Unravelling the role of system xc- in epileptogenesis

System xc- is a transmembrane cystine/glutamate antiporter and exchanges intracellular glutamate for extracellular cystine, giving it a potential role in intracellular glutathione synthesis and non-vesicular glutamate release. We recently discovered that mice lacking the specific xCT subunit of system xc- (xCT-/-mice) do not display oxidative stress-related changes or neuronal damage. We however demonstrated that system xc- is the major source of extracellular hippocampal glutamate and that its inactivation is beneficial to decrease limbic seizure susceptibility. Here we will further study in depth these anticonvulsant effects by using mice with an inducible celtype-specific xCT overexpression, Vivo-
Morpholinos and custom-made PCR arrays for genes linked to oxidative stress and glutamate neurotransmission. We propose the glial system xc- as an innovative target for the future development of antiepileptic drugs with disease-modifying or antiepileptogenic properties. Therefore we will use amygdala kindling and post-status epilepticus models, that reliably simulate the human epileptic condition, to compare various aspects of seizure development in transgenic mice (xCT-/- and xCT overexpressing mice) versus wild-type mice. We will also study xCT expression during the different phases of the post-status epilepticus model in wild-type mice and in human tissue of temporal lobe epilepsy patients as a first step to translational research.