Sleep slow-wave oscillations trigger seizures in a genetic epilepsy model of Dravet syndrome

Abstract

Sleep is the brain state when cortical activity decreases and memory consolidates. However, in human epileptic patients, including genetic epileptic seizures such as Dravet syndrome, sleep is the preferential period when epileptic spike-wave discharges (SWDs) appear, with more severe epileptic symptoms in female patients than male patients, which influencing patient sleep quality and memory. Currently, seizure onset mechanisms during sleep period still remain unknown. Our previous work has shown that the sleep-like state-dependent synaptic potentiation mechanism can trigger epileptic SWDs (Zhang et al., 2021). In this study, using one heterozygous (het) knock-in (KI) transgenic mice (GABAA receptor γ2 subunit Gabrg2Q390X mutation) and an optogenetic method, we hypothesized that slow-wave oscillations (SWOs) themselves in vivo could trigger epileptic seizures. We found that epileptic SWDs in het Gabrg2+/Q390X KI mice exhibited preferential incidence during NREM sleep period, accompanied by motor immobility/ facial myoclonus/vibrissal twitching, with more frequent incidence in female het KI mice than male het KI mice. Optogenetic induced SWOs in vivo significantly increased epileptic seizure incidence in het Gabrg2+/Q390X KI mice with increased duration of NREM sleep or quiet-wakeful states. Furthermore, suppression of SWO-related homeostatic synaptic potentiation by 4-(diethylamino)-benzaldehyde (DEAB) injection (i.p.) greatly decreased seizure incidence in het KI mice, suggesting that SWOs did trigger seizure activity in het KI mice. In addition, EEG delta-frequency (0.1-4 Hz) power spectral density during NREM sleep was significantly larger in female het Gabrg2+/Q390X KI mice than male het Gabrg2+/Q390X KI mice, which likely contributes to the gender difference in seizure incidence during NREM sleep/quiet-wake as that in human patients.

Artificial sleep-like up/down-states induce synaptic plasticity in cortical neurons from mouse brain slices

“…The replicability of this straight-forward method has been shown in our previous manuscript (Zhang et al, 2021). Regarding the synaptic EPSC potentiation mechanism, the synaptic potentiation by SWOs depends on retinoid acid synthesis (Aoto et al, 2008) (which the N,N-diethylaminobenzaldehyde (DEAB) can block) and is further replicated by in vivo experiments (Catron et al, 2023) 2021)], while 5-Hz high-level activity could attenuate sIPSCs in layer V cortical neurons [Supplementary Figure 3 in Zhang et al (2021)]. These suggest that sEPSC and sIPSC may need different thresholds of high neuronal activity to trigger depression in cortical neurons (Turrigiano, 2008;Li et al, 2019).…”