THE EFFECT OF DEPRESSING GLIAL FUNCTION IN RAT-BRAIN IN-SITU ON ION HOMEOSTASIS, SYNAPTIC TRANSMISSION, AND NEURON SURVIVAL

The supporting role of glial cells in maintaining neurons and in ion h omeostasis has been studied in situ by perfusing the gliotoxin fluoroc itrate (FC) through a microdialysis fiber in the CAI area of urethane- anesthetized rats. Extracellular direct current potential, extracellul ar potassium concentration ([K+](o)) and amino acid levels, extracellu lar pH (pH(o)), and evoked field activity were studied. Histology veri fied the swelling of glial cells after 4 hr of FC treatment. Massive n euron damage was evident after 8 hr, FC dialysis caused the rapid decr ease of glutamine, pH(o) became progressively more acid, and [K+](o) m oderately elevated. Orthodromic transmission was variably blocked with in 30 min to 4 hr. After 4 hr, spreading depression (SD) waves that or iginated from the neocortex invaded hippocampal CA1, [K+](o) increased to higher levels, pH(o) became very acid, and there were steep increa ses in taurine, glutamate, and GABA levels. Simultaneously, the antidr omic population spike (a-PS) became depressed and eventually disappear ed. When a shorter dialysis probe that spared cortex was used to sampl e CA1, no SD was seen, a-PS was not abolished, and ion homeostasis was altered less markedly. Repeated SD provoked in hippocampus in the abs ence of FC caused only mild depression of a-PS. Dialysis of high-K+ so lution in healthy neocortex or hippocampus caused only slight elevatio n of [K+](o) at distances of 200-400 mu m from the dialysis membrane. After treatment with FC, similar high-K+ dialysis raised [K+](o) much more. We conclude the following: (1) recurrent SD waves injure neurons if and only if glial function has failed; (2) neurons can regulate [K +](o), albeit imperfectly; (3) glia is required for the normal fine tu ning of [K+](o) and particularly for the recovery of pathologically el evated [K+](o); and (4) glia are required for the regulation of pH(o). The similarities between glial poisoning by FC and the reported chang es in the penumbra of ischemic infarcts suggest that the extension of neuron loss into the penumbral region might depend on failure of glial protection.