Liebowitz, Seth Harmon;
(2025)
Regulating the activity of GABAergic synapses with sulphated neurosteroids.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
γ-aminobutyric acid type A receptors (GABAARs) form the major class of inhibitory neurotransmitter receptors in the brain. Their activity can be potentiated or inhibited by naturally occurring brain neuroactive steroids that bind allosterically to the receptor. The inhibitory neurosteroids include a family of compounds known as sulphated neurosteroids (SNS). Unlike most other neurosteroids, these molecules are antagonists at GABAARs and also act to potentiate the activity of numerous other cation channels. SNS are implicated in a plethora of affective and neurodegenerative disorders and have been shown to exert a promnesic effect in the brain. Nevertheless, they have thus far had limited clinical application and their activity at GABAARs has not been completely characterized. Furthermore, for a regulatory molecule synthesized de novo in the CNS, little is known about its production, release, and the expression of their steroidogenic machinery. In this study we investigated the pharmacological profile of two naturally occurring SNS - dehydroepiandrosterone sulphate (DHEAS), which was revealed to be a potent antagonist at GABAARs; and we also demonstrate that pregnenolone sulphate (PS) governs a novel inhibitory synaptic plasticity phenomenon. This involves the retrograde release of PS and subsequent binding to presynaptic transient receptor potential (TRP) channels, causing an increase in GABA release and synaptic inhibition. Finally, imaging and immunofluorescence experiments revealed that the organic solute transporter subunit, OSTαβ, which may transport SNS, and the sulphotransferase enzyme SULT2B1 are enriched in the hippocampal and cortical regions. By using a modified PS analogue, we investigated the mechanism for PS transport in the hippocampus. Overall, this study provides new insight into the activity of SNS at the important GABAAR, and at inhibitory synapses.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Regulating the activity of GABAergic synapses with sulphated neurosteroids |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10205133 |
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