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) activation depends critically on the Cl-gradient across neuronal membranes. Previous studies demonstrated that the intracellular Cl-concentration ([Cl]) 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] changes, we performed compartmental modeling in the NEURON environment. These simulations demonstrate that GABA-induced [Cl] changes decrease at higher membrane resistance, revealing a sigmoidal dependency between both parameters. Increase in GABAergic conductivity enhances [Cl] with a logarithmic dependency, while increasing the decay time of GABA receptors leads to a nearly linear enhancement of the [Cl] changes. Implementing physiological levels of HCO₃-conductivity to GABA receptors enhances the [Cl] changes over a wide range of [Cl], 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] changes. In summary, these simulations revealed a complex interplay between several key factors that influence GABA-induced [Cl] changes. The results suggest that some of these factors, including high resting [Cl], high input resistance, slow decay time of GABA receptors and dynamic HCO₃ gradient, are specifically adapted in early postnatal neurons to facilitate limited activity-dependent [Cl] decreases.