Synaptic activation of GABAA receptors induces neuronal uptake of Ca2+ in adult rat hippocampal slices |
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Authors: | Autere A M Lamsa K Kaila K Taira T |
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Institution: | Department of Biosciences, Division of Animal Physiology, University of Helsinki, FIN-00014 Helsinki, Finland. |
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Abstract: | 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 gamma-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-na?ve slices to the GABAA receptor antagonist picrotoxin (100 microM) 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 microM), 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 microM) 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. |
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