Glutamate Dependence of GABA Levels in Neurons of Hypoxic and Hypoglycemic Rat Hippocampal Slices

Hypoxia may increase GABA levels in neurons by ATP depletion-induced activation of glutamate decarboxylase and by inhibiting GABA transaminase. Hypoglycemia, which also depletes ATP, reduces neuronal levels of GABA and its precursor glutamate. We examined whether differences in glutamate levels may contribute to these altered GABA levels in hippocampal slices. GABA levels were highly correlated with endogenous glutamate levels during both hypoxia and hypoglycemia (R=0.93 for combined data). Hypoxia maximally increased GABA levels (146+/-6.3% of control, S.E.M.) when glutamate remained above 90% of control levels and ATP was at 30% of control levels. Hypoglycemia with similar ATP levels and glutamate levels at 40% of control decreased GABA levels to 55% of control. Effects of inhibitors of glutamate decarboxylase and GABA transaminase suggested that increased synthesis and decreased catabolism may both contribute to increased hypoxic GABA levels. Immunocytochemical studies suggested that hypoxia increased GABA concentrations primarily in neurons and their processes, but not in glial cells. Severe hypoxic ATP depletion increased the release of both GABA and glutamate. Hypoxia increased GABA levels in neurons, while hypoglycemia with a similar severity of ATP depletion decreased GABA levels. Much of the difference may be related to lower levels of precursor glutamate during hypoglycemia. The twofold higher levels of neuroprotective GABA available for release during hypoxia may contribute to differences in the pathophysiology of these metabolic insults.