Potesta, C. V. | bioRxiv Science

bioRxiv2023

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

In genetic and refractory epileptic patients, seizure activity exhibits sleep-related modulation/regulation and sleep and seizure are intermingled. In this study, by using one het Gabrg2Q390X KI mice as a genetic epilepsy model and optogenetic method in vivo, we found that subcortical POA neurons were active within epileptic network from the het Gabrg2Q390XKI mice and the POA activity preceded epileptic (poly)spike-wave discharges(SWD/PSDs) in the het Gabrg2Q390X KI mice. Meanwhile, as expected, the manipulating of the POA activity relatively altered NREM sleep and wake periods in both wt and the het Gabrg2Q390X KI mice. Most importantly, the short activation of epileptic cortical neurons alone did not effectively trigger seizure activity in the het Gabrg2Q390X KI mice. In contrast, compared to the wt mice, combined the POA nucleus activation and short activation of the epileptic cortical neurons effectively triggered or suppressed epileptic activity in the het Gabrg2Q390X KI mice, indicating that the POA activity can control the brain state to trigger seizure incidence in the het Gabrg2Q390X KI mice in vivo. In addition, the suppression of POA nucleus activity decreased myoclonic jerks in the Gabrg2Q390XKI mice. Overall, this study discloses an operational mechanism for sleep-dependent seizure incidence in the genetic epilepsy model with the implications for refractory epilepsy. This operational mechanism also underlies myoclonic jerk generation, further with translational implications in seizure treatment for genetic/refractory epileptic patients and with contribution to memory/cognitive deficits in epileptic patients.

neuroscience↗

bioRxiv2022

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

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 {gamma}2 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.

neuroscience↗