The Journal of Neurophysiology Vol. 78 No. 1 July 1997, pp. 295-307
Copyright ©1997 The American Physiological Society

Effects of the Gliotoxin Fluorocitrate on Spreading Depression and Glial Membrane Potential in Rat Brain In Situ

Carlota Largo, José M. Ibarz, and Oscar Herreras

Departamento de Investigación, Hospital Ramón y Cajal, 28034 Madrid, Spain

Largo, Carlota, José M. Ibarz, and Oscar Herreras. Effects of the gliotoxin fluorocitrate on spreading depression and glial membrane potential in rat brain in situ. J. Neurophysiol. 78: 295-307, 1997. DC extracellular potential shifts (V_o) associated with spreading depression (SD) reflect massive cell depolarization, but their cellular generators remain obscure. We have recently reported that the glial specific metabolic poison fluorocitrate (FC) delivered by microdialysis in situ caused a rapid impairment of glial function followed some hours later by loss of neuronal electrogenic activity and neuron death. We have used the time windows for selective decay of cell types so created to study the relative participation of glia and neurons in SD, and we report a detailed analysis of the effects of FC on evoked SD waves and glial membrane potential (V_m). Extracellular potential (V_o), interstitial potassium concentration ([K⁺]_o), evoked potentials, and transmembrane glial potentials were monitored in the CA1 area before, during, and after administration of FC with or without elevated K⁺ concentration in the dialysate. SD waves propagated faster and lasted longer during FC treatment. V_o in stratum pyramidale, which normally are much shorter and of smaller amplitude than those in stratum radiatum, expanded during FC treatment to match those in stratum radiatum. The coalescing SD waves that develop late during prolonged high-K⁺ dialysis and are typically limited to stratum radiatum, also expanded into stratum pyramidale under the influence of FC. SD provoked in neocortex normally does not spread to the CA1, but during FC treatment it readily reached CA1 via entorhinal cortex. Once neuronal function began to deteriorate, SD waves became smaller and slower, and eventually failed to enter the region around the FC source. Slow, moderately negative V_o that mirrored [K⁺]_o increments could still be recorded well after neuronal function and SD-associated V_o had disappeared. Glial cell V_m gradually depolarized during FC administration, beginning much before depression of neuronal antidromic action potentials. Calculations based on the results predict a large decrease in glial potassium content during FC treatment. The results are compatible with neurons being the major generator of the V_o associated with SD. We conclude that energy shortage in glial cells makes brain tissue more susceptible to SD and therefore it may increase the risk of neuron damage.

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