Synaptic Activation of GABAA Receptors Induces Neuronal Uptake of Ca2+ in Adult Rat Hippocampal Slices

Synaptic activation of GABAA receptors induces neuronal uptake of Ca2+ in adult rat hippocampal slices. Synaptically evoked transmembrane movements of Ca2+ in the adult CNS have almost exclusively been attributed to activation of glutamate receptor channels and the consequent triggering of voltage-gated calcium channels (VGCCs). Using microelectrodes for measuring free extracellular Ca2+([Ca2+]o) and extracellular space (ECS) volume, we show here for the first time that synaptic stimulation of γ-aminobutyric acid-A (GABAA) receptors can result in a decrease in [Ca2+]o in adult rat hippocampal slices. High-frequency stimulation (100–200 Hz, 0.4–0.5 s) applied in stratum radiatum close (≤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-naı̈ve slices to the GABAA receptor antagonist picrotoxin (100 μM) first attenuated and only thereafter augmented the Ca2+ shifts. Application of ionotropic glutamate receptor antagonists resulted in a monotonic reduction of the Ca2+ response, 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 μM), an up-modulator of the GABAA receptor, strongly enhanced the activity-evoked changes in [Ca2+]o. We suggest that the underlying mechanism of GABA-induced Ca2+ transients is the activation of VGCCs by bicarbonate-dependent GABA-mediated depolarizing postsynaptic potentials. Accordingly, stimulation-evoked Ca2+ shifts were inhibited by the membrane-permeant inhibitor of carbonic anhydrase, ethoxyzolamide (50 μM) or in N-2-hydroxyethylpiperazine- N′-2-ethanesulfonic acid (HEPES)–buffered HCO3-free solution. Neuronal Ca2+ uptake caused by intense synaptic activation of GABAA receptors may prove to be an important mechanism in the modulation of activity-dependent neuronal plasticity, epileptogenesis, and cell survival in the adult brain.