Endogenous neurosteroid actions at GABAA receptors during neuronal development
type: CreativeWork
description: GABAA receptors (GABAARs) mediate the majority of fast inhibition in the CNS and as such are crucial to neuronal function. Two distinct modes of GABAAR mediated inhibition exist: “phasic” involves the transient activation of postsynaptic GABAARs following presynaptic vesicular GABA release and “tonic” whereby high-affinity extrasynaptic GABAARs are persistently activated by ambient GABA. GABAARs exhibit a rich pharmacology and are the target for a number of clinically useful compounds including benzodiazepines, barbiturates and certain general anaesthetics. In addition, several naturally occurring steroids typified by the progesterone metabolite 5a-pregnan-3a-ol-20-one (5a3a) are potent positive allosteric modulators of GABAAR function - a property that endows these steroids with anxiolytic, sedative and anti-convulsant actions. Importantly, in addition to importing steroids from the periphery, the brain also harbours a steroidogenic capacity and can manufacture GABA-modulatory steroids, termed “neurosteroids”, from cholesterol. Although several studies have demonstrated neurosteroids to be implicated in a variety of physiological processes including neurodevelopment, important questions remain. In particular, are neurosteroids neurone selective? Do they discriminate between particular neuronal GABAARs subtypes? Under what conditions do endogenous neurosteroids influence neuronal function? And importantly, which cells synthesise neurosteroids in the central nervous system? Therefore, the principal aims of this study were: 1) to characterise the properties of GABAAR mediated inhibition in postnatal day (P) 17-24 neurones of the mouse ventrobasal (VB) nucleus of the thalamus – neurones which have a well defined GABAAR expression profile and which exhibit both synaptic and tonic GABAAR mediated inhibition. 2) To investigate the effects of 5a3a on synaptic and tonic GABAAR mediated inhibition in VB neurones. 3) To investigate whether there is a role for endogenous neuro…
abstract: GABAA receptors (GABAARs) mediate the majority of fast inhibition in the CNS and as such are crucial to neuronal function. Two distinct modes of GABAAR mediated inhibition exist: “phasic” involves the transient activation of postsynaptic GABAARs following presynaptic vesicular GABA release and “tonic” whereby high-affinity extrasynaptic GABAARs are persistently activated by ambient GABA. GABAARs exhibit a rich pharmacology and are the target for a number of clinically useful compounds including benzodiazepines, barbiturates and certain general anaesthetics. In addition, several naturally occurring steroids typified by the progesterone metabolite 5a-pregnan-3a-ol-20-one (5a3a) are potent positive allosteric modulators of GABAAR function - a property that endows these steroids with anxiolytic, sedative and anti-convulsant actions. Importantly, in addition to importing steroids from the periphery, the brain also harbours a steroidogenic capacity and can manufacture GABA-modulatory steroids, termed “neurosteroids”, from cholesterol. Although several studies have demonstrated neurosteroids to be implicated in a variety of physiological processes including neurodevelopment, important questions remain. In particular, are neurosteroids neurone selective? Do they discriminate between particular neuronal GABAARs subtypes? Under what conditions do endogenous neurosteroids influence neuronal function? And importantly, which cells synthesise neurosteroids in the central nervous system? Therefore, the principal aims of this study were: 1) to characterise the properties of GABAAR mediated inhibition in postnatal day (P) 17-24 neurones of the mouse ventrobasal (VB) nucleus of the thalamus – neurones which have a well defined GABAAR expression profile and which exhibit both synaptic and tonic GABAAR mediated inhibition. 2) To investigate the effects of 5a3a on synaptic and tonic GABAAR mediated inhibition in VB neurones. 3) To investigate whether there is a role for endogenous neuro…
author: Brown, Adam R.
language: eng
keywords: GABAA, Neurosteroids, Development
date published: 2011
date modified: 2026-07-24T02:07:31Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee