Cellular and Molecular Pathology Graduate Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Epilepsia. 2018 Aug;59(8):1527-1539. doi: 10.1111/epi.14513. Epub 2018 Jul 15.
Circadian rhythms are affected in many neurological disorders. Although sleep disturbances are known in epilepsy, data on circadian rhythm disturbances in epilepsy are sparse. Here, we examined diurnal and circadian rest-activity and sleep-wake patterns in Kcna1-null mice, which exhibit spontaneous recurrent seizures and are a model of sudden unexpected death in epilepsy. Furthermore, we sought to determine whether seizures or aberrant oscillation of core clock genes and a regulator, sirtuin 1 (Sirt1), is associated with disrupted rhythms.
We used passive infrared actigraphy to assess rest-activity patterns, electroencephalography for seizure and sleep analysis, and reverse transcription polymerase chain reaction and Western blotting to evaluate expression of clock genes and Sirt1 in Kcna1-null and wild-type mice.
Epileptic Kcna1-null animals have disrupted diurnal and circadian rest-activity patterns, tending to exhibit prolonged circadian periods. Electroencephalographic analysis confirmed disturbances in sleep architecture, with more time spent awake and less asleep. Although all epileptic mice manifested disrupted diurnal and circadian rest-activity patterns, we found no correlation between actual seizure burden and degree of sleep disruption. However, we found attenuated oscillations of several clock genes (ie, Clock, Bmal1, Per1, and Per2) and diurnal Sirt1 mRNA in the anterior hypothalamus.
Attenuated oscillation of several core clock genes correlates with, and may underlie, aberrant diurnal and circadian rest-activity and sleep-wake patterns observed in Kcna1-null mice. This could contribute to late complications in epilepsy, such as sudden unexpected death in epilepsy. Sirt1 may represent a useful therapeutic target for rescuing circadian clock gene rhythmicity and sleep patterns in epilepsy.
许多神经紊乱都会影响昼夜节律。尽管癫痫患者中存在睡眠障碍，但有关癫痫昼夜节律紊乱的数据却很少。在这里，我们研究了 Kcna1 基因敲除小鼠的昼夜节律和睡眠-觉醒模式，该小鼠表现出自发性反复性癫痫发作，是癫痫猝死的模型。此外，我们试图确定癫痫发作或核心时钟基因和调节因子 Sirtuin 1（Sirt1）的异常振荡是否与节律紊乱有关。
我们使用被动红外活动记录仪评估休息-活动模式，使用脑电图进行癫痫发作和睡眠分析，使用逆转录聚合酶链反应和 Western blot 分析评估时钟基因和 Sirt1 在 Kcna1 基因敲除和野生型小鼠中的表达。
患有癫痫的 Kcna1 基因敲除动物的昼夜节律和昼夜节律休息-活动模式受到干扰，表现出较长的昼夜周期。脑电图分析证实了睡眠结构的紊乱，表现为更多的清醒时间和更少的睡眠时间。尽管所有癫痫小鼠都表现出昼夜和昼夜休息-活动模式的紊乱，但我们没有发现实际癫痫发作负担与睡眠障碍程度之间的相关性。然而，我们发现前下丘脑的几个时钟基因（即 Clock、Bmal1、Per1 和 Per2）和日间 Sirt1 mRNA 的振荡减弱。
几个核心时钟基因的振荡减弱与 Kcna1 基因敲除小鼠观察到的异常昼夜和昼夜休息-活动和睡眠-觉醒模式相关，并可能是其基础。这可能导致癫痫的晚期并发症，如癫痫猝死。Sirt1 可能代表一种有用的治疗靶点，可用于挽救癫痫中的昼夜节律基因节律性和睡眠模式。
