System xc- is an important source of extracellular glutamate and involved in the pathogenesis of several neurological disorders

System xc- or the cystine/glutamate antiporter imports one cystine in exchange for one glutamate molecule. Cystine is intracellularly reduced to cysteine, the rate-limiting building block of glutathione. Malfunctioning of system xc- can thus cause oxidative stress as well as excitotoxicity, important phenomenons in the pathogenesis of Parkinson's disease, epilepsy, multiple sclerosis and many other neurological disorders. However, deletion of xCT (xCT-/- mice) did not affect striatal or hippocampal glutathione levels and no signs of increased oxidative stress were seen in xCT-/- mice. Interestingly, extracellular hippocampal and striatal glutamate levels were decreased by >60% in xCT-/- mice compared to controls. In addition, intrahippocampal perfusion with system xc- inhibitors lowered extracellular glutamate whereas the system xc- activator N-acetylcysteine elevated extracellular glutamate in rat hippocampus, suggesting that system xc- might be an interesting target for pathologies associated with excessive extracellular glutamate release. Indeed, we observed increased expression levels of xCT, the specific subunit of system xc-, in brain samples of rodent models for several neurological disorders as well as patients. To investigate the relevance of this altered expression of xCT, we used xCT-/- mice to study in vivo the effect of system xc- deficiency on the behavioral and/or neurochemical outcome in models for Parkinson's disease, limbic seizures, epilepsy and multiple sclerosis. xCT deletion resulted in protection of the mice in models for Parkinson's disease, limbic seizures and epilepsy. Loss of xCT did not affect the susceptibility of mice in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis. The current data sustain that system xc- is an important source of hippocampal and striatal extracellular glutamate that might become activated in pathological conditions and as such cause accumulation of extracellular glutamate to toxic levels. Inhibition of system xc- might thus represent an innovative strategy for the future development of drugs for the treatment of neurological disorders that are characterized by dysregulated glutamatergic neurotransmission.