Thalamocortical Tonic Inhibition, Absence Epilepsy and Sleep
Absence epilepsy is characterized by EEG spike-and-wave discharges (SWDs) and behavioral arrests.
Previous studies in several rodent models proposed that enhanced GABAergic thalamic tonic inhibition is “necessary and sufficient” to cause typical absence epilepsy. In contrast, here we show that knock-in mice expressing a human absence epilepsy mutation in the GABA-A receptor (?2R43Q) have typical absence seizures but have a complete loss, rather than enhancement, of tonic inhibition in principal cells of both thalamus and cortex. Furthermore, pharmacological blockade of tonic inhibition in wild type mice is sufficient to provoke SWDs, whereas pharmacological rescue of tonic inhibition in mutant mice suppresses SWDs by ~60%.
Like many humans with various epilepsies, ?2R43Q knock-in mice also have disrupted sleep cycles, with SWDs occurring preferentially within minutes after abrupt transitions from NREM to Wake stages. This sleep/seizure linkage appears to be reduced by rescue of tonic inhibition. Together with previous results, these data suggest that an optimal level of GABAergic tonic inhibition throughout the thalamocortical circuit is required for normal function and that deviation from this optimum in either direction results in pathological thalamocortical function including absence seizures and sleep disruptions. Pharmacological rescue of tonic inhibition is thus a potential treatment for certain subtypes of absence epilepsy and associated sleep disruption.