γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter released at GABAergic synapses, mediating fast-acting phasic inhibition. Emerging lines of evidence unequivocally indicate that a small amount of extracellular GABA — GABA tone — exists in the brain and induces a tonic GABA current that controls neuronal activity on a slow timescale relative to that of phasic inhibition. Surprisingly, studies indicate that glial cells that synthesize GABA, such as astrocytes, release GABA through non-vesicular mechanisms, such as channel-mediated release, and thereby act as the source of GABA tone in the brain. In this Review, we first provide an overview of major advances in our understanding of the cell-specific molecular and cellular mechanisms of GABA synthesis, release and clearance that regulate GABA tone in various brain regions. We next examine the diverse ways in which the tonic GABA current regulates synaptic transmission and synaptic plasticity through extrasynaptic GABAA-receptor-mediated mechanisms. Last, we discuss the physiological mechanisms through which tonic inhibition modulates cognitive function on a slow timescale. In this Review, we emphasize that the cognitive functions of tonic GABA current extend beyond mere inhibition, laying a foundation for future research on the physiological and pathophysiological roles of GABA tone regulation in normal and abnormal psychiatric conditions.
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This study was supported by the Center for Cognition and Sociality (grant IBS-R001-D2 to C.J.L.) and a Young Scientist Fellowship (grant IBS-R001-Y1 to W.K.) from the Institute for Basic Science, South Korea, by the National Research Foundation (grant NRF-2021R1A2C3007164 and grant NRF-2022M3E5E8016325 to E.C. and grant NRF-2021R1C1C2007673 to H.K.) funded by the Ministry of ICT and Science (MSIT) of the Korean government, and by the Samsung Science and Technology Foundation (grant SSTF-BA2201-12 to E.C.).
The authors declare no competing interests.
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Koh, W., Kwak, H., Cheong, E. et al. GABA tone regulation and its cognitive functions in the brain. Nat. Rev. Neurosci. 24, 523–539 (2023). https://doi.org/10.1038/s41583-023-00724-7