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 HCO(3)(−)-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 HCO(3)(−) 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 HCO(3)(−) gradient, are specifically adapted in early postnatal neurons to facilitate limited activity-dependent [Cl(−)](i) decreases.