RT Journal Article
SR Electronic
T1 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
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5792
OP 5803
DO 10.1523/JNEUROSCI.5465-10.2011
VO 31
IS 15
A1 Dimitri De Bundel
A1 Anneleen Schallier
A1 Ellen Loyens
A1 Ruani Fernando
A1 Hirohisa Miyashita
A1 Joeri Van Liefferinge
A1 Katia Vermoesen
A1 Shiro Bannai
A1 Hideyo Sato
A1 Yvette Michotte
A1 Ilse Smolders
A1 Ann Massie
YR 2011
UL http://www.jneurosci.org/content/31/15/5792.abstract
AB 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 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 wild-type 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.