Molecular Neurobiology

, Volume 40, Issue 2, pp 108–121

GSK3β in Ethanol Neurotoxicity



Alcohol consumption during pregnancy is a significant public health problem and may result in a wide range of adverse outcomes for the child. The developing central nervous system (CNS) is particularly susceptible to ethanol toxicity. Children with fetal alcohol spectrum disorders (FASD) have a variety of cognitive, behavioral, and neurological impairments. FASD currently represents the leading cause of mental retardation in North America ahead of Down syndrome and cerebral palsy. Ethanol exposure during development causes multiple abnormalities in the brain such as permanent loss of neurons, ectopic neurons, and alterations in synaptogenesis and myelinogenesis. These alcohol-induced structural alterations in the developing brain underlie many of the behavioral deficits observed in FASD. The cellular and molecular mechanisms of ethanol neurotoxicity, however, remain unclear. Ethanol elicits cellular stresses, including oxidative stress and endoplasmic reticulum stress. Glycogen synthase kinase 3β (GSK3β), a multifunctional serine/threonine kinase, responds to various cellular stresses. GSK3β is particularly abundant in the developing CNS, and regulates diverse developmental events in the immature brain, such as neurogenesis and neuronal differentiation, migration, and survival. Available evidence indicates that the activity of GSK3β in the CNS is affected by ethanol. GSK3β inhibition provides protection against ethanol neurotoxicity, whereas high GSK3β activity/expression sensitizes neuronal cells to ethanol-induced damages. It appears that GSK3β is a converging signaling point that mediates some of ethanol’s neurotoxic effects.


Alcohol Apoptosis Development Fetal alcohol syndrome Neurodegeneration 


  1. 1.
    Riley EP, McGee CL (2005) Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behavior. Exp Biol Med (Maywood) 230:357–365Google Scholar
  2. 2.
    Sampson PD, Streissguth AP, Bookstein FL, Little RE, Clarren SK, Dehaene P, Hanson JW, Graham JM Jr (1997) Incidence of fetal alcohol syndrome and prevalence of alcohol-related neurodevelopmental disorder. Teratology 56:317–326PubMedGoogle Scholar
  3. 3.
    May PA, Gossage JP (2001) Estimating the prevalence of fetal alcohol syndrome. Alcohol Res Health 25:159–167PubMedGoogle Scholar
  4. 4.
    Stratton K, Howe C, Battagila F, eds. (1996) Fetal alcohol syndrome: diagnosis, epidemiology, prevention, and treatment. National Academy Press, Washington D.C.Google Scholar
  5. 5.
    Nash K, Sheard E, Rovet J, Koren G (2008) Understanding fetal alcohol spectrum disorders (FASDs): toward identification of a behavioral phenotype. Scientific World Journal 8:873–882PubMedGoogle Scholar
  6. 6.
    Mattson SN, Schoenfeld AM, Riley EP (2001) Teratogenic effects of alcohol on brain and behavior. Alcohol Res Health 25:185–191PubMedGoogle Scholar
  7. 7.
    O’Malley KD, Nanson J (2002) Clinical implications of a link between fetal alcohol spectrum disorder and attention-deficit hyperactivity disorder. Can J Psychiatry 47:349–354PubMedGoogle Scholar
  8. 8.
    O’Callaghan FV, O’Callaghan M, Najman JM, Williams GM, Bor W (2003) Maternal alcohol consumption during pregnancy and physical outcomes up to 5 years of age: a longitudinal study. Early Hum Dev 71:137–148PubMedGoogle Scholar
  9. 9.
    O’Callaghan FV, O’Callaghan M, Najman JM, Williams GM, Bor W (2007) Prenatal alcohol exposure and attention, learning and intellectual ability at 14 years: a prospective longitudinal study. Early Hum Dev 83:115–123PubMedGoogle Scholar
  10. 10.
    Lupton C, Burd L, Harwood R (2004) Cost of fetal alcohol spectrum disorders. Am J Med Genet C Semin Med Genet 127C:42–50PubMedGoogle Scholar
  11. 11.
    Clarren SK, Alvord EJ, Sumi SM, Streissguth AP, Smith DW (1978) Brain malformations related to prenatal exposure to ethanol. J Pediatr 92:64–67PubMedGoogle Scholar
  12. 12.
    Danis RP, Newton N, Keith L (1981) Pregnancy and alcohol. Curr Probl Obstet Gynecol 4:2–48PubMedGoogle Scholar
  13. 13.
    Swayze VW 2nd, Johnson VP, Hanson JW, Piven J, Sato Y, Giedd JN, Mosnik D, Andreasen NC (1997) Magnetic resonance imaging of brain anomalies in fetal alcohol syndrome. Pediatrics 99:232–240PubMedGoogle Scholar
  14. 14.
    Archibald SL, Fennema-Notestine C, Gamst A, Riley EP, Mattson SN, Jernigan TL (2001) Brain dysmorphology in individuals with severe prenatal alcohol exposure. Dev Med Child Neurol 43:148–154PubMedGoogle Scholar
  15. 15.
    Bookstein FL, Streissguth AP, Connor PD, Sampson PD (2006) Damage to the human cerebellum from prenatal alcohol exposure: the anatomy of a simple biometrical explanation. Anat Rec B New Anat 289:195–209PubMedGoogle Scholar
  16. 16.
    Sowell ER, Mattson SN, Kan E, Thompson PM, Riley EP, Toga AW (2008) Abnormal cortical thickness and brain-behavior correlation patterns in individuals with heavy prenatal alcohol exposure. Cereb Cortex 18:136–144PubMedGoogle Scholar
  17. 17.
    Miller MW (1993) Migration of cortical neurons is altered by gestational exposure to ethanol. Alcohol Clin Exp Res 17:304–314PubMedGoogle Scholar
  18. 18.
    Swanson DJ, King MA, Walker DW, Heaton MB (1995) Chronic prenatal ethanol exposure alters the normal ontogeny of choline acetyltransferase activity in the rat septohippocampal system. Alcohol Clin Exp Res 19:1252–1260PubMedGoogle Scholar
  19. 19.
    Miller MW (1996) Limited ethanol exposure selectively alters the proliferation of precursor cells in the cerebral cortex. Alcohol Clin Exp Res 20:139–143PubMedGoogle Scholar
  20. 20.
    Luo J, Miller MW (1998) Growth factor-mediated neural proliferation: target of ethanol toxicity. Brain Res Brain Res Rev 27:157–167PubMedGoogle Scholar
  21. 21.
    Minana R, Climent E, Barettino D, Segui JM, Renau-Piqueras J, Guerri C (2000) Alcohol exposure alters the expression pattern of neural cell adhesion molecules during brain development. J Neurochem 75:954–964PubMedGoogle Scholar
  22. 22.
    Olney JW, Ishimaru MJ, Bittigau P, Ikonomidou C (2000) Ethanol-induced apoptotic neurodegeneration in the developing brain. Apoptosis 5:515–521PubMedGoogle Scholar
  23. 23.
    Yanni PA, Lindsley TA (2000) Ethanol inhibits development of dendrites and synapses in rat hippocampal pyramidal neuron cultures. Brain Res Dev Brain Res 120:233–243PubMedGoogle Scholar
  24. 24.
    Bearer CF (2001) L1 cell adhesion molecule signal cascades: targets for ethanol developmental neurotoxicity. Neurotoxicology 22:625–633PubMedGoogle Scholar
  25. 25.
    Ikonomidou C, Bittigau P, Koch C, Genz K, Hoerster F, Felderhoff-Mueser U, Tenkova T, Dikranian K, Olney JW (2001) Neurotransmitters and apoptosis in the developing brain. Biochem Pharmacol 62:401–405PubMedGoogle Scholar
  26. 26.
    Goodlett CR, Horn KH, Zhou FC (2005) Alcohol teratogenesis: mechanisms of damage and strategies for intervention. Exp Biol Med (Maywood) 230:394–406Google Scholar
  27. 27.
    Soscia SJ, Tong M, Xu XJ, Cohen AC, Chu J, Wands JR, de la Monte SM (2006) Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain. Cell Mol Life Sci 63:2039–2056PubMedGoogle Scholar
  28. 28.
    Kumada T, Jiang Y, Cameron DB, Komuro H (2007) How does alcohol impair neuronal migration? J Neurosci Res 85:465–470PubMedGoogle Scholar
  29. 29.
    Hoffman EJ, Mintz CD, Wang S, McNickle DG, Salton SR, Benson DL (2008) Effects of ethanol on axon outgrowth and branching in developing rat cortical neurons. Neuroscience 157:556–565PubMedGoogle Scholar
  30. 30.
    Ebrahim SH, Diekman ST, Floyd RL, Decoufle P (1999) Comparison of binge drinking among pregnant and nonpregnant women, United States, 1991–1995. Am J Obstet Gynecol 180:1–7PubMedGoogle Scholar
  31. 31.
    Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175–1186PubMedGoogle Scholar
  32. 32.
    Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65:391–426PubMedGoogle Scholar
  33. 33.
    Luo J (2009) Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. Cancer Lett 273:194–200PubMedGoogle Scholar
  34. 34.
    Kaytor MD, Orr HT (2002) The GSK3 beta signaling cascade and neurodegenerative disease. Curr Opin Neurobiol 12:275–278PubMedGoogle Scholar
  35. 35.
    Hartigan JA, Johnson GV (1999) Transient increases in intracellular calcium result in prolonged site-selective increases in Tau phosphorylation through a glycogen synthase kinase 3beta-dependent pathway. J Biol Chem 274:21395–21401PubMedGoogle Scholar
  36. 36.
    Lesort M, Jope RS, Johnson GV (1999) Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3beta and Fyn tyrosine kinase. J Neurochem 72:576–584PubMedGoogle Scholar
  37. 37.
    Hartigan JA, Xiong XC, Johnson GV (2001) Glycogen synthase kinase 3beta is tyrosine phosphorylated by PYK2. Biochem Biophys Res Commun 284:485–489PubMedGoogle Scholar
  38. 38.
    Sayas CL, Ariaens A, Ponsioen B, Moolenaar WH (2006) GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-mediated neurite retraction. Mol Biol Cell 17:1834–1844PubMedGoogle Scholar
  39. 39.
    Takahashi-Yanaga F, Shiraishi F, Hirata M, Miwa Y, Morimoto S, Sasaguri T (2004) Glycogen synthase kinase-3beta is tyrosine-phosphorylated by MEK1 in human skin fibroblasts. Biochem Biophys Res Commun 316:411–415PubMedGoogle Scholar
  40. 40.
    Cole A, Frame S, Cohen P (2004) Further evidence that the tyrosine phosphorylation of glycogen synthase kinase-3 (GSK3) in mammalian cells is an autophosphorylation event. Biochem J 377:249–255PubMedGoogle Scholar
  41. 41.
    Baltzis D, Pluquet O, Papadakis AI, Kazemi S, Qu LK, Koromilas AE (2007) The eIF2alpha kinases PERK and PKR activate glycogen synthase kinase 3 to promote the proteasomal degradation of p53. J Biol Chem 282:31675–31687PubMedGoogle Scholar
  42. 42.
    Diehl JA, Cheng M, Roussel MF, Sherr CJ (1998) Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12:3499–3511PubMedGoogle Scholar
  43. 43.
    Bhat RV, Shanley J, Correll MP, Fieles WE, Keith RA, Scott CW, Lee CM (2000) Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci U S A 97:11074–11079PubMedGoogle Scholar
  44. 44.
    Meares GP, Jope RS (2007) Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis. J Biol Chem 282:16989–17001PubMedGoogle Scholar
  45. 45.
    Ille F, Sommer L (2005) Wnt signaling: multiple functions in neural development. Cell Mol Life Sci 62:1100–1108PubMedGoogle Scholar
  46. 46.
    Patapoutian A, Reichardt LF (2000) Roles of Wnt proteins in neural development and maintenance. Curr Opin Neurobiol 10:392–399PubMedGoogle Scholar
  47. 47.
    Malaterre J, Ramsay RG, Mantamadiotis T (2007) Wnt-Frizzled signalling and the many paths to neural development and adult brain homeostasis. Front Biosci 12:492–506PubMedGoogle Scholar
  48. 48.
    Manoukian AS, Woodgett JR (2002) Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways. Adv Cancer Res 84:203–229PubMedGoogle Scholar
  49. 49.
    Woodgett JR (1990) Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J 9:2431–2438PubMedGoogle Scholar
  50. 50.
    Leroy K, Brion JP (1999) Developmental expression and localization of glycogen synthase kinase-3beta in rat brain. J Chem Neuroanat 16:279–293PubMedGoogle Scholar
  51. 51.
    Takahashi M, Tomizawa K, Ishiguro K (2000) Distribution of tau protein kinase I/glycogen synthase kinase-3beta, phosphatases 2A and 2B, and phosphorylated tau in the developing rat brain. Brain Res 857:193–206PubMedGoogle Scholar
  52. 52.
    Coyle-Rink J, Del Valle L, Sweet T, Khalili K, Amini S (2002) Developmental expression of Wnt signaling factors in mouse brain. Cancer Biol Ther 1:640–645PubMedGoogle Scholar
  53. 53.
    Heaton MB, Paiva M, Madorsky I, Shaw G (2003) Ethanol effects on neonatal rat cortex: comparative analyses of neurotrophic factors, apoptosis-related proteins, and oxidative processes during vulnerable and resistant periods. Brain Res Dev Brain Res 145:249–262PubMedGoogle Scholar
  54. 54.
    Livy DJ, Miller EK, Maier SE, West JR (2003) Fetal alcohol exposure and temporal vulnerability: effects of binge-like alcohol exposure on the developing rat hippocampus. Neurotoxicol Teratol 25:447–458PubMedGoogle Scholar
  55. 55.
    Spittaels K, Van den Haute C, Van Dorpe J, Geerts H, Mercken M, Bruynseels K, Lasrado R, Vandezande K, Laenen I, Boon T, Van Lint J, Vandenheede J, Moechars D, Loos R, Van Leuven F (2000) Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem 275:41340–41349PubMedGoogle Scholar
  56. 56.
    Spittaels K, Van den Haute C, Van Dorpe J, Terwel D, Vandezande K, Lasrado R, Bruynseels K, Irizarry M, Verhoye M, Van Lint J, Vandenheede JR, Ashton D, Mercken M, Loos R, Hyman B, Van der Linden A, Geerts H, Van Leuven F (2002) Neonatal neuronal overexpression of glycogen synthase kinase-3beta reduces brain size in transgenic mice. Neuroscience 113:797–808PubMedGoogle Scholar
  57. 57.
    Cui H, Meng Y, Bulleit RF (1998) Inhibition of glycogen synthase kinase 3beta activity regulates proliferation of cultured cerebellar granule cells. Brain Res Dev Brain Res 111:177–188PubMedGoogle Scholar
  58. 58.
    Knoepfler PS, Kenney AM (2006) Neural precursor cycling at sonic speed: N-Myc pedals, GSK-3 brakes. Cell Cycle 5:47–52PubMedGoogle Scholar
  59. 59.
    Boku S, Nakagawa S, Masuda T, Nishikawa H, Kato A, Kitaichi Y, Inoue T, Koyama T (2009) Glucocorticoids and lithium reciprocally regulate the proliferation of adult dentate gyrus-derived neural precursor cells through GSK-3beta and beta-catenin/TCF pathway. Neuropsychopharmacology 34:805–815PubMedGoogle Scholar
  60. 60.
    Shimizu T, Kagawa T, Inoue T, Nonaka A, Takada S, Aburatani H, Taga T (2008) Stabilized beta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells. Mol Cell Biol 28:7427–7441PubMedGoogle Scholar
  61. 61.
    Jin L, Hu X, Feng L (2005) NT3 inhibits FGF2-induced neural progenitor cell proliferation via the PI3K/GSK3 pathway. J Neurochem 93:1251–1261PubMedGoogle Scholar
  62. 62.
    Maurer MH, Brömme JO, Feldmann RE Jr, Järve A, Sabouri F, Bürgers HF, Schelshorn DW, Krüger C, Schneider A, Kuschinsky W (2007) Glycogen synthase kinase 3beta (GSK3beta) regulates differentiation and proliferation in neural stem cells from the rat subventricular zone. J Proteome Res 6:1198–1208PubMedGoogle Scholar
  63. 63.
    Yeste-Velasco M, Folch J, Trullàs R, Abad MA, Enguita M, Pallàs M, Camins A (2007) Glycogen synthase kinase-3 is involved in the regulation of the cell cycle in cerebellar granule cells. Neuropharmacology 53:295–307PubMedGoogle Scholar
  64. 64.
    Ma C, Wang J, Gao Y, Gao TW, Chen G, Bower KA, Odetallah M, Ding M, Ke Z, Luo J (2007) The role of glycogen synthase kinase 3beta in the transformation of epidermal cells. Cancer Res 67:7756–7764PubMedGoogle Scholar
  65. 65.
    Huang W, Chang HY, Fei T, Wu H, Chen YG (2007) GSK3 beta mediates suppression of cyclin D2 expression by tumor suppressor PTEN. Oncogene 26:2471–2482PubMedGoogle Scholar
  66. 66.
    Cheng TS, Hsiao YL, Lin CC, Yu CT, Hsu CM, Chang MS, Lee CI, Huang CY, Howng SL, Hong YR (2008) Glycogen synthase kinase 3beta interacts with and phosphorylates the spindle-associated protein astrin. J Biol Chem 283:2454–2464PubMedGoogle Scholar
  67. 67.
    Ciani L, Salinas PC (2007) c-Jun N-terminal kinase (JNK) cooperates with Gsk3beta to regulate dishevelled-mediated microtubule stability. BMC Cell Biol 8:27PubMedGoogle Scholar
  68. 68.
    Barth AI, Caro-Gonzalez HY, Nelson WJ (2008) Role of adenomatous polyposis coli (APC) and microtubules in directional cell migration and neuronal polarization. Semin Cell Dev Biol 19:245–251PubMedGoogle Scholar
  69. 69.
    Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120:137–149PubMedGoogle Scholar
  70. 70.
    Gärtner A, Huang X, Hall A (2006) Neuronal polarity is regulated by glycogen synthase kinase-3 (GSK-3beta) independently of Akt/PKB serine phosphorylation. J Cell Sci 119:3927–3934PubMedGoogle Scholar
  71. 71.
    González-Billault C, Del Río JA, Ureña JM, Jiménez-Mateos EM, Barallobre MJ, Pascual M, Pujadas L, Simó S, Torre AL, Gavin R, Wandosell F, Soriano E, Avila J (2005) A role of MAP1B in Reelin-dependent neuronal migration. Cereb Cortex 15:1134–1145PubMedGoogle Scholar
  72. 72.
    Tong N, Sanchez JF, Maggirwar SB, Ramirez SH, Guo H, Dewhurst S, Gelbard HA (2001) Activation of glycogen synthase kinase 3beta (GSK-3beta) by platelet activating factor mediates migration and cell death in cerebellar granule neurons. Eur J Neurosci 13:1913–1922PubMedGoogle Scholar
  73. 73.
    Hanks SK, Ryzhova L, Shin NY, Brábek J (2003) Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility. Front Biosci 8:d982–996PubMedGoogle Scholar
  74. 74.
    Bianchi M, De Lucchini S, Marin O, Turner DL, Hanks SK, Villa-Moruzzi E (2005) Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration. Biochem J 391:359–370PubMedGoogle Scholar
  75. 75.
    Carter JJ, Tong M, Silbermann E, Lahousse SA, Ding FF, Longato L, Roper N, Wands JR, de la Monte SM (2008) Ethanol impaired neuronal migration is associated with reduced aspartyl-asparaginyl-beta-hydroxylase expression. Acta Neuropathol 116:303–315PubMedGoogle Scholar
  76. 76.
    Yuskaitis CJ, Jope RS (2009) Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell Signal 21:264–273PubMedGoogle Scholar
  77. 77.
    Arévalo JC, Chao MV (2005) Axonal growth: where neurotrophins meet Wnts. Curr Opin Cell Biol 17:112–115PubMedGoogle Scholar
  78. 78.
    Muñoz-Montaño JR, Lim F, Moreno FJ, Avila J, Díaz-Nido J (1999) Glycogen synthase kinase-3 modulates neurite outgrowth in cultured neurons: possible implications for neurite pathology in Alzheimer’s disease. J Alzheimers Dis 1:361–378PubMedGoogle Scholar
  79. 79.
    Orme MH, Giannini AL, Vivanco MD, Kypta RM (2003) Glycogen synthase kinase-3 and Axin function in a beta-catenin-independent pathway that regulates neurite outgrowth in neuroblastoma cells. Mol Cell Neurosci 24:673–686PubMedGoogle Scholar
  80. 80.
    Castelo-Branco G, Rawal N, Arenas E (2004) GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons. J Cell Sci 117:5731–5737PubMedGoogle Scholar
  81. 81.
    Dill J, Wang H, Zhou F, Li S (2008) Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS. J Neurosci 28:8914–8928PubMedGoogle Scholar
  82. 82.
    Chen G, Bower KA, Xu M, Ding M, Shi X, Ke ZJ, Luo J (2009) Cyanidin-3-glucoside reverses ethanol-induced inhibition of neurite outgrowth: role of glycogen synthase kinase 3beta. Neurotox Res 15:321–31PubMedCrossRefGoogle Scholar
  83. 83.
    Valerio A, Ghisi V, Dossena M, Tonello C, Giordano A, Frontini A, Ferrario M, Pizzi M, Spano P, Carruba MO, Nisoli E (2006) Leptin increases axonal growth cone size in developing mouse cortical neurons by convergent signals inactivating glycogen synthase kinase-3beta. J Biol Chem 281:12950–12958PubMedGoogle Scholar
  84. 84.
    Takahashi M, Yasutake K, Tomizawa K (1999) Lithium inhibits neurite growth and tau protein kinase I/glycogen synthase kinase-3beta-dependent phosphorylation of juvenile tau in cultured hippocampal neurons. J Neurochem 73:2073–2083PubMedGoogle Scholar
  85. 85.
    Owen R, Gordon-Weeks PR (2003) Inhibition of glycogen synthase kinase 3beta in sensory neurons in culture alters filopodia dynamics and microtubule distribution in growth cones. Mol Cell Neurosci 23:626–637PubMedGoogle Scholar
  86. 86.
    Goold RG, Gordon-Weeks PR (2001) Microtubule-associated protein 1B phosphorylation by glycogen synthase kinase 3beta is induced during PC12 cell differentiation. J Cell Sci 114:4273–4284PubMedGoogle Scholar
  87. 87.
    Goold RG, Gordon-Weeks PR (2005) The MAP kinase pathway is upstream of the activation of GSK3beta that enables it to phosphorylate MAP1B and contributes to the stimulation of axon growth. Mol Cell Neurosci 28:524–534PubMedGoogle Scholar
  88. 88.
    Trivedi N, Marsh P, Goold RG, Wood-Kaczmar A, Gordon-Weeks PR (2005) Glycogen synthase kinase-3beta phosphorylation of MAP1B at Ser1260 and Thr1265 is spatially restricted to growing axons. J Cell Sci 118:993–1005PubMedGoogle Scholar
  89. 89.
    Seng S, Avraham HK, Jiang S, Venkatesh S, Avraham S (2006) KLHL1/MRP2 mediates neurite outgrowth in a glycogen synthase kinase 3beta-dependent manner. Mol Cell Biol 26:8371–8384PubMedGoogle Scholar
  90. 90.
    Zhou F, Zhang L, Wang A, Song B, Gong K, Zhang L, Hu M, Zhang X, Zhao N, Gong Y (2008) The association of GSK3 beta with E2F1 facilitates nerve growth factor-induced neural cell differentiation. J Biol Chem 283:14506–14515PubMedGoogle Scholar
  91. 91.
    Zhang W, Smith A, Liu JP, Cheung NS, Zhou S, Liu K, Li QT, Duan W (2009) GSK3beta modulates PACAP-induced neuritogenesis in PC12 cells by acting downstream of Rap1 in a caveolae-dependent manner. Cell Signal 21:237–245PubMedGoogle Scholar
  92. 92.
    Gonzalez-Billault C, Avila J, Cáceres A (2001) Evidence for the role of MAP1B in axon formation. Mol Biol Cell 12:2087–2098PubMedGoogle Scholar
  93. 93.
    Messing RO, Henteleff M, Park JJ (1991) Ethanol enhances growth factor-induced neurite formation in PC12 cells. Brain Res 565:301–311PubMedGoogle Scholar
  94. 94.
    Zou J, Rabin RA, Pentney RJ (1993) Ethanol enhances neurite outgrowth in primary cultures of rat cerebellar macroneurons. Brain Res Dev Brain Res 72:75–84PubMedGoogle Scholar
  95. 95.
    Saunders DE, Zajac CS, Wappler NL (1995) Alcohol inhibits neurite extension and increases N-myc and c-myc proteins. Alcohol 12:475–483PubMedGoogle Scholar
  96. 96.
    Lindsley TA, Kerlin AM, Rising LJ (2003) Time-lapse analysis of ethanol’s effects on axon growth in vitro. Brain Res Dev Brain Res 147:191–199PubMedGoogle Scholar
  97. 97.
    Bingham SM, Mudd LM, Lopez TF, Montague JR (2004) Effects of ethanol on cultured embryonic neurons from the cerebral cortex of the rat. Alcohol 32:129–135PubMedGoogle Scholar
  98. 98.
    Beurel E, Jope RS (2006) The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol 79:173–189PubMedGoogle Scholar
  99. 99.
    Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J (2001) Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 20:27–39PubMedGoogle Scholar
  100. 100.
    Pap M, Cooper GM (1998) Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem 273:19929–19932PubMedGoogle Scholar
  101. 101.
    Crowder RJ, Freeman RS (2000) Glycogen synthase kinase-3beta activity is critical for neuronal death caused by inhibiting phosphatidylinositol 3-kinase or Akt but not for death caused by nerve growth factor withdrawal. J Biol Chem 275:34266–34271PubMedGoogle Scholar
  102. 102.
    Hetman M, Cavanaugh JE, Kimelman D, Xia Z (2000) Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci 20:2567–2574PubMedGoogle Scholar
  103. 103.
    Song L, De Sarno P, Jope RS (2002) Central role of glycogen synthase kinase-3beta in endoplasmic reticulum stress-induced caspase-3 activation. J Biol Chem 277:44701–44708PubMedGoogle Scholar
  104. 104.
    Bijur GN, De Sarno P, Jope RS (2000) Glycogen synthase kinase-3beta facilitates staurosporine- and heat shock-induced apoptosis. Protection by lithium. J Biol Chem 275:7583–7590PubMedGoogle Scholar
  105. 105.
    Bhat RV, Budd SL (2002) GSK3beta signalling: casting a wide net in Alzheimer’s disease. Neurosignals 11:251–261PubMedGoogle Scholar
  106. 106.
    Aghdam SY, Barger SW (2007) Glycogen synthase kinase-3 in neurodegeneration and neuroprotection: lessons from lithium. Curr Alzheimer Res 4:21–31PubMedGoogle Scholar
  107. 107.
    Takashima A, Yamaguchi H, Noguchi K, Michel G, Ishiguro K, Sato K, Hoshino T, Hoshi M, Imahori K (1995) Amyloid beta peptide induces cytoplasmic accumulation of amyloid protein precursor via tau protein kinase I/glycogen synthase kinase-3beta in rat hippocampal neurons. Neurosci Lett 198:83–86PubMedGoogle Scholar
  108. 108.
    Everall IP, Bell C, Mallory M, Langford D, Adame A, Rockestein E, Masliah E (2002) Lithium ameliorates HIV-gp120-mediated neurotoxicity. Mol Cell Neurosci 21:493–501PubMedGoogle Scholar
  109. 109.
    Chen G, Bower KA, Ma C, Fang S, Thiele CJ, Luo J (2004) Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. FASEB J 18:1162–1164PubMedGoogle Scholar
  110. 110.
    Koh SH, Lee YB, Kim KS, Kim HJ, Kim M, Lee YJ, Kim J, Lee KW, Kim SH (2005) Role of GSK-3beta activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene. Eur J Neurosci 22:301–309PubMedGoogle Scholar
  111. 111.
    Liu F, Gong X, Zhang G, Marquis K, Reinhart P, Andree TH (2005) The inhibition of glycogen synthase kinase 3beta by a metabotropic glutamate receptor 5 mediated pathway confers neuroprotection to Abeta peptides. J Neurochem 95:1363–1372PubMedGoogle Scholar
  112. 112.
    Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A 102:6990–6995PubMedGoogle Scholar
  113. 113.
    Wang W, Yang Y, Ying C, Li W, Ruan H, Zhu X, You Y, Han Y, Chen R, Wang Y, Li M (2007) Inhibition of glycogen synthase kinase-3beta protects dopaminergic neurons from MPTP toxicity. Neuropharmacology 52:1678–1684PubMedGoogle Scholar
  114. 114.
    Chen YY, Chen G, Fan Z, Luo J, Ke ZJ (2008) GSK3beta and endoplasmic reticulum stress mediate rotenone-induced death of SK-N-MC neuroblastoma cells. Biochem Pharmacol 76:128–138PubMedGoogle Scholar
  115. 115.
    Toiber D, Berson A, Greenberg D, Melamed-Book N, Diamant S, Soreq H (2008) N-acetylcholinesterase-induced apoptosis in Alzheimer’s disease. PLoS ONE 3:e3108PubMedGoogle Scholar
  116. 116.
    Brewster JL, Linseman DA, Bouchard RJ, Loucks FA, Precht TA, Esch EA, Heidenreich KA (2006) Endoplasmic reticulum stress and trophic factor withdrawal activate distinct signaling cascades that induce glycogen synthase kinase-3beta and a caspase-9-dependent apoptosis in cerebellar granule neurons. Mol Cell Neurosci 32:242–253PubMedGoogle Scholar
  117. 117.
    Lee KY, Koh SH, Noh MY, Park KW, Lee YJ, Kim SH (2007) Glycogen synthase kinase-3beta activity plays very important roles in determining the fate of oxidative stress-inflicted neuronal cells. Brain Res 1129:89–99PubMedGoogle Scholar
  118. 118.
    Eom TY, Roth KA, Jope RS (2007) Neural precursor cells are protected from apoptosis induced by trophic factor withdrawal or genotoxic stress by inhibitors of glycogen synthase kinase 3. J Biol Chem 282:22856–22864PubMedGoogle Scholar
  119. 119.
    Takadera T, Fujibayashi M, Kaniyu H, Sakota N, Ohyashiki T (2007) Caspase-dependent apoptosis induced by thapsigargin was prevented by glycogen synthase kinase-3 inhibitors in cultured rat cortical neurons. Neurochem Res 32:1336–1342PubMedGoogle Scholar
  120. 120.
    Maggirwar SB, Tong N, Ramirez S, Gelbard HA, Dewhurst S (1999) HIV-1 Tat-mediated activation of glycogen synthase kinase-3beta contributes to Tat-mediated neurotoxicity. J Neurochem 73:578–586PubMedGoogle Scholar
  121. 121.
    Gómez-Sintes R, Hernández F, Bortolozzi A, Artigas F, Avila J, Zaratin P, Gotteland JP, Lucas JJ (2007) Neuronal apoptosis and reversible motor deficit in dominant-negative GSK-3 conditional transgenic mice. EMBO J 26:2743–2754PubMedGoogle Scholar
  122. 122.
    D’Mello SR, Anelli R, Calissano P (1994) Lithium induces apoptosis in immature cerebellar granule cells but promotes survival of mature neurons. Exp Cell Res 211:332–338PubMedGoogle Scholar
  123. 123.
    Tsukane M, Yoshizaki C, Yamauchi T (2007) Development and specific induction of apoptosis of cultured cell models overexpressing human tau during neural differentiation: implication in Alzheimer’s disease. Anal Biochem 360:114–122PubMedGoogle Scholar
  124. 124.
    Hoshi M, Takashima A, Noguchi K, Murayama M, Sato M, Kondo S, Saitoh Y, Ishiguro K, Hoshino T, Imahori K (1996) Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. Proc Natl Acad Sci U S A 93:2719–2723PubMedGoogle Scholar
  125. 125.
    Hongisto V, Smeds N, Brecht S, Herdegen T, Courtney MJ, Coffey ET (2003) Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Mol Cell Biol 23:6027–6036PubMedGoogle Scholar
  126. 126.
    Sui Z, Sniderhan LF, Fan S, Kazmierczak K, Reisinger E, Kovács AD, Potash MJ, Dewhurst S, Gelbard HA, Maggirwar SB (2006) Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons. Eur J Neurosci 23:2623–2634PubMedGoogle Scholar
  127. 127.
    Watcharasit P, Bijur GN, Song L, Zhu J, Chen X, Jope RS (2003) Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. J Biol Chem 278:48872–48879PubMedGoogle Scholar
  128. 128.
    Mishra R, Barthwal MK, Sondarva G, Rana B, Wong L, Chatterjee M, Woodgett JR, Rana A (2007) Glycogen synthase kinase-3beta induces neuronal cell death via direct phosphorylation of mixed lineage kinase 3. J Biol Chem 282:30393–30405PubMedGoogle Scholar
  129. 129.
    Benedito AB, Lehtinen M, Massol R, Lopes UG, Kirchhausen T, Rao A, Bonni A (2005) The transcription factor NFAT3 mediates neuronal survival. J Biol Chem. 280:2818–2825PubMedGoogle Scholar
  130. 130.
    Pap M, Cooper GM (2002) Role of translation initiation factor 2B in control of cell survival by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta signaling pathway. Mol Cell Biol 22:578–586PubMedGoogle Scholar
  131. 131.
    Jope RS, Roh MS (2006) Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets 7:1421–1434PubMedGoogle Scholar
  132. 132.
    Linseman DA, Butts BD, Precht TA, Phelps RA, Le SS, Laessig TA, Bouchard RJ, Florez-McClure ML, Heidenreich KA (2004) Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 24:9993–10002PubMedGoogle Scholar
  133. 133.
    Jope RS, Yuskaitis CJ, Beurel E (2007) Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res 32:577–595PubMedGoogle Scholar
  134. 134.
    Liu Y, Chen G, Ma C, Bower KA, Xu M, Fan Z, Shi X, Ke ZJ, Luo J (2009) Over-expression of GSK3 beta sensitizes neuronal cells to ethanol toxicity. J Neurosci Res [Epub ahead of print]Google Scholar
  135. 135.
    de la Monte SM, Wands JR (2002) Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons. Cell Mol Life Sci 59:882–893PubMedGoogle Scholar
  136. 136.
    Xu J, Yeon JE, Chang H, Tison G, Chen GJ, Wands J, de la Monte S (2003) Ethanol impairs insulin-stimulated neuronal survival in the developing brain: role of PTEN phosphatase. J Biol Chem 278:26929–26937PubMedGoogle Scholar
  137. 137.
    Neznanova O, Björk K, Rimondini R, Hansson AC, Hyytiä P, Heilig M, Sommer WH (2009) Acute ethanol challenge inhibits glycogen synthase kinase-3beta in the rat prefrontal cortex. Int J Neuropsychopharmacol 12:275–280PubMedGoogle Scholar
  138. 138.
    Zhou K, Zhang L, Xi J, Tian W, Xu Z (2009) Ethanol prevents oxidant-induced mitochondrial permeability transition pore opening in cardiac cells. Alcohol Alcohol 44:20–24PubMedGoogle Scholar
  139. 139.
    Jope RS (2003) Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci 24:441–443PubMedGoogle Scholar
  140. 140.
    Zhong J, Yang X, Yao W, Lee W (2006) Lithium protects ethanol-induced neuronal apoptosis. Biochem Biophys Res Commun 350:905–910PubMedGoogle Scholar
  141. 141.
    Chakraborty G, Saito M, Mao RF, Wang R, Vadasz C, Saito M (2008) Lithium blocks ethanol-induced modulation of protein kinases in the developing brain. Biochem Biophys Res Commun 367:597–602PubMedGoogle Scholar
  142. 142.
    Sasaki T, Han F, Shioda N, Moriguchi S, Kasahara J, Ishiguro K, Fukunaga K (2006) Lithium-induced activation of Akt and CaM kinase II contributes to its neuroprotective action in a rat microsphere embolism model. Brain Res 1108:98–106PubMedGoogle Scholar
  143. 143.
    Liang MH, Wendland JR, Chuang DM (2008) Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling. Mol Cell Neurosci 37:440–453PubMedGoogle Scholar
  144. 144.
    Takadera T, Ohyashiki T (2004) Glycogen synthase kinase-3 inhibitors prevent caspase-dependent apoptosis induced by ethanol in cultured rat cortical neurons. Eur J Pharmacol 499:239–245PubMedGoogle Scholar
  145. 145.
    Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L, Mills D, Brown MJ, Haigh D, Ward RW, Smith DG, Murray KJ, Reith AD, Holder JC (2000) Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol 7:793–803PubMedGoogle Scholar
  146. 146.
    Leost M, Schultz C, Link A, Wu YZ, Biernat J, Mandelkow EM, Bibb JA, Snyder GL, Greengard P, Zaharevitz DW, Gussio R, Senderowicz AM, Sausville EA, Kunick C, Meijer L (2000) Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Eur J Biochem 267:5983–5994PubMedGoogle Scholar
  147. 147.
    Martinez A, Alonso M, Castro A, Pérez C, Moreno FJ (2002) First non-ATP competitive glycogen synthase kinase 3beta (GSK-3beta) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer’s disease. J Med Chem 45:1292–1299PubMedGoogle Scholar
  148. 148.
    Chen G, Ma C, Bower KA, Shi X, Ke Z, Luo J (2008) Ethanol promotes endoplasmic reticulum stress-induced neuronal death: involvement of oxidative stress. J Neurosci Res 86:937–946PubMedGoogle Scholar
  149. 149.
    Crews FT, Nixon K (2009) Mechanisms of neurodegeneration and regeneration in alcoholism. Alcohol Alcohol 44:115–127PubMedGoogle Scholar
  150. 150.
    Liangpunsakul S, Wou SE, Zeng Y, Ross RA, Jayaram HN, Crabb DW (2008) Effect of ethanol on hydrogen peroxide-induced AMPK phosphorylation. Am J Physiol Gastrointest Liver Physiol 295:G1173–1181PubMedGoogle Scholar
  151. 151.
    Dolcet X, Egea J, Soler RM, Martin-Zanca D, Comella JX (1999) Activation of phosphatidylinositol 3-kinase, but not extracellular-regulated kinases, is necessary to mediate brain-derived neurotrophic factor-induced motoneuron survival. J Neurochem 73:521–531PubMedGoogle Scholar
  152. 152.
    Duarte AI, Santos P, Oliveira CR, Santos MS, Rego AC (2008) Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression. Biochim Biophys Acta 1783:994–1002PubMedGoogle Scholar
  153. 153.
    Li Z, Ding M, Thiele CJ, Luo J (2004) Ethanol inhibits brain-derived neurotrophic factor-mediated intracellular signaling and activator protein-1 activation in cerebellar granule neurons. Neuroscience 126:149–162PubMedGoogle Scholar
  154. 154.
    Kalluri HS, Ticku MK (2003) Regulation of ERK phosphorylation by ethanol in fetal cortical neurons. Neurochem Res 28:765–769PubMedGoogle Scholar
  155. 155.
    Asyyed A, Storm D, Diamond I (2006) Ethanol activates cAMP response element-mediated gene expression in select regions of the mouse brain. Brain Res 1106:63–71PubMedGoogle Scholar
  156. 156.
    Wilkie MB, Besheer J, Kelley SP, Kumar S, O’Buckley TK, Morrow AL, Hodge CW (2007) Acute ethanol administration rapidly increases phosphorylation of conventional protein kinase C in specific mammalian brain regions in vivo. Alcohol Clin Exp Res 31:1259–1267PubMedGoogle Scholar
  157. 157.
    Pandey SC (2004) The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction. Pharmacol Ther 104:47–58PubMedGoogle Scholar
  158. 158.
    Li J, Li YH, Yuan XR (2003) Changes of phosphorylation of cAMP response element binding protein in rat nucleus accumbens after chronic ethanol intake: naloxone reversal. Acta Pharmacol Sin 24:930–936PubMedGoogle Scholar
  159. 159.
    Pandey SC, Zhang H, Ugale R, Prakash A, Xu T, Misra K (2008) Effector immediate-early gene arc in the amygdala plays a critical role in alcoholism. J Neurosci 28:2589–2600PubMedGoogle Scholar
  160. 160.
    Yang X, Horn K, Wand GS (1998a) Chronic ethanol exposure impairs phosphorylation of CREB and CRE-binding activity in rat striatum. Alcohol Clin Exp Res 22:382–390Google Scholar
  161. 161.
    Yang X, Horn K, Baraban JM, Wand GS (1998b) Chronic ethanol administration decreases phosphorylation of cyclic AMP response element-binding protein in granule cells of rat cerebellum. J Neurochem 70:224–232CrossRefGoogle Scholar
  162. 162.
    Woodgett JR (2003) Physiological roles of glycogen synthase kinase-3: potential as a therapeutic target for diabetes and other disorders. Curr Drug Targets Immune Endocr Metabol Disord 3:281–290PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of Kentucky College of MedicineLexingtonUSA

Personalised recommendations