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Fast synaptic inhibition determines neuronal response properties in the mammalian brain and is mediated by chloride-permeable ionotropic GABA-A receptors (GABAARs). Despite their fundamental role, it is still not known how GABAARs signal in the intact brain. Here, we use in vivo gramicidin recordings to investigate synaptic GABAAR signaling in mouse cortical pyramidal neurons under conditions that preserve native transmembrane chloride gradients. In anesthetized cortex, synaptic GABAARs exert classic hyperpolarizing effects. In contrast, GABAAR-mediated synaptic signaling in awake cortex is found to be predominantly shunting. This is due to more depolarized GABAAR equilibrium potentials (EGABAAR), which are shown to result from the high levels of synaptic activity that characterize awake cortical networks. Synaptic EGABAAR observed in awake cortex facilitates the desynchronizing effects of inhibitory inputs upon local networks, which increases the flexibility of spiking responses to external inputs. Our findings therefore suggest that GABAAR signaling adapts to optimize cortical functions.

Original publication

DOI

10.1016/j.neuron.2023.08.005

Type

Journal article

Journal

Neuron

Publication Date

11/2023

Volume

111

Pages

3531 - 3540.e6

Addresses

Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK; Oxford Epilepsy Research Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.

Keywords

Pyramidal Cells, Neurons, Animals, Mammals, Mice, Chlorides, gamma-Aminobutyric Acid, Receptors, GABA-A