Extracellular acidity potentiates AMPA receptor-mediated cortical neuronal death

The extracellular acidity that accompanies brain hypoxia-ischemia is known to reduce both NMDA and AMPA-kainate receptor-mediated currents and NMDA receptor-mediated neurotoxicity. Although a protective effect of acidic pH on AMPA-kainate receptor-mediated excitotoxicity has been assumed, such has not been demonstrated. Paradoxically, we found that lowering extracellular pH selectively increased AMPA-kainate receptor-mediated neurotoxicity in neocortical cell cultures, despite reducing peak elevations in intracellular free Ca²⁺. This injury potentiation may, at least in part, be related to a slowed recovery of intracellular Ca²⁺ homeostasis, observed after AMPA-kainate receptor activation, but not after NMDA receptor activation or exposure to high K⁺. The ability of acidic pH to selectively augment AMPA-kainate receptor-mediated excitotoxicity may contribute to the prominent role that these receptors play in selective neuronal death after transient global ischemia.