Spike-and-Wave Discharges Are Not Pathological Sleep Spindles, Network-Level Aspects of Age-Dependent Absence Seizure Development in Rats

Abstract

Spike-and-wave discharges (SWDs) of absence epilepsy are considered as pathologic alterations of sleep spindles; however, their network-level relationship has never been convincingly revealed. In order to observe the development and generalization of the thalamocortical SWDs and the concomitant alterations of sleep related oscillations, we performed local field potential (LFP) and single unit recordings in rats for three months during their maturation. We found that while SWDs and spindles look similar in young, they become different with maturation and shift to appear in different brain states. Thus, despite being generated by the same network, they are likely two distinct manifestations of the thalamocortical activity. We show that while spindles are already mainly global oscillations, SWDs appear mainly only focally in young. They become capable to generalize later with maturation, when the out-of-focus brain regions develop a decreased inhibitory/excitatory balance. These results suggest that a hyperexcitable focus is not sufficient alone to drive generalized absence seizures. Importantly, we also found the gradual age dependent disappearance of sleep spindles coinciding with the simultaneous gradual emergence of spike and waves, which both could be reversed by the proper dosing of ethosuximide (ETX). Based on these observations we conclude that the absence seizure development might be a multi-step process, which might involve the functional impairment of cortical interneurons and network-level changes that negatively affect sleep quality.

From Physiology to Pathology of Cortico-Thalamo-Cortical Oscillations: Astroglia as a Target for Further Research

“…Indeed, to some extent both sleep spindles and SWDs share some anatomical, cellular and molecular mechanisms (291) and they are functionally correlated (292,293). However, the identification of SWDs as pathological transitions from sleep spindles has been recently challenged (294)(295)(296), in favor of a predominant role of cortical slow (<1 Hz) oscillations alternating active (Up) and silent (Down) cortical activity and concomitantly occurring during NREM sleep (Figures 4C,D) (273,274,(297)(298)(299)(300)(301). SWDs largely arise in a specific critical vigilance window in correspondence with passive wakefulness, transitions to NREM slow-wave sleep as well as during transitions between internal substages of NREM sleep (stage I to III; N1: light sleep or passive wakefulness, N2: light slow-wave sleep and N3: deep slow-wave sleep, respectively) (Figure 4E).…”

The Molecular Genetic Interaction Between Circadian Rhythms and Susceptibility to Seizures and Epilepsy

“…The reticular nucleus of the thalamus controls both sleep spindles and epileptiform discharges (34), an anatomical correlation that is consistent with a functional role for sleep spindle mechanisms in seizures and epilepsy. Although animal models provide support for an association between sleep spindles and epilepsy (35), recent evidence indicates that spike-wave discharges are not pathological sleep spindles (36). Additional research is required to clarify possible mechanistic links between changes in sleep spindle characteristics and epileptogenesis.…”

Sleep Disturbances in Rats With Genetic Pre-disposition to Spike-Wave Epilepsy (WAG/Rij)

“…It is commonly acknowledged that SWDs result from aberrant functioning of thalamocortical neuronal networks [ (6,(16)(17)(18), see (19)]. As far as spike-wave epilepsy is directly linked to abnormal thalamocortical rhythmogenesis, it is considered a prototypical thalamocortical dysrhythmia (17,20).…”

“…As far as spike-wave epilepsy is directly linked to abnormal thalamocortical rhythmogenesis, it is considered a prototypical thalamocortical dysrhythmia (17,20). In the last several decades, many researchers have thoroughly studied thalamocortical circuit abnormalities underlying SWDs (6,(16)(17)(18)(21)(22)(23)(24). At the same time, thalamocortical neuronal circuitry is known to be involved in physiological slow-wave sleep oscillations, such as delta waves (22), that are critical for sleep homeostasis (25).…”