Interference with glutamate antiporter system xc⁻ enables post‐hypoxic long‐term potentiation in hippocampus

Our group previously showed that genetic or pharmacological inhibition of the cystine/glutamate antiporter, system x c − , mitigates excitotoxicity after anoxia by increasing latency to anoxic depolarization, thus attenuating the ischaemic core. Hypoxia, however, which prevails in the ischaemic penumbra, is a condition where neurotransmission is altered, but excitotoxicity is not triggered. The present study employed mild hypoxia to further probe ischaemia‐induced changes in neuronal responsiveness from wild‐type and xCT KO (xCT −/− ) mice. Synaptic transmission was monitored in hippocampal slices from both genotypes before, during and after a hypoxic episode. Although wild‐type and xCT −/− slices showed equal suppression of synaptic transmission during hypoxia, mutant slices exhibited a persistent potentiation upon re‐oxygenation, an effect we termed ‘post‐hypoxic long‐term potentiation (LTP)’. Blocking synaptic suppression during hypoxia by antagonizing adenosine A 1 receptors did not preclude post‐hypoxic LTP. Further examination of the induction and expression mechanisms of this plasticity revealed that post‐hypoxic LTP was driven by NMDA receptor activation, as well as increased calcium influx, with no change in paired‐pulse facilitation. Hence, the observed phenomenon engaged similar mechanisms as classical LTP. This was a remarkable finding as theta‐burst stimulation‐induced LTP was equivalent between genotypes. Importantly, post‐hypoxic LTP was generated in wild‐type slices pretreated with system x c − inhibitor, S ‐4‐carboxyphenylglycine, thereby confirming the antiporter's role in this phenomenon. Collectively, these data indicate that system x c − interference enables neuroplasticity in response to mild hypoxia, and, together with its regulation of cellular damage in the ischaemic core, suggest a role for the antiporter in post‐ischaemic recovery of the penumbra.