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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1249-1264.e7
JournalCurrent Biology
Issue number7
Early online date10 Apr 2023
Publication statusPublished - 10 Apr 2023


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


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