Interactions between Membrane Resistance, GABA-A Receptor Properties, Bicarbonate Dynamics and Cl⁻-Transport Shape Activity-Dependent Changes of Intracellular Cl⁻ Concentration

The effects of ionotropic γ-aminobutyric acid receptor (GABA-A, GABA_A) 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 GABA_A receptors leads to a nearly linear enhancement of the [Cl⁻]_i changes. Implementing physiological levels of HCO₃⁻-conductivity to GABA_A 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 GABA_A receptors and dynamic HCO₃⁻ gradient, are specifically adapted in early postnatal neurons to facilitate limited activity-dependent [Cl⁻]_i decreases. View Full-Text