Altered circadian rhythms and oscillation of clock genes and sirtuin 1 in a model of sudden unexpected death in epilepsy

• Published in: Epilepsia (Copenhagen) Vol. 59; no. 8; pp. 1527 - 1539
• Main Authors: Wallace, Eli, Wright, Samantha, Schoenike, Barry, Roopra, Avtar, Rho, Jong M., Maganti, Rama K.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2018
• Subjects: Actigraphy; Activity patterns; Animals; BMAL1 protein; Circadian rhythm; Circadian Rhythm - genetics; Circadian rhythms; Clock gene; clock genes; CLOCK Proteins - genetics; CLOCK Proteins - metabolism; Death; Death, Sudden; Disease Models, Animal; Diurnal; EEG; Electroencephalography; Electromyography; Epilepsy; Epilepsy - genetics; Epilepsy - metabolism; Epilepsy - physiopathology; Gene Expression Regulation - genetics; Hypothalamus (anterior); Kcna1‐null; Kv1.1 Potassium Channel - genetics; Kv1.1 Potassium Channel - metabolism; Mammals; Mice; Mice, Knockout; Neurological complications; Neurological diseases; Oscillations; Period 1 protein; Period 2 protein; Polymerase chain reaction; Reverse transcription; RNA, Messenger; Seizures; SIRT1 protein; Sirtuin; Sirtuin 1 - metabolism; Sleep; Sleep - genetics; Sleep and wakefulness; Therapeutic applications; Wakefulness - genetics; Western blotting; epilepsy; clock genes; Kcna1-null; circadian rhythms; Sirtuin
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.14513

Objectives 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. Methods 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. Results 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. Significance 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.