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Journal of Neuroscience, Vol 16, 1219-1229, Copyright © 1996 by Society for Neuroscience
The effect of depressing glial function in rat brain in situ on ion homeostasis, synaptic transmission, and neuron survival
C Largo, P Cuevas, GG Somjen, R Martin del Rio and O Herreras
Departamento de Investigacion, Hospital Ramon y Cajal, Madrid, Spain.
The supporting role of glial cells in maintaining neurons and in ion
homeostasis has been studied in situ by perfusing the gliotoxin
fluorocitrate (FC) through a microdialysis fiber in the CA1 area of
urethane-anesthetized rats. Extracellular direct current potential,
extracellular potassium concentration ([K+]o) and amino acid levels,
extracellular pH (pHo), and evoked field activity were studied. Histology
verified the swelling of glial cells after 4 hr of FC treatment. Massive
neuron damage was evident after 8 hr. FC dialysis caused the rapid decrease
of glutamine, pHo became progressively more acid, and [K+]o moderately
elevated. Orthodromic transmission was variably blocked within 30 min to 4
hr. After 4 hr, spreading depression (SD) waves that originated from the
neocortex invaded hippocampal CA1, [K+]o increased to higher levels, pHo
became very acid, and there were steep increases in taurine, glutamate, and
GABA levels. Simultaneously, the antidromic population spike (a-PS) became
depressed and eventually disappeared. When a shorter dialysis probe that
spared cortex was used to sample CA1, no SD was seen, a-PS was not
abolished, and ion homeostasis was altered less markedly. Repeated SD
provoked in hippocampus in the absence of FC caused only mild depression of
a-PS. Dialysis of high-K+ solution in healthy neocortex or hippocampus
caused only slight elevation of [K+]o at distances of 200-400 microns 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 tuning of [K+]o and particularly for the recovery of pathologically
elevated [K+]o; and (4) glia are required for the regulation of pHo. The
similarities between glial poisoning by FC and the reported changes in the
penumbra of ischemic infarcts suggest that the extension of neuron loss
into the penumbral region might depend on failure of glial protection.
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