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

Sleep is the preferential period when epileptic spike–wave discharges appear in human epileptic patients, including genetic epileptic seizures such as Dravet syndrome with multiple mutations including SCN1A mutation and GABA(A) receptor γ2 subunit Gabrg2(Q390X) mutation in patients, which presents more severe epileptic symptoms in female patients than male patients. However, the seizure onset mechanism during sleep still remains unknown. Our previous work has shown that the sleep-like state-dependent homeostatic synaptic potentiation can trigger epileptic spike–wave discharges in one transgenic heterozygous Gabrg2(+/Q390X) knock-in mouse model.(1) Here, using this heterozygous knock-in mouse model, we hypothesized that slow-wave oscillations themselves in vivo could trigger epileptic seizures. We found that epileptic spike–wave discharges in heterozygous Gabrg2(+/Q390X) knock-in mice exhibited preferential incidence during non-rapid eye movement sleep period, accompanied by motor immobility/facial myoclonus/vibrissal twitching and more frequent spike–wave discharge incidence appeared in female heterozygous knock-in mice than male heterozygous knock-in mice. Optogenetically induced slow-wave oscillations in vivo significantly increased epileptic spike–wave discharge incidence in heterozygous Gabrg2(+/Q390X) knock-in mice with longer duration of non-rapid eye movement sleep or quiet–wakeful states. Furthermore, suppression of slow-wave oscillation-related homeostatic synaptic potentiation by 4-(diethylamino)-benzaldehyde injection (i.p.) greatly attenuated spike–wave discharge incidence in heterozygous knock-in mice, suggesting that slow-wave oscillations in vivo did trigger seizure activity in heterozygous knock-in mice. Meanwhile, sleep spindle generation in wild-type littermates and heterozygous Gabrg2(+/Q390X) knock-in mice involved the slow-wave oscillation-related homeostatic synaptic potentiation that also contributed to epileptic spike–wave discharge generation in heterozygous Gabrg2(+/Q390X) knock-in mice. In addition, EEG spectral power of delta frequency (0.1–4 Hz) during non-rapid eye movement sleep was significantly larger in female heterozygous Gabrg2(+/Q390X) knock-in mice than that in male heterozygous Gabrg2(+/Q390X) knock-in mice, which likely contributes to the gender difference in seizure incidence during non-rapid eye movement sleep/quiet–wake states of human patients. Overall, all these results indicate that slow-wave oscillations in vivo trigger the seizure onset in heterozygous Gabrg2(+/Q390X) knock-in mice, preferentially during non-rapid eye movement sleep period and likely generate the sex difference in seizure incidence between male and female heterozygous Gabrg2(+/Q390X) knock-in mice.