To Sleep, Perchance to <i>Seize</i> . Ay, There's the Rub

Preoptic Area Influences Sleep-Related Seizures in a Genetic Epilepsy Mouse Model. Potesta CV, Cargile MS, Yan A, Xiong S, Macdonald RL, Gallagher MJ, Zhou C. Cerebral Cortex . 2025 July;35(7):bhaf187. https://doi.org/10.1093/cercor/bhaf187 In patients with refractory epilepsy, states of sleep and wakefulness affect the expression of seizures. However, the mechanism by which subcortical sleep circuitry affects seizures is unknown. Here, using Gabrg2 Q390X knock-in (KI) genetic epileptic mouse model, we found that during sleep, subcortical preoptic area (POA) neurons were active in het Gabrg2 Q390X KI mice and their activity preceded or/and coincided with epileptic (poly)spike–wave discharges. Optogenetic manipulating the POA activity altered sleep/wake periods in wild-type (wt) and the het Gabrg2 Q390X KI mice. Most importantly, short-period optogenetic activation of epileptic cortical neurons alone did not effectively trigger seizures in the het Gabrg2 Q390X KI mice, while optogenetic activation of the POA nucleus slightly influenced spontaneous epileptic activity in the het Gabrg2 Q390X KI mice. In contrast, coordinated optogenetic activation/suppression of the subcortical POA nucleus with the optogenetic activation of epileptic cortical neurons effectively enhanced or suppressed epileptic activity in the het Gabrg2 Q390X KI mice, indicating that the subcortical POA activation exacerbates seizures in the het Gabrg2 Q390X KI mice . In addition, suppression of the subcortical POA nucleus decreased myoclonic jerks in the Gabrg2 Q390X KI mice. Overall, this study reveals a circuit-based mechanism of sleep-preferential seizures in one genetic epilepsy model with implications for refractory epilepsy.