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

Int J Mol Sci. 2019 Mar 20;20(6):1416. doi: 10.3390/ijms20061416.

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.

Keywords: CA3; Cl−-homeostasis; Na+-K+-Cl−-Cotransporter, Isoform 1 (NKCC1); computational neuroscience; development; giant depolarizing potentials; hippocampus; ionic plasticity; mouse.

MeSH terms

  • Animals
  • Bicarbonates / metabolism*
  • Chlorides / metabolism*
  • Kinetics
  • Mice
  • Models, Theoretical
  • Neurons / drug effects
  • Neurons / metabolism
  • Receptors, GABA-A / metabolism*
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • Bicarbonates
  • Chlorides
  • Receptors, GABA-A
  • gamma-Aminobutyric Acid