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- Title
Loss of System x<sub>c</sub><sup>-</sup> Does Not Induce Oxidative Stress But Decreases Extracellular Glutamate in Hippocampus and Influences Spatial Working Memory and Limbic Seizure Susceptibility.
- Authors
De Bundel, Dimitri; Schallier, Anneleen; Loyens, Ellen; Fernando, Ruani; Miyashita, Hirohisa; Van Liefferinge, Joeri; Vermoesen, Katia; Bannai, Shiro; Sato, Hideyo; Michotte, Yvette; Smolders, Ilse; Massie, Ann
- Abstract
System Xc- exchanges intracellular glutamate for extracellular cystine, giving it a potential role in intracellular glutathione synthesis and nonvesicular 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 aging. Together these results indicate that loss of system xcc- 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 wild-type littermates. Moreover, intrahippocampal perfusion with system xcc- inhibitors lowered extracellular glutamate, whereas the system xcc- activator N-acetylcysteine elevated extracellular glutamate in the rat hippocampus. This indicates that system xcc- 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 xcc- is an important source of extracellular glutamate in the hippocampus. System xcc- is required for optimal spatial working memory, but its inactivation is clearly beneficial to decrease susceptibility for limbic epileptic seizures.
- Subjects
GLUTAMIC acid; GLUTATHIONE; OXIDATIVE stress; ATROPHY; SHORT-term memory; AGING
- Publication
Journal of Neuroscience, 2011, Vol 31, Issue 15, p5792
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5465-10.2011