Involvement of the cystine/glutamate antiporter in hippocampal functioning: implications for seizure sensitivity

System xc- exchanges intracellular glutamate for extracellular cystine, giving it a potential role in intracellular glutathione synthesis and regulating extracellular glutamate levels. We used mice lacking the xCT subunit of system xc- (xCT-/-) to investigate the possible involvement of this transporter in the susceptibility for limbic seizures. In a first set of experiments we could not detect alterations in hippocampal glutathione content, oxidative stress or brain atrophy in the xCT-/- mice. On the other hand, extracellular hippocampal glutamate levels were significantly decreased. Consequently, xCT deletion elevated the threshold for limbic seizures. xCT-/- mice were less susceptible to the well known chemoconvulsants pilocarpine, kainic acid and NMDA. Furthermore, N-acetylcysteine, an activator of system xc-, was proconvulsant in the pilocarpine and 6 Hz model. This proconvulsant effect was absent in the xCT-/- mice. These findings sustain that system xc- is the major hippocampal source of extracellular glutamate and that impairing system xc- is clearly beneficial to decrease susceptibility for limbic seizures.