Authors:	Lombardi, Aniello Jedlicka, Peter Luhmann, Heiko Kilb, Werner
Title:	Interactions between membrane resistance, GABA-A receptor properties, bicarbonate dynamics and Cl<sup>−</sup> -transport shape activity-dependent changes of intracellular Cl<sup>−</sup> concentration
Online publication date:	8-Jul-2019
Year of first publication:	2019
Language:	english
Abstract:	The effects of ionotropic %26gamma;-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.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-167
URN:	urn:nbn:de:hebis:77-publ-591355
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	International journal of molecular sciences 20 6
Pages or article number:	Art. 1416
Publisher:	Molecular Diversity Preservation International
Publisher place:	Basel
Issue date:	2019
ISSN:	1422-0067
Publisher URL:	http://dx.doi.org/10.3390/ijms20061416
Publisher DOI:	10.3390/ijms20061416
Appears in collections:	JGU-Publikationen