Synaptic activation of GABA(A) receptors induces neuronal uptake of Ca2+ in adult rat hippocampal slices

Synaptically evoked transmembrane movements of Ca2+ in the adult CNS have a lmost exclusively been attributed to activation of glutamate receptor chann els and the consequent triggering of voltage-gated calcium channels (VGCCs) . Using microelectrodes for measuring free extracellular Ca2+ ([Ca2+](o)) a nd extracellular space (ECS) volume, we show here for the first time that s ynaptic stimulation of gamma-aminobutyric acid-A (GABA,) receptors can resu lt in a decrease in [Ca2+](o) in adult rat hippocampal slices. High-frequen cy stimulation (100-200 Hz, 0.4-0.5 s) applied in stratum radiatum close (l ess than or equal to 0.5 mm) to the recording site induced a 0.1- to 0.3-mM transient fall in [Ca2+](o) from a baseline level of 1.6 mM. Concomitantly , a 30-40% decrease in the ECS volume was seen. Exposure of drug-naive slic es to the GABA, receptor antagonist picrotoxin (100 mu M) first attenuated and only thereafter augmented the Ca2+ shifts. Application of ionotropic gl utamate receptor antagonists resulted in a monotonic reduction of the Ca2response, but a large Ca2+ shift persisted (60-70% of the original), which was attenuated by a subsequent application of picrotoxin or bicuculline. In the absence of ionotropic glutamatergic transmission, pentobarbital sodium (100 mu M), an up-modulator of the GABA, receptor, strongly enhanced the a ctivity-evoked changes in [Ca2+](o). We suggest that the underlying mechani sm of GABA-induced Ca2+ transients is the activation of VGCCs by bicarbonat e-dependent GABA-mediated depolarizing postsynaptic potentials. Accordingly , stimulation-evoked Ca2+ shifts were inhibited by the membrane-permeant in hibitor of carbonic anhydrase, ethoxyzolamide (50 mu M) or in N-2-hydroxyet hylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered HCO3-free solution. Neuronal Ca2+ uptake caused by intense synaptic activation of GABA, recept ors may prove to be an important mechanism in the modulation of activity-de pendent neuronal plasticity, epileptogenesis, and cell survival in the adul t brain.