Temporal and Potential Predictive Relationships between Sleep Spindle Density and Spike-and-Wave Discharges

Abstract

Spike-and-wave discharges (SWDs) and sleep spindles are characteristic electroencephalographic (EEG) hallmarks of absence seizures and non-rapid eye movement (NREM) sleep, respectively. They are commonly generated by the cortico-thalamo-cortical (CTC) network including the thalamic reticular nucleus (TRN). It has been reported that SWD development is accompanied by a decrease in sleep spindle density in absence seizure patients and animal models. However, whether the decrease in sleep spindle density precedes, coincides with, or follows, the SWD development remains unknown. To clarify this, we exploited Pvalb-tetracycline transactivator (tTA)::tetO-ArchT (PV-ArchT) double-transgenic mouse, which can induce an absence seizure phenotype in a time-controllable manner by expressing ArchT in PV neurons of the TRN. In these mice, EEG recordings demonstrated that a decrease in sleep spindle density occurred 1 week before the onset of typical SWDs, with the expression of ArchT. To confirm such temporal relationship observed in these genetic model mice, we used a gamma-butyrolactone (GBL) pharmacological model of SWDs. Prior to GBL administration, we administered caffeine to wild-type mice for 3 consecutive days to induce a decrease in sleep spindle density. We then administered low-dose GBL, which cannot induce SWDs in normally conditioned mice, but led to the occurrence of SWDs in caffeine-conditioned mice. These findings indicate a temporal relationship in which the decrease in sleep spindle density consistently precedes SWD development. Furthermore, the decrease in sleep spindle activity may have a role in facilitating the development of SWDs. Our findings suggest that sleep spindle reductions could serve as early indicators of seizure susceptibility.

Significance Statement This study uncovers a crucial temporal link between sleep spindle reduction and the onset of spike-and-wave discharges (SWDs), hallmarks of absence seizures. By demonstrating that a decrease in sleep spindle density precedes SWD development in both genetic and pharmacological mouse models, our findings suggest that sleep spindle alterations could serve as early indicators of seizure susceptibility. This research opens new avenues for early detection and intervention strategies in absence seizures, potentially improving patient outcomes and advancing our understanding of seizure mechanisms.