Osmotic tension as a possible link between GABAA receptor activation and intracellular calcium elevation

Intracellular calcium concentration rises have been reported following activation of GABA(A) receptors in neonatal preparations and attributed to activation of voltage-dependent Ca2+ channels. However, we show that, in cerebellar interneurons, GABA(A) agonists induce a somatodendritic Ca2+ rise that persists at least until postnatal day 20 and is not mediated by depolarization-induced Ca2+ entry. A local Ca2+ elevation can likewise be elicited by repetitive stimulation of presynaptic GABAergic afferent fibers. We find that, following GABA(A) receptor activation, bicarbonate-induced Cl- entry leads to cell depolarization, Cl- accumulation, and osmotic tension. We propose that this tension induces the intracellular Ca2+ rise as part of a regulatory volume decrease reaction. This mechanism introduces an unexpected link between activation of GABA(A) receptors and intracellular Call elevation, which could contribute to activity-driven synaptic plasticity.