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

• Published in: Current biology 2023-04, Vol.33 (7), p.1249-1264.e7
• Main Authors: Magloire, Vincent, Savtchenko, Leonid P., Jensen, Thomas P., Sylantyev, Sergyi, Kopach, Olga, Cole, Nicholas, Tyurikova, Olga, Kullmann, Dimitri M., Walker, Matthew C., Marvin, Jonathan S., Looger, Loren L., Hasseman, Jeremy P., Kolb, Ilya, Pavlov, Ivan, Rusakov, Dmitri A.
• Format: Article
• Language: English
• Subjects: brain rhythms; epilepsy; extracellular GABA; GABA uptake; gamma-Aminobutyric Acid; GAT-1; Hippocampus; iGABASnFR2; Interneurons - physiology; Life Sciences; Neurons; Neurons and Cognition; spiking neural networks; Synaptic Transmission - physiology; tonic GABA conductance; volume transmission
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2023.02.051

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. •GABA sniffer and optical sensor report [GABA]e rises before interictal events•Interneuronal network models relate rhythmicity to volume-transmitted GABA actions•Multi-cell recordings support the concept of periodical GABA-driven disinhibition•GABA transporters tune the rhythms of interictal events Magloire et al. show that periodic epileptiform discharges are preceded by transient waves of extracellular GABA, which appear critical for the timing of such brain network rhythms.