Journal of Neuroscience, Vol 15, 699-708, Copyright © 1995 by Society for Neuroscience
Endogenous GABA attenuates CNS white matter dysfunction following anoxia
R Fern, SG Waxman and BR Ransom
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510.
We studied the effects of GABA on anoxia-induced injury in CNS white matter
using optic nerves exposed to 60 min of anoxia. Injury was assessed by
recording pre- and postanoxic compound action potentials (CAPs). GABA (1
microM) significantly increased postanoxic CAP recovery when applied 60 min
prior to anoxia. This effect was bicuculline (100 microM) insensitive,
mimicked by baclofen (1 microM), blocked by GABA-B antagonists, and not
mimicked by selective GABA-A agonists. GABA therefore acted at GABA-B
receptors. High concentrations of GABA and baclofen did not influence
recovery, possibly indicating GABA-B receptor desensitization at high
agonist concentrations. Pertussis toxin (PTX) treatment reduced postanoxic
CAP recovery in the presence of 1 microM GABA to control levels, indicating
the recruitment of a G- protein-linked intracellular pathway. Protein
kinase C (PKC) activation with 12-myristate 13-acetate (PMA) mimicked the
effects of GABA. Inhibition of PKC with
1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7) or
staurosporine reduced postanoxic recovery in the presence of GABA to lower
levels than under control conditions, confirming the involvement of PKC in
the protective effect of GABA and indicating that this GABA-B
receptor/G-protein/PKC protective pathway might be active under control
conditions. This was confirmed by the observation that GABA-B receptor
blockade, in the absence of exogenous GABA, significantly reduced
postanoxia recovery. Thus, activation of the protective mechanism under
control conditions is due to endogenous GABA release. Increasing the level
of endogenous extracellular GABA by blocking GABA uptake with 1 mM
nipecotic acid also protected against anoxia. We propose a model where
release of GABA in white matter helps to limit nerve fiber injury during
anoxia via recruitment of a G- protein/PKC pathway with subsequent
phosphorylation of an unknown target protein.
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