High Extracellular Potassium, and not Extracellular Glutamate, is Required
for the Propagation of Spreading Depression.
Obrenovitch, T. P., and E. Zilkha.
Department of Neurological Surgery, Institute of Neurology, Queen Square,
London WC1N 3BG, United Kingdom.
APStracts 2:0060N, 1995.
SUMMARY AND CONCLUSIONS
1 . Cortical spreading depression (SD) is a propagating transient suppression
of electrical activity associated with depolarization, which may contribute to
the pathophysiology of important neurological disorders, 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 microdialysis probes perfused with
artificial cerebrospinal fluid (ACSF) was much smaller than that recorded with
conventional glass microelectrodes, presumably because some SD-induced
transient changes in the extracellular fluid composition were buffered by
ACSF. We have exploited this effect to determine whether perfusion with a
medium containing increasing amounts of K + and/or glutamate favors SD
propagation. 3 . Increasing 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 potent
uptake mechanisms may efficiently clear exogenous glutamate from the
extracellular space, the effect of local inhibition of high-affinity glutamate
uptake was also studied. Perfusion of the recording microdialysis probe with 1
mmol/l L- trans -pyrrolidine-2,4-dicarboxylate (L- trans -PDC), either alone
or togetherwith 200 [mu]mol/l glutamate, had no effect. In addition, L- trans
-PDC did not potentiate the positive effect of 30 mmol/l K + on SD
propagation. 5 . These results strongly suggest that high extracellular K + ,
and not extracellular glutamate, is the driving force sustaining SD
propagation. Because there is compelling pharmacological evidence that SD
depends on Ca 2+ fluxes through N -methyl-d-aspartate (NMDA)-activated ion
channels, these results challenge the notion that high extracellular glutamate
is the major cause of excessive ionic fluxes through these channels. The
relief of the voltage-dependent Mg 2+ -block of the NMDA receptor ionophore
complex by depolarization may be a more critical element.
Received 23 June 1994; accepted in final form 8 February 1995.
APS Manuscript Number J373-4.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 3 April 1995.