Extrasynaptic GABA waves underlie epileptiform rhythms in the hippocampal network

The cellular and circuit mechanisms that trigger and maintain epileptiform discharges remain the subject of intense debate. We have earlier reported a bell-shape dependence of spiking activity of interneuronal populations on tonic GABAA receptor conductance (Gtonic), suggesting an innate mechanism to enable slow self-sustained network oscillations. In the brain, Gtonic is controlled by the slow changes of the extracellular GABA concentration ([GABA]e), which in turn depends on spiking activity of interneurons. Here, we employ outside-out patch-clamp recordings of GABAA receptor and fluorescence imaging of a GABA sensor to show that periodic epileptiform discharges are preceded by [GABA]e rises. Computer simulations of spiking interneuronal networks reveal that incorporating extrasynaptic waves of [GABA]e readily enables periodic occurrences of synchronised interneuronal spiking, which are in phase with rises in Gtonic and can trigger short bursts of principal cell spiking. Simultaneous recording from multiple neurons and selective optogenetic stimulation of parvalbumin-positive (PV+) interneurons confirmed the modelling predictions, consistent with a causal relationship between synchronisation of interneuronal activity, inhibitory synaptic input, Gtonic, and interictal events. Our findings suggest a key role of [GABA]e dynamics in enabling and pacing regenerative rhythmic activity of brain networks.