathogenesis of Parkinson's disease. Interestingly, xCT deficient mice showed a decreased sensitivity towards 6-OHDA induced neurodegeneration. At 3 and 10 days after striatal 6-OHDA injection, young (3 month) and old (12-18 month) wildtype mice showed significant neurodegeneration (young 3d: ~10%; young 10d: ~25.0%; old 3d and 10d: ~25%) whereas young and old xCT knockout littermates are devoid of neurodegeneration at 3 days and showed a significant smaller loss of neurons at 10 days (~5%). xCT knockout mice do not show a loss of striatal glutathione or any signs of increased oxidative stress in the striatum or substantia nigra, compared to their wildtype littermates. Yet, in vivo microdialysis experiments revealed that the xCT knockout mice show a decrease of ~75% in striatal extracellular glutamate concentration. This loss of striatal extracellular glutamate is not linked to compensatory changes in expression level of other glutamate transporters as investigated using semi-quantitative Western blotting. We here provide for the first time a clear link between system xc- and neurodegeneration in a model for Parkinson's disease. Moreover, we have in vivo evidence that the major source of extracellular glutamate in the mouse striatum is glutamate release via system xc- as described before by Baker et al. (2002) in the nucleus accumbens of the rat. Our data suggest that preventing release of glutamate via system xc- under pathological conditions might protect the brain against neurodegeneration.