在癫痫猝死模型中昼夜节律改变和时钟基因及 Sirtuin 1 的振荡_Journal of Epilepsy

Authors：

EliWallace ,  SamanthaWright , BarrySchoenike , 高慧　译 , 童馨　慕洁　审

;

Corresponding author：

SamanthaWright, Email: Maganti@neurology.wisc.edu

Keywords：

昼夜节律; 时钟基因; 癫痫; Kcna1 缺失; Sirtuin

DOI：

10.7507/2096-0247.20190038

Video：

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Abstract Full text Figures/Tables Video References Cited by

许多神经系统疾病都会影响昼夜节律。尽管已知癫痫常伴睡眠障碍，但与癫痫昼夜节律紊乱相关的数据却很少。文章检验了 Kcna1 缺失小鼠的昼夜休息活动以及睡眠-觉醒模式。该小鼠模型表现出反复自发癫痫发作，也是研究癫痫猝死的模型。此外，研究试图确定癫痫发作以及核心时钟基因和调节因子 Sirtuin 1（Sirt1）的异常变化是否与昼夜节律紊乱有关。研究使用被动红外活动记录仪评估休息活动模式，使用脑电图（EEG）进行癫痫发作和睡眠分析，并且使用逆转录聚合酶链反应和蛋白质印迹法评估时钟基因和 Sirt1 在 Kcna1 缺失和野生型小鼠中的表达情况。癫痫 Kcna1 缺失动物模型存在昼夜休息活动模式紊乱，趋于表现出延长的昼夜节律。EEG 分析证实了睡眠结构的破坏，清醒时间更多并且睡眠不足。尽管所有癫痫小鼠都表现出昼夜休息活动模式的紊乱，但该研究发现实际癫痫发作负担与睡眠紊乱程度之间没有相关性。发现前下丘脑中几个时钟基因（即 Clock，Bmal1，Per1 和 Per2）和昼间 Sirt1 mRNA 的衰减振荡。几个核心时钟基因的振荡衰减与 Kcna1 缺失小鼠中观察到的异常昼夜休息活动以及睡眠-觉醒模式改变相关，可能是其基础原因，并可能导致癫痫晚期并发症，例如癫痫猝死。Sirt1 可能是恢复生物钟基因节律和癫痫睡眠模式的潜在治疗靶点之一。

Citation： EliWallace, SamanthaWright, BarrySchoenike, 高慧　译, 童馨　慕洁　审. 在癫痫猝死模型中昼夜节律改变和时钟基因及 Sirtuin 1 的振荡. Journal of Epilepsy, 2019, 5(3): 209-219. doi: 10.7507/2096-0247.20190038 Copy

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3.	Devinsky O, Hesdorffer DC, Thurman DJ, et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol, 2016, 15(10): 1075-1088.
4.	Glasscock E, Yoo JW, Chen TT, et al. Kv1. 1 potassium channel deficiency reveals brain‐driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy. J Neurosci, 2010, 30(15): 5167-5175.
5.	Fenoglio-Simeone K, Wilke J, Milligan H, et al. Ketogenic diet treatment abolishes seizure periodicity and improves diurnal rhythmicity in epileptic Kcna1‐null mice. Epilepsia, 2009, 50(9): 2027-2034.
6.	Wright S, Wallace E, Hwang Y, et al. Seizure phenotypes, periodicity, and sleep-wake pattern of seizures in Kcna‐1 null mice. Epilepsy Behav, 2016, 55: 24-29.
7.	Iyer S, Matthews S, Simeone T, et al. Accumulation of rest deficiency precedes sudden death of epileptic Kv1. 1 knockout mice, a model of sudden unexpected death in epilepsy. Epilepsia, 2018, 59(1): 92-105.
8.	Baxter P. Epilepsy and sleep. Dev Med Child Neurol, 2005, 47(11): 723.
9.	Yamaguchi S, Isejima H, Matsuo T, et al. Synchronization of cellular clocks in the suprachiasmatic nucleus. Science, 2003, 302(5649): 1408-1412.
10.	Mohawk J, Takahashi J. Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators. Trends Neurosci, 2011, 34(7): 349-358.
11.	Ko C, Takahashi J. Molecular components of the mammalian circadian clock. Human Mol Genet, 2006, 15(Suppl 2): 271-277.
12.	Kondratov R, Chernov M, Kondratova A, et al. BMAL1‐dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes Dev, 2003, 17(15): 1921-1932.
13.	Schibler U, Sassone-Corsi P. A web of circadian pacemakers. Cell, 2002, 111(7): 919-922.
14.	Kuhlman SJ, McMahon DG. Rhythmic regulation of membrane potential and potassium current persists in SCN neurons in the absence of environmental input. Eur J Neurosci, 2004, 20(4): 1113-1117.
15.	Colwell C. Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci, 2011, 12(10): 553-569.
16.	Etchegaray J-P, Lee C, Wade PA, Reppert SM. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature, 2003, 421(6919): 177-182.
17.	Hirayama J, Sahar S, Grimaldi B, et al. CLOCK‐mediated acetylation of BMAL1 controls circadian function. Nature, 2007, 450(7172): 1086-1090.
18.	Chang HC, Guarente L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell, 2013, 153(7): 1448-1460.
19.	Xu H, Gustafson CL, Sammons PJ, et al. Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus. Nat Struct Mol Biol, 2015, 22(6): 476-484.
20.	Jones C, Huang A, Ptáček L, et al. Genetic basis of human circadian rhythm disorders. Exp Neurol, 2013, 243: 28-33.
21.	Allada R, Emery P, Takahashi J, et al. STOPPING TIME: the genetics of fly and mouse circadian clocks. Annu Rev Neurosci, 2001, 24: 1091-1119.
22.	Wallace E, Kim D, Kim K-M, et al. Differential effects of duration of sleep fragmentation on spatial learning and synaptic plasticity in pubertal mice. Brain Res, 2015, 1615: 116-128.
23.	Oliverio M. Wheel running sleep in two strains of mice: plasticity and rigidity in the expression of circadian rhythmicity. Brain Res, 1979, 163(1): 121-133.
24.	Benloucif S, Dubocovich M. Melatonin and light induce phase shifts of circadian activity rhythms in the C3H/HeN Mouse. J Biol Rhythms, 1996, 11(2): 113-125.
25.	Orozco-Solis R, Sassone-Corsi P. Circadian clock: linking epigenetics to aging. Curr Opin Genet Dev, 2014, 26: 66-72.
26.	Wulff K, Gatti S, Wettstein J, et al. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci, 2010, 11(8): 589-599.
27.	Herman ST, Walczak TS, Bazil CW. Distribution of partial seizures during the sleep-wake cycle: differences by seizure onset site. Neurology, 2001, 56(11): 1453-1459.
28.	Staba R, Wilson C, Bragin A, et al. Sleep states differentiate single neuron activity recorded from human epileptic hippocampus, entorhinal cortex, and subiculum. J Neurosci, 2002, 22(13): 5694-5704.
29.	Weiss G, Lucero K, Fernandez M, et al. The effect of adrenalectomy on the circadian variation in the rate of kindled seizure development. Brain Res, 1993, 612(1-2): 354-356.
30.	Hellier J, Dudek FE. Spontaneous motor seizures of rats with kainate‐induced epilepsy: effect of time of day and activity state. Epilepsy Res, 1999, 35(1): 47-57.
31.	Unterberger I, Gabelia D, Prieschl M, et al. Sleep disorders and circadian rhythm in epilepsy revisited: a prospective controlled study. Sleep Med, 2015, 16(2): 237-242.
32.	Holley S, Whitney A, Kirkham FJ, et al. Executive function and sleep problems in childhood epilepsy. Epilepsy Behav, 2014, 37: 20-25.
33.	Quigg M, Clayburn H, Straume M, et al. Effects of circadian regulation and rest‐activity state on spontaneous seizures in a rat model of limbic epilepsy. Epilepsia, 2000, 41(5): 502-509.
34.	Stewart LS, Leung LS, Persinger MA. Diurnal variation in pilocarpine‐induced generalized tonic‐clonic seizure activity. Epilepsy Res, 2001, 44(2-3): 207-212.
35.	Fenoglio-Simeone K, Mazarati A, Sefidvash-Hockley S, et al. Anticonvulsant effects of the selective melatonin receptor agonist ramelteon. Epilepsy Behav, 2009, 16(1): 52-57.
36.	Maywood E, O'Neill J, Chesham J, et al. Minireview: the circadian clockwork of the suprachiasmatic nuclei-analysis of a cellular oscillator that drives endocrine rhythms. Endocrinology, 2007, 148(12): 5624-5634.
37.	Wang X, Wang L, Yu Q, et al. Alterations in the expression of Per1 and Per2 induced by Aβ31‐35 in the suprachiasmatic nucleus, hippocampus, and heart of C57BL/6 mouse. Brain Res, 2016, 1642: 51-58.
38.	Bonaconsa M, Colavito V, Pifferi F, et al. Cell clocks and neu- ronal networks: neuron ticking and synchronization in aging and aging‐related neurodegenerative disease. Curr Alzheimer Res, 2013, 10(6): 597-608.
39.	Duncan M, Smith T, Franklin K, et al. Effects of aging and genotype on circadian rhythms, sleep, and clock gene expression in APPxPS1 knock‐in mice, a model for Alzheimer's disease. Exp Neurol, 2012, 236(2): 249-258.
40.	Mongrain V, Spada F, Curie T, et al. Sleep loss reduces the DNA‐binding of BMAL1, CLOCK, and NPAS2 to specific clock genes in the mouse cerebral cortex. PLoS ONE, 2011, (10).
41.	Wisor J, Pasumarthi R, Gerashchenko D, et al. Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel electroencephalographic differences among mouse strains. J Neurosci, 2008, 28: 7193-7201.
42.	Liu Y, Beyer A, Aebersold R. On the dependency of cellular protein levels on mRNA abundance. Cell, 2016, 165(3): 535-550.
43.	Yin L, Wu N, Curtin J, et al. Rev‐erbα, a heme sensor that coordinates metabolic and circadian pathways. Science, 2007, 318(5857): 1786-1789.
44.	Grimaldi B, Nakahata Y, Kaluzova M, et al. Chromatin remodeling, metabolism and circadian clocks: the interplay of CLOCK and SIRT1. Int J Biochem Cell Biol, 2008, 41(1): 81-86.
45.	Asher G, Gatfield D, Stratmann M, et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell(2), 2008, 134: 317-328.
46.	Maalouf M, Rho J, Mattson M. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev, 2009, 59(2): 293-315.
47.	Genzer Y, Dadon M, Burg C, et al. Ketogenic diet delays the phase of circadian rhythms and does not affect AMP‐activated protein kinase (AMPK) in mouse liver. Mol Cell Endocrinol, 2015, 417: 124-130.
48.	Irani S, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel‐complex proteins leucine‐rich, glioma inactivated 1 protein and contactin‐associated protein‐2 in limbic encephalitis. Morvan's syndrome and acquired neuromyotonia. Brain, 2010, 133(9): 2734-2748.

1. Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav, 2014, 37: 59-70.
2. Coan AC, Cendes F. Epilepsy as progressive disorders: what is the evidence that can guide our clinical decisions and how can neuroimaging help? . Epilepsy Behav, 2013, 26(3): 313-321.
3. Devinsky O, Hesdorffer DC, Thurman DJ, et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol, 2016, 15(10): 1075-1088.
4. Glasscock E, Yoo JW, Chen TT, et al. Kv1. 1 potassium channel deficiency reveals brain‐driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy. J Neurosci, 2010, 30(15): 5167-5175.
5. Fenoglio-Simeone K, Wilke J, Milligan H, et al. Ketogenic diet treatment abolishes seizure periodicity and improves diurnal rhythmicity in epileptic Kcna1‐null mice. Epilepsia, 2009, 50(9): 2027-2034.
6. Wright S, Wallace E, Hwang Y, et al. Seizure phenotypes, periodicity, and sleep-wake pattern of seizures in Kcna‐1 null mice. Epilepsy Behav, 2016, 55: 24-29.
7. Iyer S, Matthews S, Simeone T, et al. Accumulation of rest deficiency precedes sudden death of epileptic Kv1. 1 knockout mice, a model of sudden unexpected death in epilepsy. Epilepsia, 2018, 59(1): 92-105.
8. Baxter P. Epilepsy and sleep. Dev Med Child Neurol, 2005, 47(11): 723.
9. Yamaguchi S, Isejima H, Matsuo T, et al. Synchronization of cellular clocks in the suprachiasmatic nucleus. Science, 2003, 302(5649): 1408-1412.
10. Mohawk J, Takahashi J. Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators. Trends Neurosci, 2011, 34(7): 349-358.
11. Ko C, Takahashi J. Molecular components of the mammalian circadian clock. Human Mol Genet, 2006, 15(Suppl 2): 271-277.
12. Kondratov R, Chernov M, Kondratova A, et al. BMAL1‐dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes Dev, 2003, 17(15): 1921-1932.
13. Schibler U, Sassone-Corsi P. A web of circadian pacemakers. Cell, 2002, 111(7): 919-922.
14. Kuhlman SJ, McMahon DG. Rhythmic regulation of membrane potential and potassium current persists in SCN neurons in the absence of environmental input. Eur J Neurosci, 2004, 20(4): 1113-1117.
15. Colwell C. Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci, 2011, 12(10): 553-569.
16. Etchegaray J-P, Lee C, Wade PA, Reppert SM. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature, 2003, 421(6919): 177-182.
17. Hirayama J, Sahar S, Grimaldi B, et al. CLOCK‐mediated acetylation of BMAL1 controls circadian function. Nature, 2007, 450(7172): 1086-1090.
18. Chang HC, Guarente L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell, 2013, 153(7): 1448-1460.
19. Xu H, Gustafson CL, Sammons PJ, et al. Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus. Nat Struct Mol Biol, 2015, 22(6): 476-484.
20. Jones C, Huang A, Ptáček L, et al. Genetic basis of human circadian rhythm disorders. Exp Neurol, 2013, 243: 28-33.
21. Allada R, Emery P, Takahashi J, et al. STOPPING TIME: the genetics of fly and mouse circadian clocks. Annu Rev Neurosci, 2001, 24: 1091-1119.
22. Wallace E, Kim D, Kim K-M, et al. Differential effects of duration of sleep fragmentation on spatial learning and synaptic plasticity in pubertal mice. Brain Res, 2015, 1615: 116-128.
23. Oliverio M. Wheel running sleep in two strains of mice: plasticity and rigidity in the expression of circadian rhythmicity. Brain Res, 1979, 163(1): 121-133.
24. Benloucif S, Dubocovich M. Melatonin and light induce phase shifts of circadian activity rhythms in the C3H/HeN Mouse. J Biol Rhythms, 1996, 11(2): 113-125.
25. Orozco-Solis R, Sassone-Corsi P. Circadian clock: linking epigenetics to aging. Curr Opin Genet Dev, 2014, 26: 66-72.
26. Wulff K, Gatti S, Wettstein J, et al. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci, 2010, 11(8): 589-599.
27. Herman ST, Walczak TS, Bazil CW. Distribution of partial seizures during the sleep-wake cycle: differences by seizure onset site. Neurology, 2001, 56(11): 1453-1459.
28. Staba R, Wilson C, Bragin A, et al. Sleep states differentiate single neuron activity recorded from human epileptic hippocampus, entorhinal cortex, and subiculum. J Neurosci, 2002, 22(13): 5694-5704.
29. Weiss G, Lucero K, Fernandez M, et al. The effect of adrenalectomy on the circadian variation in the rate of kindled seizure development. Brain Res, 1993, 612(1-2): 354-356.
30. Hellier J, Dudek FE. Spontaneous motor seizures of rats with kainate‐induced epilepsy: effect of time of day and activity state. Epilepsy Res, 1999, 35(1): 47-57.
31. Unterberger I, Gabelia D, Prieschl M, et al. Sleep disorders and circadian rhythm in epilepsy revisited: a prospective controlled study. Sleep Med, 2015, 16(2): 237-242.
32. Holley S, Whitney A, Kirkham FJ, et al. Executive function and sleep problems in childhood epilepsy. Epilepsy Behav, 2014, 37: 20-25.
33. Quigg M, Clayburn H, Straume M, et al. Effects of circadian regulation and rest‐activity state on spontaneous seizures in a rat model of limbic epilepsy. Epilepsia, 2000, 41(5): 502-509.
34. Stewart LS, Leung LS, Persinger MA. Diurnal variation in pilocarpine‐induced generalized tonic‐clonic seizure activity. Epilepsy Res, 2001, 44(2-3): 207-212.
35. Fenoglio-Simeone K, Mazarati A, Sefidvash-Hockley S, et al. Anticonvulsant effects of the selective melatonin receptor agonist ramelteon. Epilepsy Behav, 2009, 16(1): 52-57.
36. Maywood E, O'Neill J, Chesham J, et al. Minireview: the circadian clockwork of the suprachiasmatic nuclei-analysis of a cellular oscillator that drives endocrine rhythms. Endocrinology, 2007, 148(12): 5624-5634.
37. Wang X, Wang L, Yu Q, et al. Alterations in the expression of Per1 and Per2 induced by Aβ31‐35 in the suprachiasmatic nucleus, hippocampus, and heart of C57BL/6 mouse. Brain Res, 2016, 1642: 51-58.
38. Bonaconsa M, Colavito V, Pifferi F, et al. Cell clocks and neu- ronal networks: neuron ticking and synchronization in aging and aging‐related neurodegenerative disease. Curr Alzheimer Res, 2013, 10(6): 597-608.
39. Duncan M, Smith T, Franklin K, et al. Effects of aging and genotype on circadian rhythms, sleep, and clock gene expression in APPxPS1 knock‐in mice, a model for Alzheimer's disease. Exp Neurol, 2012, 236(2): 249-258.
40. Mongrain V, Spada F, Curie T, et al. Sleep loss reduces the DNA‐binding of BMAL1, CLOCK, and NPAS2 to specific clock genes in the mouse cerebral cortex. PLoS ONE, 2011, (10).
41. Wisor J, Pasumarthi R, Gerashchenko D, et al. Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel electroencephalographic differences among mouse strains. J Neurosci, 2008, 28: 7193-7201.
42. Liu Y, Beyer A, Aebersold R. On the dependency of cellular protein levels on mRNA abundance. Cell, 2016, 165(3): 535-550.
43. Yin L, Wu N, Curtin J, et al. Rev‐erbα, a heme sensor that coordinates metabolic and circadian pathways. Science, 2007, 318(5857): 1786-1789.
44. Grimaldi B, Nakahata Y, Kaluzova M, et al. Chromatin remodeling, metabolism and circadian clocks: the interplay of CLOCK and SIRT1. Int J Biochem Cell Biol, 2008, 41(1): 81-86.
45. Asher G, Gatfield D, Stratmann M, et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell(2), 2008, 134: 317-328.
46. Maalouf M, Rho J, Mattson M. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev, 2009, 59(2): 293-315.
47. Genzer Y, Dadon M, Burg C, et al. Ketogenic diet delays the phase of circadian rhythms and does not affect AMP‐activated protein kinase (AMPK) in mouse liver. Mol Cell Endocrinol, 2015, 417: 124-130.
48. Irani S, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel‐complex proteins leucine‐rich, glioma inactivated 1 protein and contactin‐associated protein‐2 in limbic encephalitis. Morvan's syndrome and acquired neuromyotonia. Brain, 2010, 133(9): 2734-2748.

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在癫痫猝死模型中昼夜节律改变和时钟基因及 Sirtuin 1 的振荡

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