EFFECTS OF THE GLIOTOXIN FLUOROCITRATE ON SPREADING DEPRESSION AND GLIAL MEMBRANE-POTENTIAL IN RAT-BRAIN IN-SITU

DC extracellular potential shifts (Delta V-o) associated with spreadin g depression (SD) reflect massive cell depolarization, but their cellu lar generators remain obscure. We have recently reported that the glia l specific metabolic poison fluorocitrate (FC) delivered by microdialy sis 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 c reated 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 wa ves and glial membrane potential (V-m). Extracellular potential (V-o), interstitial potassium concentration ([K+](o)), evoked potentials, an d transmembrane glial potentials were monitored in the CA1 area before , during, and after administration of FC with or without elevated K+ c oncentration in the dialysate. SD waves propagated faster and lasted l onger during FC treatment. Delta V-o in stratum pyramidale, which norm ally are much shorter and of smaller amplitude than those in stratum r adiatum, expanded during FC treatment to match those in stratum radiat um. 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 neo cortex normally does not spread to the CA1, but during FC treatment it readily reached CA1 via entorhinal cortex. Once neuronal function beg an to deteriorate, SD waves became smaller and slower, and eventually failed to enter the region around the FC source. Slow, moderately nega tive Delta V-o that mirrored [K+](o) increments could still be recorde d well after neuronal function and SD-associated V-o had disappeared. Glial cell V-m gradually depolarized during FC administration, beginni ng much before depression of neuronal antidromic action potentials. Ca lculations based on the results predict a large decrease in glial pota ssium content during FC treatment. The results are compatible with neu rons being the major generator of the Delta 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 dam age.