The Journal of Neurophysiology Vol. 81 No. 4 April 1999, pp. 1988-1991
Copyright ©1999 by the American Physiological Society

RAPID COMMUNICATION

Endogenous pH Shifts Facilitate Spreading Depression by Effect on NMDA Receptors

Department of Physiology and Neuroscience and Department of Neurosurgery, New York University Medical Center, New York City, New York 10016

Tong, C. K. and M. Chesler. Endogenous pH shifts facilitate spreading depression by effect on NMDA receptors. Rapid extracellular alkalinizations accompany normal neuronal activity and have been implicated in the modulation of N-methyl-D-aspartate (NMDA) receptors. Particularly large alkaline transients also occur at the onset of spreading depression (SD). To test whether these endogenous pH shifts can modulate SD, the alkaline shift was amplified using benzolamide, a poorly permeant inhibitor of interstitial carbonic anhydrase. SD was evoked by microinjection of 1.2 M KCl into the CA1 stratum radiatum of rat hippocampal slices and recorded by a proximal double-barreled pH microelectrode and a distal potential electrode. In Ringer solution of pH 7.1 containing picrotoxin (but not at a bath pH of 7.4), addition of 10 µM benzolamide increased the SD alkaline shift from 0.20 ± 0.07 to 0.38 ± 0.17 unit pH (means ± SE). This was correlated with a significant shortening of the latency and an increase in the conduction velocity by 26 ± 16%. In the presence of the NMDA receptor antagonist DL2-amino-5-phosphonovaleric acid (APV), benzolamide still amplified the alkaline transient, however, its effect on the SD latency and propagation velocity was abolished. The intrinsic modulation of SD by its alkaline transient may play an important role under focal ischemic conditions by removing the proton block of NMDA receptors where interstitial acidosis would otherwise limit NMDA receptor activity.