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

Abstract

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 GABAA receptor γ2 subunit Gabrg2Q390X 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 model1. 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.

Preoptic area controls sleep-related seizure onset in a genetic epilepsy mouse model

“…One pair of EMG leads were inserted into the trapezius muscles to monitor mouse motor activity such as head movements and staring along with simultaneous videos. EEG/multi-unit recordings in vivo As the methods before 21 , post-surgery mice were continuously monitored for recovery from anesthesia and remained in the animal care facility for at least 5 days or 1 week (normal wake/sleep circadian rhythm) before simultaneous EEG/multiunit activity recordings in vivo, along with epileptic behavior being video-recorded for Racinestage scoring. Two-channel EEG (band filtered at 0.1~100Hz) and one-channel POA multi-unit recordings (band filtered 300-10K Hz) along with one channel EMG(band filtered 10-400Hz) were collected by using two multiClamp 700B amplifiers (total 4 channels and all in currentclamp mode) (Molecular devices Inc., Union City, CA) and Clampex 10 software (Molecular Devices Inc., Union City, CA), and digitized at 20 kHz using a Digidata 1440A.…”

“…Using one genetic epilepsy mouse model with a Gabrg2 Q390X mutation in gabaergic receptor γ-subunit in cortical neurons and optogenetic method 21,41 , we found that POA multi-unit activity preceded epileptic activity in the het Gabrg2 Q390X KI mice and the POA neurons were active due to epileptic activity in the het Gabrg2 Q390X KI mice. Further, manipulating of the POA activity triggered or suppressed epilepsy incidence in the het Gabrg2 Q390X KI mice, supporting one operational mechanism that the subcortical POA can trigger or regulate epilepsy incidence in this genetic epilepsy model with implications in memory and cognitive deficits in epileptic patients.…”

“…Sleep rhythm seems to modulate epilepsy incidence in refractory epileptic patients 9,11,14,19,20 and in genetic epileptic animal models 21,22 . Our genetic mouse model with het Gabrg2 Q390X mutation exhibits seizure incident preference during non-rapid eye movement (NREM) sleep 21 . So far, thalamocortical circuitry [23][24][25] underlies the circuitry basis to generate sleep spindles and epileptic spike-wave discharges (SWDs) in animal models 10,24,[26][27][28] and in human pathological conditions 10,29 .…”

“…At the same time, during sleep, cortical neurons within thalamocortical circuitry exhibit up/down-state alteration 7,[33][34][35][36][37][38][39][40] . Our previous work indicates that sleep-related up-states (in slow-wave oscillation during NREM sleep) selectively and balanced potentiate excitatory and inhibitory synaptic strength in cortical neurons from wild-type (wt) mice, while sleep-related up-states only potentiate excitatory synaptic strength in cortical neurons from one genetic mouse model with Gabrg2 Q390X mutation 21,41 . Thus, we hypothesize that the subcortical POA can use this synaptic potentiation mechanism to trigger or regulate epilepsy incidence in the het Gabrg2 Q390X knock-in(KI) mice.…”

Slow Down and Seize: Seizures Triggered by Slow Wave Oscillations in a GABAergic Model of Dravet Syndrome

“…4 Using the Gabrg2 þ/Q390X knock-in mouse model, Catron and colleagues evaluated slow wave mechanisms for seizures. 5 This mutation has been identified in a subset of patients with the epileptic Dravet syndrome. While most Dravet syndrome cases involve one of many mutations in Scn1a, the gene encoding the voltage-gated sodium channel Na V 1.1, other mutations have been identified, including this one in Gabrg2, the gene for the gamma subunit of the GABA A receptor.…”