System xc- exchanges intracellular glutamate for extracellular cystine, giving it a potential role in intracellular glutathione synthesis and non-vesicular glutamate release. We report that mice lacking the specific xCT subunit of system xc- (xCT-/-) do not have a lower hippocampal glutathione content, increased oxidative stress or brain atrophy, nor exacerbated spatial reference memory deficits with ageing. Together these results indicate that loss of system xc- does not induce oxidative stress in vivo. Young xCT-/- mice did however display a spatial working memory deficit. Interestingly, we observed significantly lower extracellular hippocampal glutamate concentrations in xCT-/- mice compared to wildtype littermates. Moreover, intrahippocampal perfusion with system xc- inhibitors lowered extracellular glutamate whereas the system xc- activator N-acetylcysteine elevated extracellular glutamate in the rat hippocampus. This indicates that system xc- may be an interesting target for pathologies associated with excessive extracellular glutamate release in the hippocampus. Correspondingly, xCT deletion in mice elevated the threshold for limbic seizures and abolished the proconvulsive effects of N-acetylcysteine. These novel findings sustain that system xc- is an important source of extracellular glutamate in the hippocampus. System xc- is required for optimal spatial working memory, but its inactivation is clearly beneficial to decrease susceptibility for limbic epileptic seizures.
Original languageEnglish
Pages (from-to)5792-5803
JournalJournal of Neuroscience
Volume31
Issue number15
Publication statusPublished - 13 Apr 2011

    Research areas

  • xCT, hippocampus, glutamate, epilepsy, memory

ID: 2029833