HIGH EXTRACELLULAR POTASSIUM, AND NOT EXTRACELLULAR GLUTAMATE, IS REQUIRED FOR THE PROPAGATION OF SPREADING DEPRESSION

1. Cortical spreading depression (SD) is a propagating transient suppr ession of electrical activity associated with depolarization, which ma y contribute to the pathophysiology of important neurological disorder s, including cerebral ischemia and migraine. The purpose of this study is to ascertain whether SD propagation depends on local accumulation of extracellular K+ or glutamate. 2. Propagating SD recorded through m icrodialysis probes perfused with artificial cerebrospinal fluid (ACSF ) was much smaller than that recorded with conventional glass microele ctrodes, presumably because some SD-induced transient changes in the e xtracellular fluid composition were buffered by ACSF. We have exploite d this effect to determine whether perfusion with a medium containing increasing amounts of K+ and/or glutamate favors SD propagation 3. Inc reasing the concentration of K+ (15-60 mmol/l) in the perfusion medium dose-dependently restored SD propagation, whereas application of 100- 250 mu mol/l glutamate through the microdialysis probe had no effect. Superimposing 200 mu mol/l glutamate onto 15 and 30 mmol/l K+ did not further improve the restoration of SD propagation by K+. 4. Because po tent uptake mechanisms may efficiently clear exogenous glutamate from the extracellular space, the effect of local inhibition of high-affini ty glutamate uptake was also studied. Perfusion of the recording micro dialysis probe with 1 mmol/l L-trans-pyrrolidine-2,4-dicarboxylate (L- trans-PDC), either alone or together with 200 mu mol/l glutamate, had no effect. In addition, L-trans-PDC did not potentiate the positive ef fect of 30 mmol/l KC on SD propagation. 5. These results strongly sugg est that high extracellular K+, and not extracellular glutamate, is th e driving force sustaining SD propagation. Because there is compelling pharmacological evidence that SD depends on Ca2+ fluxes through N-met hyl-D-aspartate (NMDA)-activated ion channels, these results challenge the notion that high extracellular glutamate is the major cause of ex cessive ionic fluxes through these channels, The relief of the voltage -dependent Mg2+-block of the NMDA receptor ionophore complex by depola rization may be a more critical element.