title: Loss of system x(c)- does not induce oxidative stress but decreases extracellular glutamate in hippocampus and influences spatial working memory and limbic seizure susceptibility.
abstract: System x(c)- 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 x(c)- (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 x(c)- 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 x(c)- inhibitors lowered extracellular glutamate, whereas the system x(c)- activator N-acetylcysteine elevated extracellular glutamate in the rat hippocampus. This indicates that system x(c)- 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 x(c)-) is an important source of extracellular glutamate in the hippocampus. System x(c)(-) is required for optimal spatial working memory, but its inactivation is clearly beneficial to decrease susceptibility for limbic epileptic seizures.
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neuroscience, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors.forename: Dimitri
authors.initials: D
authors.lastname: De Bundel
authors.forename: Anneleen
authors.initials: A
authors.lastname: Schallier
authors.forename: Ellen
authors.initials: E
authors.lastname: Loyens
authors.forename: Ruani
authors.initials: R
authors.lastname: Fernando
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Miyashita
authors.forename: Joeri
authors.initials: J
authors.lastname: Van Liefferinge
authors.forename: Katia
authors.initials: K
authors.lastname: Vermoesen
authors.forename: Shiro
authors.initials: S
authors.lastname: Bannai
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.forename: Ann
authors.initials: A
authors.lastname: Massie
mesh_terms: D027182:Amino Acid Transport System y+ / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000033:anatomy & histology; D004247:DNA / Q000235:genetics; D004569:Electroencephalography; D005110:Extracellular Space / Q000378:metabolism*; D005838:Genotype; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology*; D007150:Immunohistochemistry; D008032:Limbic System / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009043:Motor Activity / Q000502:physiology; D009457:Neuroglia / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D013028:Space Perception / Q000502:physiology*
chemical_list: D027182:Amino Acid Transport System y+; C492255:Slc7a11 protein, mouse; D018698:Glutamic Acid; D004247:DNA; D005978:Glutathione