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

Dimitri De Bundel, Anneleen Schallier, Ellen Loyens, Ruani Fernando, Hirohisa Miyashita, Joeri Van Liefferinge, Katia Vermoesen, Shiro Bannai, Hideyo Sato, Yvette Michotte, Ilse Smolders, Ann Massie

Research output: Contribution to journalArticle

111 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5792-5803
Number of pages12
JournalJournal of Neuroscience
Volume31
Issue number15
DOIs
Publication statusPublished - 13 Apr 2011

Keywords

  • Amino Acid Transport System y+
  • Animals
  • Blotting, Western
  • Brain
  • DNA
  • Electroencephalography
  • Extracellular Space
  • Genotype
  • Glutamic Acid
  • Glutathione
  • Hippocampus
  • Immunohistochemistry
  • Limbic System
  • Male
  • Maze Learning
  • Memory, Short-Term
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microdialysis
  • Motor Activity
  • Neuroglia
  • Oxidative Stress
  • Psychomotor Performance
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Seizures
  • Space Perception

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