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Volume 16, Number 13,
Issue of July 1, 1996
pp. 4283-4292
Copyright ©1996 Society for Neuroscience
Excitatory Actions of GABA after Neuronal Trauma
Received Jan. 31, 1996; revised April 2, 1996; accepted April 5, 1996.
Anthony N. van den Pol1, 2,
Karl Obrietan2, and
Gong Chen1
1 Section of Neurosurgery, Yale University School of
Medicine, New Haven, Connecticut 06520, and 2 Department of
Biological Sciences, Stanford University, Stanford, California
94305
GABA is the dominant inhibitory neurotransmitter in the CNS.
By opening Cl channels, GABA generally
hyperpolarizes the membrane potential, decreases neuronal activity, and
reduces intracellular Ca2+ of mature neurons. In
the present experiment, we show that after neuronal trauma, GABA, both
synaptically released and exogenously applied, exerted a novel and
opposite effect, depolarizing neurons and increasing intracellular
Ca2+. Different types of trauma that were
effective included neurite transection, replating, osmotic imbalance,
and excess heat. The depolarizing actions of GABA after trauma
increased Ca2+ levels up to fourfold in some
neurons, occurred in more than half of the severely injured neurons,
and was long lasting (>1 week). The mechanism for the reversed action
of GABA appears to be a depolarized Cl reversal
potential that results in outward rather than inward movement of
Cl, as revealed by gramicidin-perforated
whole-cell patch-clamp recording. The consequent depolarization and
resultant activation of the nimodipine sensitive L- and
conotoxin-sensitive N-type voltage-activated Ca2+
channel allows extracellular Ca2+ to enter the
neuron. The long-lasting capacity to raise Ca2+
may give GABA a greater role during recovery from trauma in modulating
gene expression, and directing and enhancing outgrowth of regenerating
neurites. On the negative side, by its depolarizing actions, GABA could
increase neuronal damage by raising cytosolic
Ca2+ levels in injured cells. Furthermore, the
excitatory actions of GABA after neuronal injury may contribute to
maladaptive signal transmission in affected GABAergic brain
circuits.
Key words:
calcium;
chloride;
injury;
GABA;
hypothalamus;
glutamate;
digital imaging
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