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|Title:||GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons.|
|Authors:||Bryson, Alexander;Hatch, Robert John;Zandt, Bas-Jan;Rossert, Christian;Berkovic, Samuel F;Reid, Christopher A;Grayden, David B;Hill, Sean L;Petrou, Steven|
|Affiliation:||Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia|
Department of Biomedical Engineering, University of Melbourne, Melbourne, VIC 3010, Australia
Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia
Blue Brain Project, École Polytechnique Fédérale de Lausanne, 1202 Geneva, Switzerland
|Citation:||Proceedings of the National Academy of Sciences of the United States of America 2020; online first: 23 January|
|Abstract:||The binding of GABA (γ-aminobutyric acid) to extrasynaptic GABAA receptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes according to variation in chloride gradient. Here, using biophysically detailed neuron models, we predict that tonic inhibition can differentially modulate the excitability of neuron subtypes according to variation in electrophysiological properties. Surprisingly, tonic inhibition increased the responsiveness (or gain) in models with features typical for somatostatin interneurons but decreased gain in models with features typical for parvalbumin interneurons. Patch-clamp recordings from cortical interneurons supported these predictions, and further in silico analysis was then performed to seek a putative mechanism underlying gain modulation. We found that gain modulation in models was dependent upon the magnitude of tonic current generated at depolarized membrane potential-a property associated with outward rectifying GABAA receptors. Furthermore, tonic inhibition produced two biophysical changes in models of relevance to neuronal excitability: 1) enhanced action potential repolarization via increased current flow into the dendritic compartment, and 2) reduced activation of voltage-dependent potassium channels. Finally, we show theoretically that reduced potassium channel activation selectively increases gain in models possessing action potential dynamics typical for somatostatin interneurons. Potassium channels in parvalbumin-type models deactivate rapidly and are unavailable for further modulation. These findings show that GABA can differentially modulate interneuron excitability and suggest a mechanism through which this occurs in silico via differences of intrinsic electrophysiological properties.|
|Appears in Collections:||Journal articles|
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