Volume-Transmitted GABA Waves Drive Epileptiform Rhythms in the Hippocampal Network

Abstract

Synchronised rhythmic activity of the brain is thought to arise from neuronal network behaviours that arise from synaptic signalling between individual cells. This notion has been a basis to explain periodic epileptiform discharges that are driven by interneuronal networks. However, interneuronal spiking not only engages cell-cell GABAergic transmission but also controls the extracellular GABA concentration ([GABA] e ) and thus tonic GABA A receptor conductance ( G tonic ). Furthermore, the firing activity of interneuron populations shows a bell-shaped dependence on G tonic , suggesting an innate susceptibility to self-sustained oscillations. Here, we employ a patch-clamp GABA 'sniffer' and fast two-photon excitation imaging of a GABA sensor to show that periodic epileptiform discharges are preceded by a region-wide, rising wave of extracellular GABA. Neural network simulations based on such observations reveal that it is the volume-transmitted, extrasynaptic actions of GABA targeting multiple off-target cells that drives synchronised interneuronal spiking prompting periodic epileptiform bursts. We validate this hypothesis using simultaneous patch-clamp recordings from multiple nerve cells and selective optogenetic stimulation of fast-spiking interneurons. Our findings thus unveil to a key role of volume-transmitted GABA actions in enabling and pacing regenerative rhythmic activity in brain networks.