IMR Press / JIN / Volume 23 / Issue 1 / DOI: 10.31083/j.jin2301024
Open Access Original Research
Cortical Tonic Inhibition Gates the Expression of Spike-and-Wave Discharges Associated with Absence Epilepsy
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1 Neuroscience Training Program, University of Wisconsin, Madison, WI 53705, USA
2 Department of Neuroscience, University of Wisconsin, Madison, WI 53705, USA
3 Department of Psychiatry, University of Wisconsin, Madison, WI 53719, USA
4 Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia
*Correspondence: (Kile P. Mangan); (Mathew V. Jones)
J. Integr. Neurosci. 2024, 23(1), 24;
Submitted: 1 May 2023 | Revised: 27 September 2023 | Accepted: 26 October 2023 | Published: 22 January 2024
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Epilepsy)
Copyright: © 2024 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Objective: Absence seizures result from aberrant thalamocortical processing that confers synchronous, bilateral spike-and-wave discharges (SWDs) and behavioral arrest. Previous work has demonstrated that SWDs can result from enhanced thalamic tonic inhibition, consistent with the mechanism of first-line antiabsence drugs that target thalamic low-voltage-activated calcium channels. However, nearly half of patients with absence epilepsy are unresponsive to first-line medications. In this study we evaluated the role of cortical tonic inhibition and its manipulation on absence seizure expression. Methods: We used video-electroencephalogram (EEG) monitoring to show that mice with a γ-aminobutyric acid type A (GABAA) receptor mutation (γ2R43Q) display absence seizures. Voltage-clamp recordings in brain slices from wild type and γ2R43Q mice were used to evaluate the amount of tonic inhibition and its selective pharmacological modulation. Finally, we determined whether modulating tonic inhibition controls seizure expression. Results: γ2R43Q mice completely lack tonic inhibition in principal neurons of both layer 2/3 cortex and ventrobasal thalamus. Blocking cortical tonic inhibition in wild type mice is sufficient to elicit SWDs. Tonic inhibition in slices from γ2R43Q mice could be rescued in a dose-dependent fashion by the synthetic neurosteroid ganaxolone. Low-dose ganaxolone suppressed seizures in γ2R43Q mice. Conclusions: Our data suggest that reduced cortical tonic inhibition promotes absence seizures and that normal function can be restored via selective pharmacological rescue. These results, together with previous findings, suggest that deviations of tonic inhibition either above or below an optimal set point can contribute to absence epilepsy. Returning the thalamocortical system to this set point may provide a novel treatment for refractory absence epilepsy.

absence epilepsy
tonic inhibition

(1) An absence-associated GABAA-receptor mutation (γ2R43Q) abolishes GABA-associated inhibitory tonic current in cortical layer 2/3 pyramidal and thalamic relay neurons.

(2) Cortical tonic inhibition is a regulating gate for absence seizure expression in γ2R43Q mice, and normal function can be rescued via selective pharmacology.

(3) A synthetic neurosteroid (ganaxolone) recovers the GABA-associated inhibitory tonic current that is deficient in γ2R43Q mice.

(4) SWD-activity in γ2R43Q mice is reduced following low-dose treatment with a synthetic neurosteroid (ganaxolone).

(5) An absence (RRL6) mouse model is produced by selectively blocking GABAergic tonic inhibition mediated by α5 subunit-containing receptors, putatively in cortical neurons.

(6) An optimal level of tonic inhibition is necessary for normal function, with deviation either above or below resulting in SWDs and absence seizures.

Epilepsy Foundation
Fig. 1.
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