EXTRACELLULAR ACIDITY POTENTIATES AMPA RECEPTOR-MEDIATED CORTICAL NEURONAL DEATH

The extracellular acidity that accompanies brain hypoxia-ischemia is k nown to reduce both NMDA and AMPA-kainate receptor-mediated currents a nd 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 intracellula r Ca2+ homeostasis, observed after AMPA-kainate receptor activation, b ut not after NMDA receptor activation or exposure to high K+. The abil ity of acidic pH to selectively augment AMPA-kainate receptor-mediated excitotoxicity may contribute to the prominent role that these recept ors play in selective neuronal death after transient global ischemia.