- Academic Editor
-
-
-
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
(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.