Seljeset, Sandra;
Liebowitz, Seth;
Bright, Damian P;
Smart, Trevor G;
(2023)
Pre- and postsynaptic modulation of hippocampal inhibitory synaptic transmission by pregnenolone sulphate.
Neuropharmacology
, 233
, Article 109530. 10.1016/j.neuropharm.2023.109530.
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Abstract
Neurosteroids are important endogenous modulators of GABAA receptor-mediated neurotransmission within the CNS and play a vital role in maintaining normal healthy brain function. Research has mainly focussed on neurosteroids such as allopregnanolone and tetrahydro-deoxycorticosterone (THDOC) which are allosteric potentiators of GABAA receptors, whilst the sulphated steroids, including pregnenolone sulphate (PS), which inhibit GABAA receptor function, have been relatively neglected. Importantly, a full description of PS effects on inhibitory synaptic transmission, at concentrations that are expected to inhibit postsynaptic GABAA receptors, is lacking. Here, we address this deficit by recording inhibitory postsynaptic currents (IPSCs) from rat hippocampal neurons both in culture and in acute brain slices and explore the impact of PS at micromolar concentrations. We reveal that PS inhibits postsynaptic GABAA receptors, evident from reductions in IPSC amplitude and decay time. Concurrently, PS also causes an increase in synaptic GABA release which we discover is due to the activation of presynaptic TRPM3 receptors located close to presynaptic GABA release sites. Pharmacological blockade of TRPM3 receptors uncovers a PS-evoked reduction in IPSC frequency. This second presynaptic effect is caused by PS activation of inwardly-rectifying Kir2.3 channels on interneurons, which act to depress synaptic GABA release. Overall, we provide a comprehensive characterisation of pre- and postsynaptic modulation by PS of inhibitory synaptic transmission onto hippocampal neurons which elucidates the diverse mechanisms by which this understudied neurosteroid can modulate brain function.
| Type: | Article |
|---|---|
| Title: | Pre- and postsynaptic modulation of hippocampal inhibitory synaptic transmission by pregnenolone sulphate |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.neuropharm.2023.109530 |
| Publisher version: | https://doi.org/10.1016/j.neuropharm.2023.109530 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | GABAA receptors, Pregnenolone sulphate, Synaptic inhibition, TRPM3 receptors, Kir2.3 channels, GABA release |
| 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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10168199 |
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