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Extracellular GABA waves regulate coincidence detection in excitatory circuits

By Sergiy Sylantyev, Leonid P Savtchenko, Nathanael O’Neill, Dmitri A. Rusakov

Posted 15 Jun 2020
bioRxiv DOI: 10.1101/2020.06.15.152652

Coincidence detection of excitatory inputs by principal neurons underpins the rules of signal integration and Hebbian plasticity in the brain. In the hippocampal circuitry, detection fidelity is thought to depend on the GABAergic synaptic input through a feed-forward inhibitory circuit also involving the hyperpolarization-activated Ih current. However, afferent connections often bypass feed-forward circuitry, suggesting that a different GABAergic mechanism might control coincidence detection in such cases. To test whether fluctuations in the extracellular GABA concentration [GABA] could play a regulatory role here, we use a GABA 'sniffer' patch in acute hippocampal slices of the rat and document strong dependence of [GABA] on network activity. We find that blocking GABAergic signalling strongly reduces the coincidence detection window of direct excitatory inputs to pyramidal cells whereas increasing [GABA] through GABA uptake blockade expands it. The underlying mechanism involves membrane-shunting tonic GABAA receptor current; it does not have to rely on Ih but depends strongly on the neuronal GABA transporter GAT-1. We use dendrite-soma dual patch-clamp recordings to show that the strong effect of membrane shunting on coincidence detection relies on nonlinear amplification of changes in the decay of dendritic synaptic currents when they reach the soma. Our results suggest that, by dynamically regulating extracellular GABA, brain network activity can optimise signal integration rules in local excitatory circuits. ### Competing Interest Statement The authors have declared no competing interest.

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