Interactions between Membrane Resistance, GABA-A Receptor Properties, Bicarbonate Dynamics and Cl^--Transport Shape...

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.