GSK3在抑郁症发病机制中的研究进展

神经药理学报 ›› 2014, Vol. 4 ›› Issue (5): 44-54.

GSK3在抑郁症发病机制中的研究进展

陈姣，楚世峰，王真真，陈乃宏

1. 中国医学科学院，药物研究所&神经科学中心，天然药物活性物质与功能国家重点实验室，北京，100050，中国
2. 湖南中医药大学药学院，长沙，410000，中国

出版日期:2014-10-26 发布日期:2015-01-20
通讯作者: 陈乃宏，男，研究员，博士生导师，研究方向：神经系统疾患创新药物开发及作用机制，E-mail：chennh@imm.ac.cn
作者简介:陈姣，女，博士研究生，研究方向：神经药理学和神经生物学，E-mail:chenjiao234@163.com
基金资助:
国家自然科学基金资助项目（No. 81274122、No. 81202507、No. 81373998、No. U1402221）；国家“重大新药创制”科技重大专项（No. 2012ZX09301002-004）；北京市自然科学基金项目(No. 7131013, No. 7142115)；教育部博士点基金重点项目（No. 20121106130001）；新药作用机制研究与药效评价北京市重点实验室资助项目（No. BZ0150）；中央级公益性科研院所基本科研业务费专项资金（No. 2014RC03）

Research Progress of GSK3 in the Pathophysiology of Depression Disorder

CHEN Jiao, CHU Shi-feng, WANG Zhen-zhen, CHEN Nai-hong

1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
2. College of Pharmacy, Traditional Chinese Medicine of Hunan University, Changsha, 410000, China

Online:2014-10-26 Published:2015-01-20
Contact: 陈乃宏，男，研究员，博士生导师，研究方向：神经系统疾患创新药物开发及作用机制，E-mail：chennh@imm.ac.cn
About author:陈姣，女，博士研究生，研究方向：神经药理学和神经生物学，E-mail:chenjiao234@163.com
Supported by:
国家自然科学基金资助项目（No. 81274122、No. 81202507、No. 81373998、No. U1402221）；国家“重大新药创制”科技重大专项（No. 2012ZX09301002-004）；北京市自然科学基金项目(No. 7131013, No. 7142115)；教育部博士点基金重点项目（No. 20121106130001）；新药作用机制研究与药效评价北京市重点实验室资助项目（No. BZ0150）；中央级公益性科研院所基本科研业务费专项资金（No. 2014RC03）

摘要/Abstract

摘要： 尽管锂制剂在临床上使用了几十年，但其确切机制并不清楚。人们通过研究认识到锂可能是通过抑制GSK3而发挥抗抑郁作用的。锂可以调控GSK3下游的许多分子，许多抗抑郁类药物可以调控GSK3的信号。使用药理方法或基因沉默方法抑制GSK3均具有稳定情绪、抵抗抑郁的作用，这些研究表明GSK3可能是抗抑郁的潜在靶点。近些年来对GSK3在神经生物学中的作用机制的研究进一步证实了锂可能是通过作用于GSK3来达到治疗目的的。比如，GSK3可以调节生物体应激反应、炎症反应、神经发生、5-HT传递过程，并参与生物周期节律的调控。因此，特异的GSK3抑制剂能否在临床上发挥抗抑郁作用有待进一步研究。本文将从GSK3在应激反应、炎症反应、神经发生、5-HT传递过程以及生物周期节律这五个方面对抑郁发病机制的研究进展进行综述。

关键词: GSK3抑制剂, 抑郁症, 炎症, 神经发生, 周期节律

Abstract: Despite many decades of clinical useness, the therapeutic target of lithium remains uncertain.It is recognized that therapeutic concentrations of lithium is to inhibit the activity of glycogen synthase kinase-3 (GSK3) to treat depression disorder. Specifically, it has been demonstrated that lithium administration regulates multiple GSK3 targets and multiple antidepressant drugs regulate GSK3 signaling. Pharmacological and genetic inhibition of GSK3 results in mood stabilizer-like and antidepressant-like behavior in rodent models. These studies implicate that GSK3 is a possible target for treatment of mood disorders. Furthermore, numerous recent studies have provided more complete understanding of the role of GSK3 in diverse neurological processes, strengthening the hypothesis that GSK3 may represent a therapeutically relevant target of lithium. For example, GSK3 is a primary regulator of oxidative stress response. Inflammatory response, neurogenesis, serotonin transmission and circadian rhythms may be involved in GSK3-regulated pathways. In this regard, further study is needed to develop novel specific GSK3 inhibitors for the treatment of depressive disorders. In this article, we will discuss the role of GSK3 in five aspects including oxidative stress response, inflammatory response, neurogenesis, serotonin transmission and circadian rhythms to summary the research progress in pathological mechanisms of depression.

Key words: GSK3 inhibitor, depressive disorders, inflammation, neurogenesis, circadian rhythm

中图分类号:

陈姣，楚世峰，王真真，陈乃宏 . GSK3在抑郁症发病机制中的研究进展[J]. 神经药理学报, 2014, 4(5): 44-54.

CHEN Jiao, CHU Shi-feng, WANG Zhen-zhen, CHEN Nai-hong. Research Progress of GSK3 in the Pathophysiology of Depression Disorder[J]. Acta Neuropharmacologica, 2014, 4(5): 44-54.

参考文献

[1] Li Xiao-hua, Richard S Jope. Is glycogen synthase kinase-3 a central modulator in mood regulation? [J]. Neuropsychopharmacology, 2010, 35(11): 2143-2154.

[2] Ana C Andreazza, Marica Kauer-Sant’anna, Benicio N Frey, et al. Oxidative stress markers in bipolar disorder: a meta-analysis[J]. J Affect Disord, 2008, 111(2-3): 135-144.

[3] Amanda V Steckert, Samira S Valvassori, Morgana Moretti, et al. Role of oxidative stress in the pathophysiology of bipolar disorder[J]. Neurochem Res, 2010, 35(9): 1295-1301.

[4] N Jennifer Klinedinst, William T Regenold. A mitochondrial bioenergetic basis of depression[J]. J Bioenerg Biomembrs, 2015, 47(1-2): 155-71.

[5] Xu Ying, Wang Chuang, Jonathan J Klabnik, et al. Novel therapeutic targets in depression and anxiety: antioxidants as a candidate treatment[J]. Curr Neuropharmacol, 2014, 12(2): 108-119.

[6] Sawsan Aboul-Fotouh. Chronic treatment with coenzyme Q10 reverses restraint stress- in duced anhedonia and enhances brain mitochondrial respiratory chain and creatine kinase activities in rats[J]. BehavPharmacol, 2013, 24(7):552-560.

[7] Piyajit Watcharasit, Apinya Thiantanawat, Jutamaad Satayavivad. GSK3 promotes arsenite-induced apoptosis via facilitation of mitochondria disruption[J]. J. Appl. Toxicol, 2008, 28(4): 466-474.

[8] Katsuhiko Ohori, Tetsuji Miura, Masaya Tanno, et al. Ser9 phosphorylation of mitochondrial GSK-3 is a primary mechanism of cardiomyocyte protection by erythropoietin against oxidant-induced apoptosis[J]. Am J Physiol Heart Circ Physiol, 2008, 295(5): 2079-2086.

[9] Lisa Nevell, Zhang Ke-zhong, Allison E Aiello, et al. Elevated systemic expression of ER stress related genes is associated with stress-related mental disorders in the Detroit Neighborhood Health Study[J]. Psychoneuroendocrinology, 2014, 43: 62-70.

[10] Ling Song, Patrizia De Sarno, Richard S Jope. Central role of glycogen synthase kinase-3 in endoplasmic reticulum stress-induced caspase-3 activation[J]. J Biol Chem, 2002, 277(47):44701-44708.

[11] Anna J Kim, Yuan-yuan Shi, Richard C Austin, et al. Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3[J]. J Cell Sci, 2004, 118(1): 89-99.

[12] Robert Dantzer, Jason C OConnor, Gregory G Freund, et al. From inflammation to sickness and depression: when the immune system subjugates the brain[J]. Nat Rev Neurosci, 2008, 9(1): 46-56.

[13] Pierre F Renault, Jay H Hoofnagle, Yoon Park, et al. Psychiatric complications of long-term interferon alfa therapy[J]. Arch Intern Med, 1987, 147(9): 1577-1580.

[14] Raz Yirmiya, Weidenfeld J, Yehuda Pollak, et al. Cytokines,“depression due to a general medical condition,” and antidepressant drugs[J]. Adv Exp Med Biol, 1999, 461: 283-316.

[15] Michael R Irwin, Andrew H Miller. Depressive disorders and immunity: 20 years of progress and discovery[J]. Brain Behav Immun, 2007, 21(4):374-383.

[16] Martin M, Rehani K, Jope R S, et al. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3[J]. Nat Immunol, 2005, 6(8): 777-784.

[17] Huang Wei-ching, Lin Yee-shin, Wang Chi-yun, et al. Glycogen synthase kinase-3 negatively regulates anti-inflammatory interleukin-10 for lipopolysaccharide-induced iNOS/NO biosynthesis and RANTES production in microglial cells[J]. Immunology, 2009, 128(1): e275-e286.

[18] Eleonore Beurel, Richard S Jope. Differential regulation of STAT family members by glycogen synthase kinase-3[J]. J Biol Chem, 2008, 283(32): 21934-21944.

[19] Eleonore Beurel, Richard S Jope. Glycogen synthase kinase-3 promotes the synergistic action of interferon-gamma on lipopolysaccharide-induced IL-6 production in RAW264.7 cells[J]. Cell Signal, 2009, 21(6): 978-985.

[20] Li Faqi, zhao Zhong-chong, Kenneth Maiese. Microglial integrity is maintained by erythropoietin through integration of Akt and its substrates of glycogen synthase kinase-3β,β-catenin,and nuclear factor-κB[J]. Curr Neurovasc Res, 2006, 3(3): 187-201.

[21] Servio H Ramirez, Fan Shong-shan, Zhang Ming, et al. Inhibition of glycogen synthase kinase 3beta(GSK3beta) decreases inflammatory responses in brain endothelial cells[J].Am J Pathol, 2010, 176(2): 881-892.

[22] Wang Mei-jen, Huang Hsin-yi, Chen Wu-fu, et al. Glycogen synthase kinase-3beta inactivation inhibits tumor necrosis factor-alpha production in microglia by modulating nuclear factor kappaB and MLK3/JNK signaling cascades[J]. J Neuroinflammation, 2010, 7(99): 1-18.

[23] Hu Xiao-yu, Paul K Paik, Janice Chen, et al. IFN- γ suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins[J]. Immunity, 2006, 24(5): 563-574.

[24] Wang Hui-zhi, Jonathan Brown, Carlos A Garcia, et al. The role of glycogen synthase kinase 3 in regulating IFN-beta-mediated IL-10 production[J]. J Immunol, 2011, 186(2): 675-684.

[25] Dai Chun-sun, Wen Xiao-yan, He Wei-chun, et al. Inhibition of proinflammatory RANTES expression by TGF-beta1 is mediated by glycogen synthase kinase-3beta-dependent beta-catenin signaling[J]. J Biol Chem, 2011, 286(9): 7052-7059.

[26] Luis C Fuentealba, Edward Eivers, Astushi Ikeda, et al. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal[J]. Cell, 2007, 131(5): 980-993.

[27] Cheng-chieh Tsai, Jui-In Kai, Huang Wei-ching, et al. Glycogen synthase kinase-3beta facilitates IFN-gamma-induced STAT1 activation by regulating Src homology-2 domain-containing phosphatase 2[J]. J Immunol, 2009, 183(2): 856-864.

[28] Harrington L E, Hatton R D, Mangan P R, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages[J]. Nat Immunol, 2005, 6(11): 1123-1132.

[29] Vaishnav Krishnan, Eric J Nestler. The molecular neurobiology of depression[J]. Nature, 2008, 455(7215): 894-902.

[30] Bruce S McEwen. Physiology and neurobiology of stress and adaptation: central role of the brain[J]. Physiol Rev, 2007, 87(3): 873-904.

[31] Dost Ongur, Wayne C Drevets, Joseph L Price. Glial reduction in the subgenual prefrontal cortex in mood disorders[J]. Proc Natl Acad Sci USA, 1998, 95(22): 13290-13295.

[32] D Chichung Lie, Song Hong-jun, Sophia A Colamarino, et al. Neurogenesis in the adult brain: new strategies for central nervous system diseases[J]. Annu Rev Pharmacol. Toxicol, 2004, 44: 399-421.

[33] Malberg J E, Duman R S. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment[J]. Neuropsychopharmacology, 2003, 28(9): 1562-1571.

[34] Jessica E Malberg, Amelia J Eisch, Eric J Nestler, et al. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus[J]. J Neurosci, 2000, 20(24): 9104-9110.

[35] David D J, Samuels B A, Rainer Q, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression[J]. Neuron, 2009, 62(4): 479-493.

[36] Tea-Yeon Eom, Richard S Jope. Blocked inhibitory serine-phosphorylation of glycogen synthase kinase-3α/βimpairs in vivo neural precursor cell proliferation[J]. Biol Psychiatry, 2009, 66(5): 494-502.

[37] Woo-Yang Kim, Wang Xin-shuo, Wu Yao-hong, et al. GSK-3 is amaster regulator of neural progenitor homeostasis[J]. Nat Neurosci, 2009, 12(11): 1390-1397.

[38] Mao Ying-wei, Ge Xue-cai, Christopher L Frank, et al. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3β/β-catenin signaling[J]. Cell, 2009, 136(6): 1017-1031.

[39] Shuken Boku, Shin Nakagawa, Takahiro Masuda, et al. Glucocorticoids and lithium reciprocally regulate the proliferation of adult dentate gyrus-derived neural precursor cells through GSK-3b and b-Catenin/TCF pathway[J]. Neuropsychopharmacology, 2009, 34(3): 805-815.

[40] Wexler E M, Geschwind D H, Palmer T D. Lithium regulates adult hippocampal progenitor development through canonical Wnt pathway activation[J]. Molecular Psychiatry, 2008, 13(3): 285-292.

[41] Ryota Hashimoto, Nobuyuki Takei, Kazuhiro Shimazu, et al. Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity[J]..Neuropharmacology, 2002, 43(7): 1173-1179.

[42] De Vivo M, Maayani S. Characterization of the 5-hydroxytryptamine1a receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes[J]. J Pharmacol Exp Ther, 1986, 238(1): 248-253.

[43] Daniel S Cowen, Rebecca S Sowers, David R Manning. Activation of a mitogen-activated protein kinase (ERK2) by the 5-hydroxytryptamine1A receptor is sensitive not only to inhibitors of phosphatidylinositol 3-kinase, but to an inhibitor of phosphatidylcholine hydrolysis[J]. J Biol Chem, 1996, 271(37): 22297-22300.

[44] Katarina Varnas, Christer Halldin, Hakan Hall. Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain[J]. Hum Brain Mapp, 2004, 22(3): 246-260.

[45] Mustapha Riad, Sylvia Garcia, Kenneth Watkins, et al. Somatodendritic localization of 5-HT1A and preterminal axonal localization of 5-HT1B serotonin receptors in adult rat brain[J]. J Comp Neurol, 2000, 417(2): 181-194.

[46] Daniel Hoyer, Jason P Hannon, Graeme R Martin. Molecular, pharmacological and functional diversity of 5- HT receptors[J]. Pharmacol Biochem Behav, 2002, 71(4): 533-554.

[47] Klaus B Fink, Manfred Gothert. 5-HT receptor regulation of neurotransmitter release[J]. Pharmacol Rev, 2007, 59(4): 360-417.

[48] Kennett G A, Dourish C T, Curzon G. Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression[J]. Eur J Pharmacol, 1987, 134(3): 265-274.

[49] Youssef Sari. Serotonin1B receptors: from protein to physiological function and behavior[J]. Neurosci Biobehav Rev, 2004, 28(6): 565-582.

[50] Lee A Dawson, Zoe A Hughes, Kathryn R Starr. Characterisation of the selective 5-HT1B receptor antagonist SB-616234-A(1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): in vivo neurochemical and behavioural evidence of anxiolytic/antidepressant activity[J]. Neuropharmacology, 2006, 50(8): 975-983.

[51] Franck Chenu, Denis David, Isabelle Leroux-Nicollet. Serotonin1B heteroreceptor activation induces anantidepressant-like effect in micewith an alteration of the serotonergic system[J]. J Psychiatry Neurosci, 2008, 33(6): 541 - 550.

[52] Per Svenningsson, Paul Greengard. P11 (S100A10)-an inducible adaptor protein that modulates neuronal functions[J]. Curr Opin Pharmacol, 2007, 7(1): 27-32.

[53] Conn P J, Elaine Sanders-Bush. Selective 5HT-2 antagonists inhibit serotonin stimulated phosphatidylinositol metabolism in cerebral cortex[J]. Neuropharmacology, 1984, 23(8): 993-996.

[54] Stephanie Watts. Activation of the mitogen-activated protein kinase pathway via the 5-HT2A receptor[J]. Ann N Y Acad Sci, 1998, 861: 162-168.

[55] Cullen L Schmid, Kirsten M Raehal, Laura M Bohn. Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo[J]. Proc. Natl. Acad. Sci.U.S.A. 2008, 105(3): 1079-1084.

[56] Miner L A, Backstrom J R, Sanders B E. Ultrastructural localization of serotonin2A receptors in the middlelayers of the rat prelimbic prefrontal cortex[J]. Neuroscience, 2003, 116(1): 107-117.

[57] Christopher J Schmidt, Gina M Fadayel. The selective 5-HT2A receptor antagonist, MDL 100,907, increases dopamine efflux in the prefrontal cortex of the rat[J]. Eur J Pharmacol, 1995, 273(3): 273-279.

[58] Gerard J Marek, Linda Carpenter, Christopher J McDougle, et al. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders[J]. Neuropsychopharmacology, 2003, 28(2): 402-412.

[59] Nichols D E. Hallucinogens[J]. Pharmacol Ther, 2004, 101(2): 131-181.

[60] Landolt H P, Wehrle R. Antagonism of serotonergic 5-HT2A/2C receptors: mutual improvement of sleep, cognition and mood?[J]. Eur J Neurosci, 2009, 29(9): 1795-1809.

[61] Joseph L Price, Wayne C Drevets. Neurocircuitry of mood disorders[J]. Neuropsychopharmacology, 2010, 35(1): 192-216.

[62] Paul R Albert, Sylvie Lemonde. 5-HT1A receptors, gene repression,and depression: guilt by association[J]. Neuroscientist, 2004, 10(6): 575-593.

[63] Markowitz J S, Brown C S, Moore T R. Atypical antipsychotics. Part I: Pharmacology, pharmacokinetics, and efficacy[J]. Ann Pharmacother, 1999, 33(1): 73-85.

[64] Li Xiao-hui, Zhu Wa-wa, Myoung-Sun Roh, et al. In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain[J]. Neuropsychopharmacology, 2004, 29(8): 1426-1431.

[65] Jean-Martin Beaulieu, Zhang Xiaod-dong, Ramona Rodriguiz. Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency[J]. Proc Natl Acad Sci USA, 2008, 105(4): 1333-1338.

[66] Abigail M Polter, Yang Su-fen, Richard S Jope, et al. Functional significance of glycogen synthase kinase-3 regulation by serotonin[J]. Cell Signal, 2012, 24(1): 265-71.

[67] Hideki Okamoto, Bhavya Voleti, Mounira Banasr, et al. Wnt2 expression and signaling is increased by different classes of antidepressant treatments[J]. Biol Psychiatry, 2010, 68(6): 521-527.

[68] Abigail Polter, Yang Su-fen, Anna A Zmijewska, et al. Forkhead box, class o transcription factors in brain: regulation and behavioral manifestation[J]. Biol Psychiatry, 2009, 65(2): 150-159.

[69] Claudie Hooper, Vladimir Markevich, Florian Plattner, et al. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation[J]. Eur J Neurosci, 2007, 25(1): 81-86.

[70] Sigeng Chen, Geoffrey C Owens, Kathryn L Crossin, et al. Serotonin stimulates mitochondrial transport in hippocampal neurons[J]. Mol Cell Neurosci, 2007, 36(4): 472-483.

[71] Daniel S Cowen, Nadine N Johnson-Farley, Tatyana Travkina. 5-HT receptors couple to activation of Akt, but not extracellular-regulated kinase (ERK), in cultured hippocampal neurons[J]. J Neurochem, 2005, 93(4): 910-917.

[72] DeWire S M, Ahn S, Lefkowitz R J, et al. Beta-arrestins and cell signaling[J]. Annu Rev Physiol, 2007, 69: 483-510.

[73] Robert J Lefkowitz, Sudha K Shenoy. Transduction of receptor signals by beta-arrestins[J]. Science, 2005, 308(5721): 512-517.

[74] Laura Bohn, Gainetdinov R R, Lin F T, et al. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence[J]. Nature, 2000, 408(6813): 720-723.

[75] Massot O, Rousselle J C, Fillion M P, et al. 5-HT1B receptors: a novel target for lithium. Possible involvement in mood disorders[J]. Neuropsychopharmacology, 1999, 21(4): 530-541.

[76] Chen L, Zhou W, Chen P, et al. Glycogen synthase kinase-3beta is a functional modulator of serotonin 1b receptors[J]. Mol Pharmacol, 2011, 79(6): 974-986.

[77] Weiner D M, Burstein E S, Nash N, et al. 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics[J]. J Pharmacol Exp Ther, 2001, 299(1): 268-276.

[78] Li Xiao-hua, Kelley M Rosborough, Ari B Friedman, et al. Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics[J]. Int J Neuropsychopharmacol, 2007, 10(1): 7-19.

[79] Jean-Martin Beaulieu, Tatyana D Sotnikova, Sebastien Marion, et al. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior[J]. Cell, 2005, 122(2): 261-273.

[80] Abigail M Polter, Li Xiao-hua. Glycogen synthase kinase-3 is an intermediate modulator of serotonin neurotransmission[J]. Frontiers in Molecular Neuroscience, 2011, 24(4): 1-14.

[81] Alex L van Bemmel. The link between sleep and depression: the effects of antidepressants on EEG sleep[J]. J Psychosom Res, 1997, 42(6): 555-564.

[82] Rao U. DSM-5: Disruptive mood dysregulation disorder[J].DMDD, 2014, 11: 119-23.

[83] Maurice M Ohayon, Thomas Roth. Place of chronic insomnia in the course of depressive and anxiety disorders[J]. J Psychiatr Res, 2003, 37(1): 9-15.

[84] Jennifer A Mohawk, Manuel Miranda-Anaya, Ozgur Tataroglu, et al. Lithium and genetic inhibition of GSK3β enhance the effect of methamphetamine on circadian rhythms in the mouse[J]. Behav Pharmacol, 2009, 20(2): 174-183.

[85] Caroline H Ko, Joseph S Takahashi. Molecular components of the mammalian circadian clock[J]. Hum Mol Genet, 2006, 15(2): 271-277.

[86] Francesco Benedetti, Alessandro Serretti, Cristina Colombo. Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression[J]. Am J Med Genet, 2003, 123(1): 23-26.

[87] Joseph T Coyle. What can a clock mutation in mice tell us about bipolar disorder?[J]. Proc Natl Acad Sci USA, 2007, 104(15): 6097-6098.

[88] Sebastian Martinek, Susan Ionog, Armen Manoukian. A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock[J]. Cell, 2001, 105(6): 769 -779.

[89] Chisato Iitaka, Kouomi Miyazaki, Toshihiro Akake. A role for glycogen synthase kinase-3beta in the mammalian circadian clock[J]. J Biol Chem, 2005, 280(33): 29397-29402.

[90] Philip Cohen, Michel Goedert. GSK3 inhibitors: development and therapeutic potential[J]. Nat Rev Drug Discov, 2004, 3(6): 479-487.