Loss of system xc- does not induce oxidative stress but decreases extracellular glutamate in hippocampus and influences spatial working memory and limbic seizure susceptibility

System xc- exchanges intracellular glutamate (Glu) for extracellular cystine, giving it a role in intracellular glutathione synthesis and non-vesicular Glu release. We report that mice lacking the specific subunit of system xc- (xCT-/-) do not have lower hippocampal glutathione content or increased oxidative stress, nor exacerbated spatial reference memory deficits with ageing, indicating that loss of system xc- does not induce oxidative stress in vivo. xCT-/- mice did however display a spatial working memory deficit. Interestingly, we observed lower extracellular hippocampal Glu in xCT-/- mice compared to controls. Moreover, local perfusion with system xc- inhibitors lowered extracellular Glu whereas the system xc- activator N-acetylcysteine (NAc) elevated extracellular Glu in rat hippocampus, indicating that system xc- may be a target for pathologies associated with excessive hippocampal Glu. Accordingly, xCT deletion in mice elevated the threshold for limbic seizures and abolished the proconvulsive effects of NAc. Our findings sustain that system xc- is an important source of extracellular hippocampal Glu. System xc- is required for optimal spatial working memory, but its inactivation is beneficial to decrease susceptibility for limbic seizures. J Neurosci (2011) 31, 5792-803

Jaar van publicatie:2011

Trefwoorden:system xc-, limbic seizures, memory