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Exploring the determinants of chloride homeostasis in neurons using biophysical models
Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl ions via activated GABAA and glycine receptors. As a result, changes to the neuronal driving force for Cl- are thought to play pivotal roles in many physiological and pathological brain processes. Established theo...
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| Format: | Thesis |
| Language: | English |
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Department of Human Biology
2019
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| _version_ | 1867613201693147136 |
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| access_status_str | Open Access |
| author | Düsterwald, Kira M |
| author2 | Raimondo, Joseph V |
| author_browse | Düsterwald, Kira M Raimondo, Joseph V |
| author_facet | Raimondo, Joseph V Düsterwald, Kira M |
| author_sort | Düsterwald, Kira M |
| collection | Thesis |
| description | Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl ions via activated GABAA and glycine receptors. As a result, changes to the neuronal driving force for Cl- are thought to play pivotal roles in many physiological and pathological brain processes. Established theories regarding the determinants of Cl- driving force have recently been questioned based on new experimental data. However, it is experimentally difficult to distinguish the respective contributions of the multiple, dynamically interacting mechanisms which may be important in Cl- homeostasis. Here I present biophysical models of Cl- homeostasis using the pump-leak formulation. By means of numerical and novel analytic solutions, I 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. Importantly, I 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, I demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signalling in neurons. This prediction is supported by a meta-analysis of multiple experimental studies, which demonstrates a strong correlation between the expression of the cationchloride cotransporter KCC2 and intracellular Cl concentration. My findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/29611 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:32:21.936Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2019 |
| publishDateRange | 2019 |
| publishDateSort | 2019 |
| publisher | Department of Human Biology |
| publisherStr | Department of Human Biology |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/29611 Exploring the determinants of chloride homeostasis in neurons using biophysical models Düsterwald, Kira M Raimondo, Joseph V Neuroscience Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl ions via activated GABAA and glycine receptors. As a result, changes to the neuronal driving force for Cl- are thought to play pivotal roles in many physiological and pathological brain processes. Established theories regarding the determinants of Cl- driving force have recently been questioned based on new experimental data. However, it is experimentally difficult to distinguish the respective contributions of the multiple, dynamically interacting mechanisms which may be important in Cl- homeostasis. Here I present biophysical models of Cl- homeostasis using the pump-leak formulation. By means of numerical and novel analytic solutions, I 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. Importantly, I 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, I demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signalling in neurons. This prediction is supported by a meta-analysis of multiple experimental studies, which demonstrates a strong correlation between the expression of the cationchloride cotransporter KCC2 and intracellular Cl concentration. My findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons. 2019-02-18T11:01:02Z 2019-02-18T11:01:02Z 2018 2019-02-18T08:25:27Z Master Thesis Masters MSc http://hdl.handle.net/11427/29611 eng application/pdf Department of Human Biology Faculty of Health Sciences University of Cape Town |
| spellingShingle | Neuroscience Düsterwald, Kira M Exploring the determinants of chloride homeostasis in neurons using biophysical models |
| thesis_degree_str | Master's |
| title | Exploring the determinants of chloride homeostasis in neurons using biophysical models |
| title_full | Exploring the determinants of chloride homeostasis in neurons using biophysical models |
| title_fullStr | Exploring the determinants of chloride homeostasis in neurons using biophysical models |
| title_full_unstemmed | Exploring the determinants of chloride homeostasis in neurons using biophysical models |
| title_short | Exploring the determinants of chloride homeostasis in neurons using biophysical models |
| title_sort | exploring the determinants of chloride homeostasis in neurons using biophysical models |
| topic | Neuroscience |
| url | http://hdl.handle.net/11427/29611 |
| work_keys_str_mv | AT dusterwaldkiram exploringthedeterminantsofchloridehomeostasisinneuronsusingbiophysicalmodels |