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Article

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

1
Institute of Physiology, University Medical Center Mainz, Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, Germany
2
ICAR3R - Interdisciplinary Centre for 3Rs in Animal Research, Faculty of Medicine, Justus-Liebig-University, Rudolf-Buchheim-Str. 6, 35392 Giessen, Germany
3
Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University, 60590 Frankfurt am Main, Germany
4
Frankfurt Institute for Advanced Studies, 60438 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1416; https://doi.org/10.3390/ijms20061416
Received: 13 February 2019 / Revised: 15 March 2019 / Accepted: 18 March 2019 / Published: 20 March 2019
(This article belongs to the Special Issue Rhine-Main Neuroscience Network: rmn^2-Oberwesel 2018)
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. View Full-Text
Keywords: development; hippocampus; CA3; Cl-homeostasis; giant depolarizing potentials; ionic plasticity; computational neuroscience; Na+-K+-Cl-Cotransporter, Isoform 1 (NKCC1); mouse development; hippocampus; CA3; Cl-homeostasis; giant depolarizing potentials; ionic plasticity; computational neuroscience; Na+-K+-Cl-Cotransporter, Isoform 1 (NKCC1); mouse
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MDPI and ACS Style

Lombardi, A.; Jedlicka, P.; Luhmann, H.J.; Kilb, W. 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, 20, 1416. https://doi.org/10.3390/ijms20061416

AMA Style

Lombardi A, Jedlicka P, Luhmann HJ, Kilb W. Interactions between Membrane Resistance, GABA-A Receptor Properties, Bicarbonate Dynamics and Cl-Transport Shape Activity-Dependent Changes of Intracellular Cl Concentration. International Journal of Molecular Sciences. 2019; 20(6):1416. https://doi.org/10.3390/ijms20061416

Chicago/Turabian Style

Lombardi, Aniello, Peter Jedlicka, Heiko J. Luhmann, and Werner Kilb. 2019. "Interactions between Membrane Resistance, GABA-A Receptor Properties, Bicarbonate Dynamics and Cl-Transport Shape Activity-Dependent Changes of Intracellular Cl Concentration" International Journal of Molecular Sciences 20, no. 6: 1416. https://doi.org/10.3390/ijms20061416

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