Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network

Vincent Magloire; Leonid P. Savtchenko; Thomas P. Jensen; Sergyi Sylantyev; Olga Kopach; Nicholas Cole; Olga Tyurikova; Dimitri M. Kullmann; Matthew C. Walker; Jonathan S. Marvin; Loren L. Looger; Jeremy P. Hasseman; Ilya Kolb; Ivan Pavlov; Dmitri A. Rusakov

doi:10.1016/j.cub.2023.02.051

Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network

Vincent Magloire^* (Corresponding Author), Leonid P. Savtchenko^* (Corresponding Author), Thomas P. Jensen, Sergyi Sylantyev, Olga Kopach, Nicholas Cole, Olga Tyurikova, Dimitri M. Kullmann, Matthew C. Walker, Jonathan S. Marvin, Loren L. Looger, Jeremy P. Hasseman, Ilya Kolb, Ivan Pavlov, Dmitri A. Rusakov^* (Corresponding Author)

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

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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 (G_tonic) 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.

Original language	English
Pages (from-to)	1249-1264.e7
Journal	Current Biology
Volume	33
Issue number	7
Early online date	10 Apr 2023
DOIs	https://doi.org/10.1016/j.cub.2023.02.051
Publication status	Published - 10 Apr 2023

Bibliographical note

Funding Information:
This work was supported by Wellcome Principal Fellowship (212251/Z/18/Z and 212285/Z/18/Z), Wellcome Collaborative Award (UNS120639 - 223131/Z/21/Z), Epilepsy Research UK (F1901), MRC (MR/W019752/1, MR/V013556/1, and MR/V034758/1), NC3Rs (NC/X001067/1), and ERC Advanced Grant (323113). Optimization and parallelization of ARACHNE algorithms for extended neural network simulations was provided by AMC Bridge (Waltham, MA) and web security by Cyber Curio (Berkhamsted, UK). L.P.S. and D.A.R. narrated the study. I.P. and V.M. designed and carried out electrophysiological and optogenetic studies. N.C. O.K. and T.P.J. designed, carried out, and analyzed iGABASnFR2 imaging experiments. S.S. carried out sniffer-patch experiments. O.T. carried out control-probing K+ imaging tests. L.P.S. designed and carried out network modeling studies and data analyses. J.S.M. L.L.L. J.P.H. and I.K. supplied optical GABA sensors and related protocols. The development of iGABASnFR2 was conducted under the aegis of the HHMI Janelia GENIE Project at Janelia Research Campus. D.M.K. and M.C.W. designed optogenetic experiments. D.A.R. designed selected experiments and simulations, carried out selected analyses, and wrote the manuscript draft, with contributions from V.M. L.P.S. and all other authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.

Publisher Copyright:
© 2023 The Author(s)

Data Availability Statement

•
Data reported in this paper will be shared by the lead contact upon request.

•
The original code for network simulation is deposited at GitHub and is publicly available as of the date of publication. Doi is specified in the key resources table.

•
Any additional information required to reanalyze the data reported in this paper is available from the lead upon request.

Keywords

brain rhythms
epilepsy
extracellular GABA
GABA uptake
GAT-1
iGABASnFR2
spiking neural networks
tonic GABA conductance
volume transmission

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Magloire_etal_CB_Volume-transmitted_GABA_waves_VOR
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Cite this

Magloire, V., Savtchenko, L. P., Jensen, T. P., Sylantyev, S., Kopach, O., Cole, N., Tyurikova, O., Kullmann, D. M., Walker, M. C., Marvin, J. S., Looger, L. L., Hasseman, J. P., Kolb, I., Pavlov, I., & Rusakov, D. A. (2023). Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network. Current Biology, 33(7), 1249-1264.e7. https://doi.org/10.1016/j.cub.2023.02.051

Magloire, V, Savtchenko, LP, Jensen, TP, Sylantyev, S, Kopach, O, Cole, N, Tyurikova, O, Kullmann, DM, Walker, MC, Marvin, JS, Looger, LL, Hasseman, JP, Kolb, I, Pavlov, I & Rusakov, DA 2023, 'Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network', Current Biology, vol. 33, no. 7, pp. 1249-1264.e7. https://doi.org/10.1016/j.cub.2023.02.051

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title = "Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network",

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.",

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author = "Vincent Magloire and Savtchenko, {Leonid P.} and Jensen, {Thomas P.} and Sergyi Sylantyev and Olga Kopach and Nicholas Cole and Olga Tyurikova and Kullmann, {Dimitri M.} and Walker, {Matthew C.} and Marvin, {Jonathan S.} and Looger, {Loren L.} and Hasseman, {Jeremy P.} and Ilya Kolb and Ivan Pavlov and Rusakov, {Dmitri A.}",

note = "Funding Information: This work was supported by Wellcome Principal Fellowship (212251/Z/18/Z and 212285/Z/18/Z), Wellcome Collaborative Award (UNS120639 - 223131/Z/21/Z), Epilepsy Research UK (F1901), MRC (MR/W019752/1, MR/V013556/1, and MR/V034758/1), NC3Rs (NC/X001067/1), and ERC Advanced Grant (323113). Optimization and parallelization of ARACHNE algorithms for extended neural network simulations was provided by AMC Bridge (Waltham, MA) and web security by Cyber Curio (Berkhamsted, UK). L.P.S. and D.A.R. narrated the study. I.P. and V.M. designed and carried out electrophysiological and optogenetic studies. N.C. O.K. and T.P.J. designed, carried out, and analyzed iGABASnFR2 imaging experiments. S.S. carried out sniffer-patch experiments. O.T. carried out control-probing K+ imaging tests. L.P.S. designed and carried out network modeling studies and data analyses. J.S.M. L.L.L. J.P.H. and I.K. supplied optical GABA sensors and related protocols. The development of iGABASnFR2 was conducted under the aegis of the HHMI Janelia GENIE Project at Janelia Research Campus. D.M.K. and M.C.W. designed optogenetic experiments. D.A.R. designed selected experiments and simulations, carried out selected analyses, and wrote the manuscript draft, with contributions from V.M. L.P.S. and all other authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

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AU - Savtchenko, Leonid P.

AU - Jensen, Thomas P.

AU - Sylantyev, Sergyi

AU - Kopach, Olga

AU - Cole, Nicholas

AU - Tyurikova, Olga

AU - Kullmann, Dimitri M.

AU - Walker, Matthew C.

AU - Marvin, Jonathan S.

AU - Looger, Loren L.

AU - Hasseman, Jeremy P.

AU - Kolb, Ilya

AU - Pavlov, Ivan

AU - Rusakov, Dmitri A.

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N2 - 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.

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KW - epilepsy

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KW - GABA uptake

KW - GAT-1

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KW - volume transmission

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IS - 7

ER -

Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network

Abstract

Bibliographical note

Data Availability Statement

Keywords

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