Cortical Tonic Inhibition Gates the Expression of Spike-and-Wave Discharges Associated with Absence Epilepsy.

Autor:	Mangan KP; Neuroscience Training Program, University of Wisconsin, Madison, WI 53705, USA.; Department of Neuroscience, University of Wisconsin, Madison, WI 53705, USA., Nelson AB; Neuroscience Training Program, University of Wisconsin, Madison, WI 53705, USA.; Department of Psychiatry, University of Wisconsin, Madison, WI 53719, USA., Petrou S; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia., Cirelli C; Department of Psychiatry, University of Wisconsin, Madison, WI 53719, USA., Jones MV; Department of Neuroscience, University of Wisconsin, Madison, WI 53705, USA.
Jazyk:	angličtina
Zdroj:	Journal of integrative neuroscience [J Integr Neurosci] 2024 Jan 22; Vol. 23 (1), pp. 24.
DOI:	10.31083/j.jin2301024
Abstrakt:	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. Competing Interests: The authors disclose that KPM, MVJ, ABN, and CC are included on the United States patent US9629853B2 titled “Uses of Ganaxolone”. The authors declare no conflict of interest. (© 2024 The Author(s). Published by IMR Press.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu