Interactions between membrane resistance, GABA-A receptor properties, bicarbonate dynamics and Cl−-transport shape activity-dependent changes of intracellular Cl− concentration

Abstract

The effects of ionotropic γ-aminobutyric acid receptor (GABA-A, GABAA ) activation depends critically on the Cl−-gradient across neuronal membranes. Previous studies demonstrated that the intracellular Cl−-concentration ([Cl− ]i ) is not stable but shows a considerable amount of activity-dependent plasticity. To characterize how membrane properties and different molecules that are directly or indirectly involved in GABAergic synaptic transmission affect GABA-induced [Cl− ]i changes, we performed compartmental modeling in the NEURON environment. These simulations demonstrate that GABA-induced [Cl− ]i changes decrease at higher membrane resistance, revealing a sigmoidal dependency between both parameters. Increase in GABAergic conductivity enhances [Cl− ]i with a logarithmic dependency, while increasing the decay time of GABAA receptors leads to a nearly linear enhancement of the [Cl− ]i changes. Implementing physiological levels of HCO3−-conductivity to GABAA receptors enhances the [Cl− ]i changes over a wide range of [Cl− ]i, but this effect depends on the stability of the HCO3− gradient and the intracellular pH. Finally, these simulations show that pure diffusional Cl−-elimination from dendrites is slow and that a high activity of Cl−-transport is required to improve the spatiotemporal restriction of GABA-induced [Cl− ]i changes. In summary, these simulations revealed a complex interplay between several key factors that influence GABA-induced [Cl]i changes. The results suggest that some of these factors, including high resting [Cl− ]i, high input resistance, slow decay time of GABAA receptors and dynamic HCO3− gradient, are specifically adapted in early postnatal neurons to facilitate limited activity-dependent [Cl− ]i decreases.