Magloire, Vincent;
Savtchenko, Leonid P;
Jensen, Thomas P;
Sylantyev, Sergyi;
Kopach, Olga;
Cole, Nicholas;
Tyurikova, Olga;
... Rusakov, Dmitri A; + view all
(2023)
Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network.
Current Biology
10.1016/j.cub.2023.02.051.
(In press).
Preview |
PDF
1-s2.0-S0960982223001914-main.pdf - Published Version Download (12MB) | Preview |
Abstract
Mechanisms that entrain and pace rhythmic epileptiform discharges remain debated. Traditionally, the quest to understand them has focused on interneuronal networks driven by synaptic GABAergic connections. However, synchronized interneuronal discharges could also trigger the transient elevations of extracellular GABA across the tissue volume, thus raising tonic conductance (Gtonic) of synaptic and extrasynaptic GABA receptors in multiple cells. Here, we monitor extracellular GABA in hippocampal slices using patch-clamp GABA "sniffer" and a novel optical GABA sensor, showing that periodic epileptiform discharges are preceded by transient, region-wide waves of extracellular GABA. Neural network simulations that incorporate volume-transmitted GABA signals point to a cycle of GABA-driven network inhibition and disinhibition underpinning this relationship. We test and validate this hypothesis using simultaneous patch-clamp recordings from multiple neurons and selective optogenetic stimulation of fast-spiking interneurons. Critically, reducing GABA uptake in order to decelerate extracellular GABA fluctuations-without affecting synaptic GABAergic transmission or resting GABA levels-slows down rhythmic activity. Our findings thus unveil a key role of extrasynaptic, volume-transmitted GABA in pacing regenerative rhythmic activity in brain networks.
| Type: | Article |
|---|---|
| Title: | Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.cub.2023.02.051 |
| Publisher version: | https://doi.org/10.1016/j.cub.2023.02.051 |
| Language: | English |
| Additional information: | ©2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | GABA uptake, GAT-1, brain rhythms, epilepsy, extracellular GABA, iGABASnFR2, spiking neural networks, tonic GABA conductance, volume transmission |
| 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 Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10166979 |
Archive Staff Only
 |
View Item |
