Epileptic activity in genetic generalized epilepsy (GGE) patients preferentially appears during sleep and its mechanism remains unknown. Here, we found that sleep-like slow-wave oscillations (0.5 Hz SWOs) potentiated excitatory and inhibitory synaptic currents in layer V cortical pyramidal neurons from wild-type (wt) mouse brain slices. In contrast, SWOs potentiated excitatory, but not inhibitory, currents in cortical neurons from a heterozygous (het) knock-in (KI) Gabrg2^+Q/390X model of Dravet epilepsy syndrome. This created an imbalance between evoked excitatory and inhibitory currents to effectively prompt neuronal action potential firings. Similarly, physiologically similar up-/down-state induction (present during slow-wave sleep) in cortical neurons also potentiated excitatory synaptic currents within brain slices from wt and het KI mice. Moreover, this state-dependent potentiation of excitatory synaptic currents entailed some signaling pathways of homeostatic synaptic plasticity. Consequently, in het KI mice, in vivo SWO induction (using optogenetic methods) triggered generalized epileptic spike-wave discharges (SWDs), being accompanied by sudden immobility, facial myoclonus, and vibrissa twitching. In contrast, in wt littermates, SWO induction did not cause epileptic SWDs and motor behaviors. To our knowledge, this is the first mechanism to explain why epileptic SWDs preferentially happen during non rapid eye-movement sleep and quiet-wakefulness in human GGE patients.

中文翻译：

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GABAergic 突触电流的状态依赖性增强受损触发遗传广义癫痫模型中的癫痫发作。

遗传性全身性癫痫 (GGE) 患者的癫痫活动优先出现在睡眠期间，其机制仍不清楚。在这里，我们发现类似睡眠的慢波振荡 (0.5 Hz SWO) 增强了野生型 (wt) 小鼠脑切片 V 层皮质锥体神经元中的兴奋性和抑制性突触电流。相比之下，SWO 增强了来自杂合 (het) 敲入 (KI) Gabrg2 ^{+Q/390X的皮层神经元中的兴奋性电流，而不是抑制性电流}Dravet癫痫综合征模型。这造成了诱发的兴奋性和抑制性电流之间的不平衡，从而有效地促进了神经元动作电位的激发。同样，皮质神经元中生理上相似的上/下状态诱导（在慢波睡眠期间存在）也增强了 wt 和 het KI 小鼠脑切片内的兴奋性突触电流。此外，这种兴奋性突触电流的状态依赖性增强需要一些稳态突触可塑性的信号通路。因此，在 het KI 小鼠中，体内 SWO 诱导（使用光遗传学方法）触发了全身性癫痫棘波放电 (SWD)，并伴有突然不动、面部肌阵挛和触须抽搐。相反，在 wt 同窝仔猪中，SWO 诱导不会导致癫痫 SWD 和运动行为。据我们所知，