The Journal of Neurophysiology Vol. 81 No. 2 February 1999, pp. 811-816
Copyright ©1999 by the American Physiological Society

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

Department of Biosciences, Division of Animal Physiology, University of Helsinki, FIN-00014 Helsinki, Finland

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 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 -aminobutyric acid-A (GABA_A) 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 GABA_A 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 GABA_A 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 GABA_A receptors may prove to be an important mechanism in the modulation of activity-dependent neuronal plasticity, epileptogenesis, and cell survival in the adult brain.

0022-3077/99 $5.00 Copyright © 1999 The American Physiological Society