Decreased epileptogenesis in mice lacking the System x(c) (−) transporter occurs in association with a reduction in AMPA receptor subunit GluA1

OBJECTIVE: Although the cystine/glutamate antiporter System x(c) (−) (Sx(c) (−)) plays a permissive role in glioma‐associated seizures, its contribution to other acquired epilepsies has not been determined. As such, the present study investigates whether and how Sx(c) (−) contributes to the pentylenetetrazole (PTZ) chemical kindling model of epileptogenesis. METHODS: Male Sx(c) (−) null (sut/sut) mice and their wild‐type littermates were administered PTZ (i.p.) daily for up to 21 days (kindling paradigm). Seizure severity was scored on a 5‐point behavioral scale. Mossy fiber sprouting, cellular degeneration, and Sx(c) (−) light chain (xCT) messenger RNA (mRNA) were explored using Timm staining, thionin staining, and real‐time quantitative polymerase chain reaction (qPCR), respectively. Levels of reduced and oxidized glutathione and cysteine were determined via high‐performance liquid chromatography (HPLC). Plasma membrane protein levels of glutamate and γ‐aminobutyric acid (GABA) receptor subunits as well as the K(+)/Cl(−) co‐transporter KCC2 were quantified via western blot analysis. RESULTS: Repeated administration of PTZ produced chemical kindling in only 50% of Sx(c) (−) null mice as compared to 82% of wild‐type littermate control mice. Kindling did not result in any changes in xCT mRNA levels assessed in wild‐type mice. No cellular degeneration or mossy fiber sprouting was discernible in either genotype. Except for a small, but significant, decrease in oxidized cysteine in the hippocampus, no other change in measured redox couples was determined in Sx(c) (−) null mice. Cortical levels of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor subunit GluA1 were decreased in Sx(c) (−) null mice as compared to wild‐type littermates, whereas all other proteins tested showed no difference between genotypes. SIGNIFICANCE: This study provides the first evidence that Sx(c) (−) signaling contributes to epileptogenesis in the PTZ kindling model of acquired epilepsy. Further data indicate that a reduction in AMPA receptor signaling could underlie the resistance to PTZ kindling uncovered in Sx(c) (−) null mice.