Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl- ions based on the neuronal Cl- driving force. Established theories regarding the determinants of Cl- driving force have recently been questioned. Here we present biophysical models of Cl- homeostasis using the pump-leak model. Using numerical and novel analytic solutions, we demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl- driving force. Our models, together with experimental validation, show that while impermeant anions can contribute to setting [Cl-]i in neurons, they have a negligible effect on the driving force for Cl- locally and cell-wide. In contrast, we demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signalling in neurons. Our findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.
- Kira Michaela Düsterwald
- Richard Joseph Burman
- Christopher Brian Currin
- Joseph Valentino Raimondo
- Joseph Valentino Raimondo
- Colin J Akerman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: No experiments were performed on animals prior to humane killing using cervical dislocation at P7, every effort was made to minimise stress prior to killing. The use of rats in the UK (furosemide experiment) were in accordance with regulations from the United Kingdom Home Office Animals (Scientific Procedures) Act. Use of mice (electroporation experiment) at the University of Cape Town was in accordance with South African national guidelines (South African National Standard: The care and use of animals for scientific purposes, 2008) and was approved by the University of Cape Town Animal Ethics Committee protocol no 014/035.
- Kenton Jon Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
© 2018, Düsterwald et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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