Sleep slow-wave oscillations trigger seizures in a genetic epilepsy model of Dravet syndrome.
Sleep slow-wave oscillations trigger seizures in a genetic epilepsy model of Dravet syndrome.
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DOI：
10.1093/braincomms/fcac332
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发表时间：
2023
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
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睡眠是人类癫痫患者出现癫痫棘波放电的优先时段，包括遗传性癫痫发作如Dravet综合征，患者存在包括SCN 1A突变和GABAA受体γ2亚基Gabrg 2 Q390 X突变在内的多个突变，女性患者比男性患者表现出更严重的癫痫症状。然而，睡眠中癫痫发作的机制仍然未知。我们的前期工作表明，在一个转基因杂合子Gabrg 2 +/Q390 X敲入小鼠模型中，睡眠样状态依赖的稳态突触增强可以触发癫痫棘波放电。在这里，使用这种杂合基因敲入小鼠模型，我们假设慢波振荡本身在体内可以触发癫痫发作。我们发现杂合子Gabrg 2 +/Q390 X基因敲入小鼠的癫痫棘波放电在非快动眼睡眠期表现出优先发生，并伴有运动不动/面部肌阵挛/触须抽搐，且雌性杂合子基因敲入小鼠的棘波放电发生率高于雄性杂合子基因敲入小鼠。体内光遗传学诱导的慢波振荡显著增加了杂合Gabrg 2 +/Q390 X基因敲入小鼠的癫痫棘波放电发生率，这些小鼠具有较长的非快速眼动睡眠或安静觉醒状态。此外，通过4-（二乙基氨基）-苯甲醛注射（i. p.）大大减弱了杂合基因敲入小鼠的棘波放电发生率，表明体内慢波振荡确实触发了杂合基因敲入小鼠的癫痫发作活动。同时，野生型同窝仔和杂合子Gabrg 2 +/Q390 X敲入小鼠的睡眠纺锤体产生涉及慢波振荡相关的稳态突触增强，这也有助于杂合子Gabrg 2 +/Q390 X敲入小鼠癫痫棘波放电的产生。此外，在非快速眼动睡眠期间，雌性杂合Gabrg 2 +/Q390 X基因敲入小鼠的δ频率（0.1-4 Hz）的EEG谱功率显著大于雄性杂合Gabrg 2 +/Q390 X基因敲入小鼠，这可能有助于人类患者在非快速眼动睡眠/安静-觉醒状态期间癫痫发作发生率的性别差异。 总之，所有这些结果表明，体内慢波振荡触发杂合Gabrg 2 +/Q390 X基因敲入小鼠的癫痫发作，优先在非快速眼动睡眠期，并可能产生雄性和雌性杂合Gabrg 2 +/Q390 X基因敲入小鼠之间癫痫发作发生率的性别差异。Catron等人报告，在一种具有Gabrg 2 +/Q390 X突变的Dravet综合征小鼠模型中，慢波振荡增加导致癫痫活动。同时，体内抑制慢波振荡相关的突触可塑性显著抑制了het Gabrg 2 +/Q390 X小鼠的癫痫活动，表明慢波振荡可以在非快速眼动睡眠期间触发癫痫发作。
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 model. 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. Catron et al. report that increased slow-wave oscillations cause epileptic activity in one Dravet syndrome mouse model with Gabrg2+/Q390X mutation. Meanwhile, the suppression of slow-wave oscillation-related synaptic plasticity in vivo dramatically inhibits epileptic activity in the het Gabrg2+/Q390X mice, suggesting that slow-wave oscillations can trigger seizures during non-rapid eye movement sleep.
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影响因子：
5.6
作者：
Ding L;Gallagher MJ
通讯作者：
Gallagher MJ
DOI：
10.1523/jneurosci.0077-11.2011
发表时间：
2011-06-22
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bonjean M;Baker T;Lemieux M;Timofeev I;Sejnowski T;Bazhenov M
通讯作者：
Bazhenov M
影响因子：
16.2
作者：
González-Rueda A;Pedrosa V;Feord RC;Clopath C;Paulsen O
通讯作者：
Paulsen O
影响因子：
9.3
作者：
Budas, Grant R.;Disatnik, Marie-Helene;Mochly-Rosen, Dana
通讯作者：
Mochly-Rosen, Dana
影响因子：
11.9
作者：
Fukuda, N;Honma, H;Koyama, T
通讯作者：
Koyama, T