C. Largo et al., THE EFFECT OF DEPRESSING GLIAL FUNCTION IN RAT-BRAIN IN-SITU ON ION HOMEOSTASIS, SYNAPTIC TRANSMISSION, AND NEURON SURVIVAL, The Journal of neuroscience, 16(3), 1996, pp. 1219-1229
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.