Enhanced GABA release in cell-damaging conditions in the adult and developing mouse hippocampus

The release of [3H]GABA from hippocampal slices from adult (3-month-old) and developing (7-day-old) mice was studied in cell-damaging conditions in vitro using a superfusion system. Cell damage was induced by modified superfusion media, including hypoxia, hypoglycemia, ischemia, the presence of Free radicals and oxidative stress. The basal release of GABA from the immature and mature hippocampus was generally markedly increased in all cell-damaging conditions. In 7-day-old mice the release was enhanced most in the presence of free radicals. 1.0 mM NaCN and ischemia, whereas in the adults 1.0 mM NaCN provoked the largest release of GABA, followed by ischemia and free radical-containing media. Potassium stimulation (50 mM K+) was still able to potentiate the release in all cell-damaging conditions in both age groups. It was shown by superfusing the slices in Ca- and Na-free media that ischemia-induced GABA release was Ca-independent, occurring by a reversed operation of Na-dependent cell membrane carriers in both adult and developing hippocampus. Glutamate and its receptor agonists, N-methyl-D-aspartate (NMDA), kainate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), potentiated GABA release only in the immature hippocampus by a receptor-mediated mechanism. The enhancement by kainate and AMPA receptors also operated under ischemic conditions. The massive amount of GABA released simultaneously with excitatory amino acids in the mature and immature hippocampus may be an important protective mechanism against excitotoxicity, counteracting harmful effects that lead to neuronal death. The GABA release induced by activation of presynaptic glutamate receptors may contribute particularly to the maintenance of homeostasis in the hippocampus upon impending hyperexcitation.