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 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-naïve 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.
Department of Biosciences, Division of Animal Physiology, University of Helsinki, FIN-00014 Helsinki, Finland.
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D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D004558:Electric Stimulation; D005016:Ethoxzolamide / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D005731:Ganglionic Stimulants / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D009474:Neurons / Q000378:metabolism*; D010424:Pentobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
D002118:Calcium; D002257:Carbonic Anhydrase Inhibitors; D005016:Ethoxzolamide; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018757:GABA Modulators; D005731:Ganglionic Stimulants; D010424:Pentobarbital; D010852:Picrotoxin; D000644:Quaternary Ammonium Compounds; D011963:Receptors, GABA-A; C027917:tetramethylammonium