Signal Transduction Pathways in the Pathophysiology of Bipolar Disorder

  • Jeremy W. Gawryluk
  • L. Trevor YoungEmail author
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 5)


Signal transduction pathways and genes associated with cellular life and death have received much attention in bipolar disorder (BPD) and provide scientists with molecular targets for understanding the biological basis of BPD. In this chapter, we describe the signal transduction pathways involved in the molecular biology of BPD and the indications for the mechanisms of disease and treatment. We discuss the BPD literature with respect to the disease itself and the effects of mood stabilizer treatment on cellular receptors, including G-protein-coupled receptors, glutamate receptors, and tyrosine receptor kinase. We also discuss the intracellular alterations observed in BPD to second messenger systems, such as cyclic adenosine monophosphate (cAMP), protein kinase A, phosphoinositide pathways, glycogen synthase kinase-3, protein kinase B, Wnt, and arachidonic acid. We describe how receptor activation and modulation of second messengers occurs, and how transcription factors are activated and altered in this disease (e.g., the transcription factors ?-catenin, cAMP response element binding protein, heat shock transcription factor-1, and activator protein-1). Abnormalities in intracellular signal transduction pathways could generate a functional discrepancy in numerous neurotransmitter systems, which may explain the varied clinical symptoms observed in BPD. The influence of mood stabilizers on transcription factors may be important in connecting the regulation of gene expression to neuroplasticity and cellular resilience.


Mood Stabilizer cAMP Response Element Binding Serum BDNF Level cAMP Response Element Binding Phosphorylation Chronic Lithium Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Alda M, Grof P, Rouleau GA et al (2005) Investigating rcspondcrs to lithium prophylaxis as a strategy for mapping susceptibility genes for bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 29(6):1038–1045PubMedGoogle Scholar
  2. Andreazza AC, Cassini C, Rosa AR, Leite MC, de Almeida LM, Nardin P et al (2007) Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res 41(6):523–529PubMedGoogle Scholar
  3. Asghari V, Wang JF, Reiach JS, Young LT (1998) Differential effects of mood stabilizers on Fos/Jun proteins and AP-1 DNA binding activity in human neuroblastoma S11-SY5Y cells. Brain Res Mol Brain Res 58(l-2):95–102PubMedGoogle Scholar
  4. Arevalo JC, Chao MV (2005) Axonal growth: where neurotrophins meet Wnts. Curr Opin Cell Biol 17(2):112–115PubMedGoogle Scholar
  5. Avissar S, Nechamkin Y, Barki-Harrington L, Roitman G, Schreiber G (1997) Differential G protein measures in mononuclear leukocytes of patients with bipolar mood disorder arc state dependent. J Affect Disord 43(2):85–93PubMedGoogle Scholar
  6. Axelrod J (1990) Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transduction. Biochem Soc Trans 18(4):503–507PubMedGoogle Scholar
  7. Barbour B, Szatkowski M, Ingledew N, Attwell D (1989) Arachidonic acid induces a prolonged inhibition of glutamate uptake into glial cells. Nature 342(6252):918–920PubMedGoogle Scholar
  8. Barker N (2008) The canonical Wnt/beta-catenin signalling pathway. Methods Mol Biol 468:5–15PubMedGoogle Scholar
  9. Basselin M, Chang L, Bell JM, Rappoport SI (2006) Chronic lithium chloride administration attenuates brain NMDA receptor-initiated signaling via arachidonic acid in unanesthetized rats. Neuropsychopharmacology 31:1659–1674PubMedGoogle Scholar
  10. Basselin M, Villacreses NE, Chen M, Bell JM, Rapoport SI (2007) Chronic carbamazepine administration reduces N-methyl-D-aspartate receptor-initiated signaling via arachidonic acid in rat brain. Biol Psychiatry 62(8):934–943PubMedPubMedCentralGoogle Scholar
  11. Bauer M, Alda M, Priller J, Young LT, International Group for the Study of Lithium Treated Patients (IGSLI) (2003) Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders. Pharmacopsychiatry 36(Suppl 3):S250–S254PubMedGoogle Scholar
  12. Bazinet RP (2009) Is the brain arachidonic acid cascade a common target of drugs used to manage bipolar disorder? Biochem Soc Trans 37(5):1104–1109PubMedGoogle Scholar
  13. Beasley C, Cotter D, Khan N, Pollard C, Sheppard P, Varndell I et al (2001) Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia. Neurosci Lett 302(2–3):117–120PubMedGoogle Scholar
  14. Beaulieu JM, Tirotta E, Sotnikova TD, Masri B, Salahpour A, Gainetdinov RR et al (2007) Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo. J Neurosci 27(4):881–885PubMedGoogle Scholar
  15. Beaulieu JM, Gainetdinov RR, Caron MG (2009) Akt/GSK3 signaling in the action of psychotropic drugs. Annu Rev Pharmacol Toxicol 49:327–347PubMedGoogle Scholar
  16. Beavo JA, Bechtel PJ, Krebs EG (1974) Activation of protein kinase by physiological concentrations of cyclic AMP. Proc Natl Acad Sci USA 71(9):3580–3583PubMedPubMedCentralGoogle Scholar
  17. Belmaker RH (2004) Bipolar disorder. N Engl J Med 351(5):476–486PubMedGoogle Scholar
  18. Belmaker RH, Shapiro J, Vainer E, Nemanov L, Ebstein RP, Agam G (2002) Reduced inositol content in lymphocyte-derived cell lines from bipolar patients. Bipolar Disord 4(1):67–69PubMedGoogle Scholar
  19. Benedetti F, Serretti A, Colombo C, Lorenzi C, Tubazio V, Smeraldi E (2004) A glycogen synthase kinase 3-beta promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression. Neurosci Lett 368(2):123–126PubMedGoogle Scholar
  20. Benedetti F, Serretti A, Pontiggia A, Bernasconi A, Lorenzi C, Colombo C et al (2005) Long-term response to lithium salts in bipolar illness is influenced by the glycogen synthase kinase 3-beta -50 T/C SNP. Neurosci Lett 376(1):51–55PubMedGoogle Scholar
  21. Berridge MJ, Dawson RM, Downes CP, Heslop JP, Irvine RF (1983) Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides. Biochem J 212(2):473–482PubMedPubMedCentralGoogle Scholar
  22. 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(4):173–189PubMedPubMedCentralGoogle Scholar
  23. Bezchlibnyk Y, Young LT (2002) The neurobiology of bipolar disorder: focus on signal transduction pathways and the regulation of gene expression. Can J Psychiatry 47(2):135–148PubMedGoogle Scholar
  24. Bijur GN, Jope RS (2003) Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria. Neuroreport 14(18):2415–2419PubMedGoogle Scholar
  25. Blumberg HP, Krystal JH, Bansal R, Martin A, Dziura J, Durkin K et al (2006) Age, rapid-cycling, and pharmacotherapy effects on ventral prefrontal cortex in bipolar disorder: a cross-sectional study. Biol Psychiatry 59(7):611–618PubMedGoogle Scholar
  26. Boer U, Eglins J, Krause D, Schnell S, Schofl C, Knepel W (2007) Enhancement by lithium of cAMP-induced CRE/CREB-directed gene transcription conferred by TORC on the CREB basic leucine zipper domain. Biochem J 408(1):69–77PubMedPubMedCentralGoogle Scholar
  27. Boer U, Cierny I, Krause D, Heinrich A, Lin H, Mayr G et al (2008) Chronic lithium salt treatment reduces CRE/CREB-directed gene transcription and reverses its upregulation by chronic psychosocial stress in transgenic reporter gene mice. Neuropsychopharmacology 33(10):2407–2415PubMedGoogle Scholar
  28. Boyle WJ, Smeal T, Defize LH, Angel P, Woodgett JR, Karin M et al. (1991) Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell 64(3):573–584PubMedGoogle Scholar
  29. Brown AS, Mallinger AG, Renbaum LC (1993) Elevated platelet membrane phosphatidylinositol-4, 5-bisphosphate in bipolar mania. Am J Psychiatry 150(8):1252–1254PubMedGoogle Scholar
  30. Catapano LA, Manji HK (2006) G protein-coupled receptors in major psychiatric disorders. Biochim Biophys Acta 1768(4):976–993PubMedPubMedCentralGoogle Scholar
  31. Chalecka-Franaszek E, Chuang DM (1999) Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci USA 96(15):8745–8750PubMedPubMedCentralGoogle Scholar
  32. Chang YC, Kim HW, Rapoport SI, Rao JS (2008) Chronic NMDA administration increases neuroinflammatory markers in rat frontal cortex: cross-talk between excitotoxicity and neuroinflammation. Neurochem Res 33(11):2318–2323PubMedPubMedCentralGoogle Scholar
  33. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neuroscience 4(4):299–309Google Scholar
  34. Chao MV, Rajagopal R, Lee FS (2006) Neurotrophin signalling in health and disease. Clin Sci (Lond) 110(2):167–173Google Scholar
  35. Chee IS, Lee SW, Kim JL, Wang SK, Shin YO, Shin SC et al (2001) 5-HT2A receptor gene promoter polymorphism -1438A/G and bipolar disorder. Psychiatr Genet 11(3):111–114PubMedGoogle Scholar
  36. Chen C, Bazan NG (2005) Endogenous PGE2 regulates membrane excitability and synaptic transmission inhippocarnpal CA1 pyramidal neurons. J Neurophysiol 93(2):929–941PubMedGoogle Scholar
  37. Chen RW, Chuang DM (1999) Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 274(10):6039–6042PubMedGoogle Scholar
  38. Chen B, Wang JF, Hill BC, Young LT (1999a) Lithium and valproate differentially regulate brain regional expression of phosphorylated CREB and c-Fos. Brain Res Mol Brain Res 70(1):45–53PubMedGoogle Scholar
  39. Chen G, Huang LD, Jiang YM, Manji HK (1999b) The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem 72(3):1327–1330PubMedGoogle Scholar
  40. Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK (2000) Enhancement of hippocampal neurogenesis by lithium. J Neurochem 75(4):1729–1734PubMedGoogle Scholar
  41. Chu B, Soncin F, Price BD, Stevenson MA, Calderwood SK (1996) Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. J Biol Chem 271(48):30847–30857PubMedGoogle Scholar
  42. Chu H, Soncin F, Price BD, Stevenson MA, Calderwood SK (1996) Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthasc kinasc 3 represses transcription a I activation by heat shock factor-1. J Biol Chem 27l(48):30847–30857Google Scholar
  43. Chuang DM (2004) Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? Crit Rev Neurobiol 15(1–2):83–90Google Scholar
  44. Crotty T, Cai J, Sakane F, Taketomi A, Prescott SM, Topham MK (2006) Diacylglycerol kinase delta regulates protein kinase C and epidermal growth factor receptor signaling. Proc Natl Acad Sci USA 103(42):15485–15490PubMedPubMedCentralGoogle Scholar
  45. Cunha AB, Frey BN, Andreazza AC, Goi JD, Rosa AR, Goncalves CA et al (2006) Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci Lett 398(3):215–219PubMedGoogle Scholar
  46. Daniel PB, Ilabcner JF (1998) Cyclical alternative exon splicing of transcription factor cyclic adenosine monophosphate response clement-binding protein (CREB) messenger ribonucleic acid during rat spermatogenesis. Endocrinology 139(9):3721–3729PubMedGoogle Scholar
  47. dc Oliveira GS, Cereser KM, Fernandes BS, Kauer-Sant’Anna M, Fries GR, Stertz L et al. (2009) Decreased brain-derived ncurotrophic factor in medicated and drug-free bipolar patients. J Psychiatr Res 43(14):1171–1174Google Scholar
  48. Dean O, Bush AI, Berk M, Copolov DL, van den Buuse M (2009) Glutathione depletion in the brain disrupts short-term spatial memory in the Y-maze in rats and mice. Behav Brain Res 198(1):258–262PubMedGoogle Scholar
  49. Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W (1996) The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 384(6604):39–43PubMedGoogle Scholar
  50. Diaz-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J, Sanz L et al (1996) The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Cell 86(5):777–786PubMedGoogle Scholar
  51. Divish MM, Sheftel G, Boyle A, Kalasapudi VD, Papolos DF, Lachman HM (1991) Differential effect of lithium on fos protooncogene expression mediated by receptor and postreceptor activators of protein kinase C and cyclic adenosine monophosphate: model for its antimanic action. J Neurosci Res 28(1):40–48PubMedGoogle Scholar
  52. Dowlatshahi D, MacQueen GM, Wang JF, Young LT (1998) Increased temporal cortex CREB concentrations and antidepressant treatment in major depression. Lancet 352(9142):1754–1755PubMedGoogle Scholar
  53. Dowlatshahi D, MacQueen G, Wang JF, Chen B, Young LT (2000) Increased hippocampal supragranular Timm staining in subjects with bipolar disorder. NeuroReport 11(17):3775–3778PubMedGoogle Scholar
  54. Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, Vannier M et al (1997) Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386(6627):824–827PubMedGoogle Scholar
  55. Dubovsky SL, Franks RD, Allen S, Murphy J (1986) Calcium antagonists in mania: a double-blind study of verapamil. Psychiatry Res 18(4):309–320PubMedGoogle Scholar
  56. Dubovsky SL, Thomas M, Hijazi A, Murphy J (1994) Intracellular calcium signalling in peripheral cells of patients with bipolar affective disorder. Eur Arch Psychiatry Clin Neurosci 243(5):229–234PubMedGoogle Scholar
  57. Dunham JS, Deakin JF, Miyajima F, Payton A, Toro CT (2009) Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains. J Psychiatr Res 43(14):1175–1184PubMedGoogle Scholar
  58. Eastman Q, Grosschedl R (1999) Regulation of LEF-1/TCF transcription factors by Wnt and other signals. Curr Opin Cell Biol 11(2):233–240PubMedGoogle Scholar
  59. Ebstein RP, Seamon K, Creveling CR, Daly JW (1982) Release of norepinephrine from brain vesicular preparations: effects of an adenylate cyclase activator, forskolin, and a phosphodiesterase inhibitor. Cell Mol Neurobiol 2(3):179–192PubMedGoogle Scholar
  60. Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L et al (2003) The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 23(19):7311–7316PubMedGoogle Scholar
  61. El Khoury A, Petterson U, Kallner G, Aberg-Wistedt A, Stain-Malmgren R (2002) Calcium homeostasis in long-term lithium-treated women with bipolar affective disorder. Prog Neuropsychopharmacol Biol Psychiatry 26(6):1063–1069PubMedGoogle Scholar
  62. Emamghoreishi M, Li PP, Schlichter L, Parikh SV, Cooke R, Warsh JJ (2000) Associated disturbances in calcium homeostasis and G protein-mediated cAMP signaling in bipolar I disorder. Biol Psychiatry 48(7):665–673PubMedGoogle Scholar
  63. Fan J, Ionita-Laza I, McQueen MB, Devlin B, Purcell S, Faraone SV et al (2009) Linkage disequilibrium mapping of the chromosome 6q21–22.31 bipolar I disorder susceptibility locus. Am J Med Genet B Neuropsychiatr Genet 153B(1):29–37Google Scholar
  64. Farooqui AA, Horrocks LA, Farooqui T (2007) Modulation of inflammation in brain: a matter of fat. J Neurochem 101(3):577–599PubMedGoogle Scholar
  65. Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L et al (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40(9):1056–1058PubMedPubMedCentralGoogle Scholar
  66. Fields A, Li PP, Kish SJ, Warsh JJ (1999) Increased cyclic AMP-dependent protein kinase activity in postmortem brain from patients with bipolar affective disorder. J Neurochem 73(4):1704–1710PubMedGoogle Scholar
  67. Finkbeiner S (2000) CREB couples neurotrophin signals to survival messages. Neuron 25(1):11–14PubMedGoogle Scholar
  68. Freeland K, Liu YZ, Latchman DS (2000) Distinct signalling pathways mediate the cAMP response element (CRE)-dependent activation of the calcitonin gene-related peptide gene promoter by cAMP and nerve growth factor. Biochem J 345(Pt 2):233–238PubMedPubMedCentralGoogle Scholar
  69. Frey BN, Andreazza AC, Cereser KM, Martins MR, Valvassori SS, Reus GZ et al (2006) Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania. Life Sci 79(3):281–286PubMedGoogle Scholar
  70. Friedman E, Wang HY (1996) Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects. J Neurochem 67(3):1145–1152PubMedGoogle Scholar
  71. Friedman E, Wang H-Y, Levinson D, Connell TA, Singh H (1993) Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry 33(7):520–525PubMedGoogle Scholar
  72. Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294(5548):1871–1875PubMedGoogle Scholar
  73. Gasiorowski K, Brokos B (2001) DNA repair of hydrogen peroxide-induced damage in human lymphocytes in the presence of four antimutagens. A study with alkaline single cell gel electrophoresis (comet assay). Cell Mol Biol Lett 6(4):897–911PubMedGoogle Scholar
  74. Glantz LA, Gilmore JH, Overstreet DH, Saiimi K, Lieberman JA, Jarskog LF (2010) Pro-apoptotic Par-4 and dopamine D2 receptor in temporal cortex in schizophrenia, bipolar disorder and major depression. Schizophr Res 2010 118(1–3):292–299PubMedPubMedCentralGoogle Scholar
  75. Goodwin GM, Martinez-Aran A, Glahn DC, Vieta E (2008) Cognitive impairment in bipolar disorder: neurodevelopment or neurodegeneration? An ECNP expert meeting report. Eur Neuropsychopharmacol 18(11):787–793PubMedGoogle Scholar
  76. Gooney M, Messaoudi E, Maher FO, Bramham CR, Lynch MA (2004) BDNF-induced LTP in dentate gyrus is impaired with age: analysis of changes in cell signaling events. Neurobiol Aging 25(10):1323–1331PubMedGoogle Scholar
  77. Gooney M, Messaoudi E, Maher FO, Bramham CR, Lynch MA (2004) BDNF-induced LTP in dentate gyrus is impaired with age: analysis of changes in cell signaling events. Neurobiol Aging 25(10):1323–1331PubMedGoogle Scholar
  78. Gordon GR, Mulligan SJ, MacVicar B (2007) Astrocyte control of the cerebrovasculature. Glia 55(12):1214–1221PubMedGoogle Scholar
  79. Gould TD, Manji HK (2002a) Signaling networks in the pathophysiology and treatment of mood disorders. J Psychosom Res 53(2):687–697PubMedGoogle Scholar
  80. Gould TD, Manji HK (2002b) The Wnt signaling pathway in bipolar disorder. Neuroscientist 8(5):497–511PubMedGoogle Scholar
  81. Gould TD, Picchini AM, Einat H, Manji HK (2006) Targeting glycogen synthase kinase-3 in the CNS: implications for the development of new treatments for mood disorders. Curr Drug Targets 7(11):1399–1409PubMedGoogle Scholar
  82. Gould TD, Manji HK. (2002) Signaling networks in the pathophysiology and treatment of mood disorders. J Psychosom Res 53(2):687–697PubMedGoogle Scholar
  83. Hahn CG, Friedman E (1999) Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord 1(2):81–86PubMedGoogle Scholar
  84. Hahn CG, Gomez G, Restrepo D, Friedman E, Josiassen R, Pribitkin EA et al (2005) Aberrant intracellular calcium signaling in olfactory neurons from patients with bipolar disorder. Am J Psychiatry 162(3):616–618PubMedGoogle Scholar
  85. Hashimoto R, Takei N, Shimazu K, Christ L, Lu B, Chuang DM (2002) Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology 43(7):1173–1179PubMedGoogle Scholar
  86. Hedgepeth CM, Conrad LJ, Zhang J, Huang HC, Lee VM, Klein PS (1997) Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Dev Biol 185(1):82–91PubMedGoogle Scholar
  87. Heinrich A, Boer U, Tzvetkov M, Oetjen E, Knepel W (2009) Stimulation by lithium of the interaction between the transcription factor CREB and its co-activator TORC. Biosci Rep 29(2):77–87PubMedGoogle Scholar
  88. Hertz R, Magenheim J, Berman I, Bar-Tana J (1998) Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha. Nature 392(6675):512–516PubMedGoogle Scholar
  89. Hough C, Lu SJ, Davis CL, Chuang DM, Post RM (1999) Klevatcd basal and thapsigargin-stitnulatcd intraccllular calcium of platelets and lymphocytes from bipolar affective disorder patients measured by a fluorometric microassa. Biol Psychiatry 46(2):247–255PubMedGoogle Scholar
  90. Kapczinski F, Dias VV, Frey BN, Kauer-Sant'Anna M (2009) Brain-derived neurotrophic factor in bipolar disorder: beyond trait and state: comment on ‘Decreased levels of serum brain-derived neurotrophic factor in both depressed and euthymic patients with unipolar depression and in euthymic patients with bipolar I and II disorders'. Bipolar Disord 11(2):221–222; author reply 222–223Google Scholar
  91. Karege F, Schwald M, El Kouaissi R (2004a) Drug-induced decrease of protein kinase a activity reveals alteration in BDNF expression of bipolar affective disorder. Neuropsychopharmacology 29(4):805–812PubMedGoogle Scholar
  92. Karege F, Schwald M, Papadimitriou P, Lachausse C, Cisse M (2004b) The cAMP-dependent protein kinase A and brain-derived neurotrophic factor expression in lymphoblast cells of bipolar affective disorder. J Affect Disord 79(1–3):187–192PubMedGoogle Scholar
  93. Karpinski BA, Morle GD, Huggenvik J, Uhler MD, Leiden JM (1992) Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element. Proc Natl Acad Sci USA 89(11):4820–4824PubMedPubMedCentralGoogle Scholar
  94. Kato T (2008a) Molecular neurobiology of bipolar disorder: a disease of 'mood-stabilizing neurons'? Trends Neurosci 31(10):495–503PubMedGoogle Scholar
  95. Kato T (2008b) Role of mitochondrial DNA in calcium signaling abnormality in bipolar disorder. Cell Calcium 44(1):92–102PubMedGoogle Scholar
  96. Kato T, Ishiwata M, Mori K, Washizuka S, Tajima O, Akiyama T et al (2003) Mechanisms of altered Ca2+ signalling in transformed lymphoblastoid cells from patients with bipolar disorder. Int J Neuropsychopharmacol 6(4):379–389PubMedGoogle Scholar
  97. Kato T, Kakiuchi C, Iwamoto K (2007) Comprehensive gene expression analysis in bipolar disorder. Can J Psychiatry 52(12):763–771PubMedGoogle Scholar
  98. Kauer-Sant’Anna M, Kapczinski F, Andreazza AC, Bond DJ, Lam RW, Young LT et al (2009) Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. Int J Neuropsychopharmacol 12(4):447–458PubMedGoogle Scholar
  99. Kim HW, Rapoport SI, Rao JS (2009) Altered expression of apoptotic factors and synaptic markers in postmortem brain from bipolar disorder patients. Mol Psychiatry:1–10 (Epub ahead of print)Google Scholar
  100. Kim UW, Rapoport SI, Rao JS (2009) Altered arachadonic acid cascade enzymes in postmortem brain from bipolar disorder patients. Mol Psychiatry (Hpub ahead of print): 1–10Google Scholar
  101. Kim UW, Rapoport SI, Rao JS (2010) Altered expression of apoptotic factors and synaptic markers in postmortem brain from bipolar disorder patients. Neurobiol Dis 37(3):596–603PubMedPubMedCentralGoogle Scholar
  102. Kinney JW, Sanchez-Alavez M, Barr AM, Criado JR, Crawley JN, Behrens MM et al (2009) Impairment of memory consolidation by galanin correlates with in vivo inhibition of both LTP and CREB phosphorylation. Neurobiol Learn Mem 92(3):429–438PubMedPubMedCentralGoogle Scholar
  103. Kopnisky KL, Chalecka-Franaszek E, Gonzalez-Zulueta M, Chuang DM (2003) Chronic lithium treatment antagonizes glutamate-induced decrease of phosphorylated CREB in neurons via reducing protein phosphatase 1 and increasing MEK activities. Neuroscience 116(2):425–435PubMedGoogle Scholar
  104. Kuehl FA, Humes JL, Tarnoff J, Cirillo VJ, Ham EA (1970) Prostaglandin receptor site: evidence for an essential role in the action of luteinizing hormone. Science 169(948):883–886PubMedGoogle Scholar
  105. Kupfer DJ (2005) The increasing medical burden in bipolar disorder. JAMA 293(20):2528–2530PubMedGoogle Scholar
  106. Lan MJ, Yuan P, Chen G, Manji HK (2008) Neuronal peroxisome proliferator-activated receptor gamma signaling: regulation by mood-stabilizer valproate. J Mol Neurosci 35(2):225–234PubMedPubMedCentralGoogle Scholar
  107. Lee KY, Ahn YM, Joo EJ, Jeong SH, Chang JS, Kim SC et al (2006) No association of two common SNPs at position -1727 A/T, -50 C/T of GSK-3 beta polymorphisms with schizophrenia and bipolar disorder of Korean population. Neurosci Lett 395(2):175–178PubMedGoogle Scholar
  108. Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM (2008) Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci 28(10):2576–2588PubMedGoogle Scholar
  109. Liang ZQ, Wang X, Li LY, Wang Y, Chen RW, Chuang DM et al (2007) Nuclear factor-kappaB-dependent cyclin D1 induction and DNA replication associated with N-methyl-D-aspartate receptor-mediated apoptosis in rat striatum. J Neurosci Res 85(6):1295–1309PubMedGoogle Scholar
  110. Lucas FR, Goold RG, Gordon-Weeks PR, Salinas PC (1998) Inhibition of GSK-3beta leading to the loss of phosphorylated MAP-1B is an early event in axonal remodelling induced by WNT-7a or lithium. J Cell Sci 111(Pt 10):1351–1361PubMedGoogle Scholar
  111. Machado-Vieira R, Dietrich MO, Leke R, Cereser VH, Zanatto V, Kapczinski F et al (2007) Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biol Psychiatry 61(2):142–144PubMedGoogle Scholar
  112. Maekawa M, Takashima N, Matsumata M, Ikegami S, Kontani M, Hara Y et al (2009) Arachidonic acid drives postnatal neurogenesis and elicits a beneficial effect on prepulse inhibition, a biological trait of psychiatric illnesses. PLoS ONE 4(4):e5085PubMedPubMedCentralGoogle Scholar
  113. Mamdani F, Alda M, Grof P, Young LT, Rouleau G, Turecki G (2008) Lithium response and genetic variation in the CREB family of genes. Am J Med Genet B Neuropsychiatr Genet 147B(4):500–504PubMedPubMedCentralGoogle Scholar
  114. Manji HK, Lenox RH (2000) The nature of bipolar disorder. J Clin Psychiatry 61(Suppl 13):42–57PubMedGoogle Scholar
  115. Manji HK, Potter WZ, Lenox RH (1995) Signal transduction pathways. Molecular targets for lithium's actions. Arch Gen Psychiatry 52(7):531–543PubMedGoogle Scholar
  116. Martinowich K, Scholoesser RJ, Manji HK (2009) Bipolar disorder: from genes to behavior pathways. J Clin Investig 119(4):726–736PubMedPubMedCentralGoogle Scholar
  117. Massat I, Sourey D, Del-Favero JV, Gestel S, Serretti A, Macciardi F et al (2002) Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European Multicenter Association Study of affective disorders. Am J Med Genet 114(2):177–185PubMedGoogle Scholar
  118. Mathews R, Li PP, Young LT, Kish SJ, Warsh JJ (1997) Increased G alpha q/11 immunoreactivity in postmortem occipital cortex from patients with bipolar affective disorder. Biol Psychiatry 41(6):649–656PubMedGoogle Scholar
  119. McCarty JH (2009) Cell adhesion and signaling networks in brain neurovascular units. Curr Opin Hematol 16(3):209–214PubMedPubMedCentralGoogle Scholar
  120. McInnis MG, Lan TH, Willour VL, McMahon FJ, Simpson SG, Addington AM et al (2003) Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12. Mol Psychiatry 8(3):288–298PubMedGoogle Scholar
  121. Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M et al (2007) Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 64(5):543–552PubMedPubMedCentralGoogle Scholar
  122. Meyer TE, Habener JF (1993) Cyclic adenosine 3?, 5?-monophosphate response element binding protein (CREB) and related transcription-activating deoxyribonucleic acid-binding proteins. Endocr Rev 14(3):269–290PubMedGoogle Scholar
  123. Michelon L, Meira-Lima I, Cordeiro Q, Miguita K, Breen G, Collier D et al (2006) Association study of the INPP1, 5HTT, BDNF, AP-2beta and GSK-3beta GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder. Neurosci Lett 403(3):288–293PubMedGoogle Scholar
  124. Mitchell PB, Manji HK, Chen G, Jolkovsky L, Smith-Jackson E, Denicoff K et al (1997) High levels of Gs alpha in platelets of euthymic patients with bipolar affective disorder. Am J Psychiatry 154(2):218–223PubMedGoogle Scholar
  125. Monteleone P, Serritella C, Martiadis V, Maj M (2008) Decreased levels of serum brain-derived neurotrophic factor in both depressed and euthymic patients with unipolar depression and in euthymic patients with bipolar I and II disorders. Bipolar Disord 10(1):95–100PubMedGoogle Scholar
  126. Needleman P, Minkes M, Raz A (1976) Thromboxanes: selective biosynthesis and distinct biological properties. Science 193(4248):163–165PubMedGoogle Scholar
  127. Nemanov L, Ebstein RP, Belmaker RH, Osher Y, Agam G (1999) Effect of bipolar disorder on lymphocyte inositol monophosphatase mRNA levels. Int J Neuropsychopharmacol 2(1):25–29PubMedGoogle Scholar
  128. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL (2002) The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet 71(3):651–655PubMedPubMedCentralGoogle Scholar
  129. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P et al (2005) BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 10(2):208–212PubMedGoogle Scholar
  130. Newton PM, Ron D (2007) Protein kinase C and alcohol addiction. Pharmacol Res 55(6):570–577PubMedGoogle Scholar
  131. Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16(7):2365–2372PubMedGoogle Scholar
  132. Nishiguchi N, Breen G, Russ C, St Clair D, Collier D (2006) Association analysis of the glycogen synthase kinase-3beta gene in bipolar disorder. Neurosci Lett 394(3):243–245PubMedGoogle Scholar
  133. Ongur D, Drevets WC, Price JL (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 95(22):13290–13295PubMedPubMedCentralGoogle Scholar
  134. Ongur D, Jensen JE, Prescot AP, Stork C, Lundy M, Cohen BM et al (2008) Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry 64(8):718–726PubMedPubMedCentralGoogle Scholar
  135. Orr SK, Bazinet RP (2008) The emerging role of docosahexaenoic acid in neuroinflammation. Curr Opin Investig Drugs 9(7):735–743PubMedGoogle Scholar
  136. Ou J, Tu H, Shan B, Luk A, DeBose-Boyd RA, Bashmakov Y et al (2001) Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand-dependent activation of the LXR. Proc Natl Acad Sci USA 98(11):6027–6032PubMedPubMedCentralGoogle Scholar
  137. Pandey GN, Rizavi HS, Dwivedi Y, Pavuluri MN (2008) Brain-derived neurotrophic factor gene expression in pediatric bipolar disorder: effects of treatment and clinical response. J Am Acad Child Adolesc Psychiatry 47(9):1077–1085PubMedGoogle Scholar
  138. Park SK, Nguyen MD, Fischer A, Luke MP, Affar EB, Dieffenbach PB et al (2005) Par-4 links dopamine signaling and depression. Cell 122(2):275–287PubMedGoogle Scholar
  139. Pearlson GD, Wong DF, Tune LE, Ross CA, Chase GA, Links JM et al (1995) In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder. Arch Gen Psychiatry 52(6):471–477PubMedGoogle Scholar
  140. Pellerin L, Magistretti PJ (2004) Neuroscience. Let there be (NADH) light. Science 305(5680):50–52PubMedGoogle Scholar
  141. Perez J, Tardito D, Mori S, Racagni G, Smeraldi E, Zanardi R (1999) Abnormalities of cyclic adenosine monophosphate signaling in platelets from untreated patients with bipolar disorder. Arch Gen Psychiatry 56(3):248–253PubMedGoogle Scholar
  142. Perez J, Tardito D, Mori S, Racagni G, Smeraldi E, Zanardi R (2000) Altered Rap1 endogenous phosphorylation and levels in platelets from patients with bipolar disorder. J Psychiatr Res 34(2):99–104PubMedGoogle Scholar
  143. Perez-Gordones MC, Lugo MR, Winkler M, Cervino V, Benaim G (2009) Diacylglycerol regulates the plasma membrane calcium pump from human erythrocytes by direct interaction. Arch Biochem Biophys 489(1–2):55–60PubMedGoogle Scholar
  144. Perova T, Wasserman MJ, Li PP, Warsh JJ (2008) Hyperactive intracellular calcium dynamics in B lymphoblasts from patients with bipolar I disorder. Int J Neuropsychopharmacol 11(2):185–196PubMedGoogle Scholar
  145. Perova T, Kwan M, Li PP, Warsh JJ (2010) Differential modulation of intracellular Ca2+ responses in B lymphoblasts by mood stabilizers. Int J Neuropsychopharmacol 13(6):693–702PubMedGoogle Scholar
  146. Phiel CJ, Klein PS (2001) Molecular targets of lithium action. Annu Rev Pharmacol Toxicol 41:789–813PubMedGoogle Scholar
  147. Politi P, Brondino N, Emanuele E (2008) Increased proapoptotic serum activity in patients with chronic mood disorders. Arch Med Res 39(2):242–245PubMedGoogle Scholar
  148. Post RM (2007) Kindling and sensitization as models for affective episode recurrence, cyclicity, and tolerance phenomena. Neurosci Biobehav Rev 31(6):858–873PubMedGoogle Scholar
  149. Rahman S, Li PP, Young LT, Kofman O, Kish SJ, Warsh JJ (1997) Reduced [3H]cyclic AMP binding in postmortem brain from subjects with bipolar affective disorder. J Neurochem 68(1):297–304PubMedGoogle Scholar
  150. Rajkowska G (2000) Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry 48(8):766–777PubMedGoogle Scholar
  151. Ranade SS, Mansour H, Wood J, Chowdari KV, Brar LK, Kupfer DJ et al (2003) Linkage and association between serotonin 2A receptor gene polymorphisms and bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet 121B(1):28–34PubMedGoogle Scholar
  152. Rao JS, Ertley RN, Rapoport SI, Bazinet RP, Lee HJ (2007) Chronic NMDA administration to rats up-regulates frontal cortex cytosolic phospholipase A2 and its transcription factor, activator protein-2. J Neurochem 102(6):1918–1927PubMedGoogle Scholar
  153. Rao JS, Harry GJ, Rapoport SI, Kim HW (2009) Increased excitotoxicity and ncuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry 15(4):384–392PubMedPubMedCentralGoogle Scholar
  154. Rao JS, Harry GJ, Rapoport SI, Kim HW (2009a) Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry:1–9 (Epub ahead of print)Google Scholar
  155. Rao JS, Rapoport SI, Kim HW (2009b) Decreased GRK3 but not GRK2 expression in frontal cortex from bipolar disorder patients. Int J Neuropsychopharmacol 12(6):851–860PubMedPubMedCentralGoogle Scholar
  156. Ross EM (1989) Signal sorting and amplification through G protein-coupled receptors. Neuron 3(2):141–152PubMedGoogle Scholar
  157. Rothman DL, Behar KL, Hyder F, Shulman RG (2003) In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function. Annu Rev Physiol 65:401–427PubMedGoogle Scholar
  158. Rowe MK, Chuang DM (2004) Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med 6(21):1–18PubMedGoogle Scholar
  159. Rowe MK, Wiest C, Chuang DM (2007) GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder. Neurosci Biobehav Rev 31(6):920–931PubMedPubMedCentralGoogle Scholar
  160. Rybakowski JK, Dmitrzak-Weglarz M, Suwalska A, Leszczynska-Rodziewicz A, Hauser J (2009) Dopamine D1 receptor gene polymorphism is associated with prophylactic lithium response in bipolar disorder. Pharmacopsychiatry 42(1):20–22PubMedGoogle Scholar
  161. Salinas PC, Hall AC (1999) Lithium and synaptic plasticity. Bipolar Disord 1(2):87–90PubMedGoogle Scholar
  162. Savas HA, Gergerlioglu HS, Armutcu F, Herken H, Yilmaz HR, Kocoglu E et al (2006) Elevated serum nitric oxide and superoxide dismutase in euthymic bipolar patients: impact of past episodes. World J Biol Psychiatry 7(1):51–55PubMedGoogle Scholar
  163. Schloesser RJ, Huang J, Klein PS, Manji HK (2008) Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 33(1):110–133PubMedGoogle Scholar
  164. Schreiber G, Avissar S, Danon A, Belmaker RH (1991) Hyperfunctional G proteins in mononuclear leukocytes of patients with mania. Biol Psychiatry 29(3):273–280PubMedGoogle Scholar
  165. Selek S, Savas HA, Gergerlioglu HS, Bulbul F, Uz E, Yumru M (2008) The course of nitric oxide and superoxide dismutase during treatment of bipolar depressive episode. J Affect Disord 107(1–3):89–94PubMedGoogle Scholar
  166. Shaltiel G, Shamir A, Levi I, Bersudsky Y, Agam G (2006) Lymphocyte G-protein receptor kinase (GRK)3 mRNA levels in bipolar disorder. Int J Neuropsychopharmacol 9(6):761–766PubMedGoogle Scholar
  167. Shamir A, Ebstein RP, Nemanov L, Zohar A, Belmaker RH, Agam G (1998) Inositol monophosphatase in immortalized lymphoblastoid cell lines indicates susceptibility to bipolar disorder and response to lithium therapy. Mol Psychiatry 3(6):481–482PubMedGoogle Scholar
  168. Shao L, Martin MV, Watson SJ, Schatzberg A, Akil H, Myers RM et al (2008) Mitochondrial involvement in psychiatric disorders. Ann Med 40(4):281–295PubMedPubMedCentralGoogle Scholar
  169. Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861PubMedGoogle Scholar
  170. Shimon H, Agam G, Belmaker RH, Hyde TM, Kleinman JE (1997) Reduced frontal cortex inositol levels in postmortem brain of suicide victims and patients with bipolar disorder. Am J Psychiatry 154(8):1148–1150PubMedGoogle Scholar
  171. Shtio L, Young LT, Wang JF (2005) Chronic treatment with mood stabilizers lithium and valproate prevents excitotoxicity by inhibiting oxidativc stress in rat cerebral cortical cells. Biol Psychiatry. 58(11):879–884Google Scholar
  172. Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K et al (2008) Whole-genome association study of bipolar disorder. Mol Psychiatry 13(6):558–569PubMedPubMedCentralGoogle Scholar
  173. Soares JC, Mallinger AG (1996) Abnormal phosphatidylinositol (PI)-signalling in bipolar disorder. Biol Psychiatry 39(6):461–464PubMedGoogle Scholar
  174. Soares JC, Dippold CS, Mallinger AG (1997) Platelet membrane phosphatidylinositol-4, 5-bisphosphate alterations in bipolar disorder – evidence from a single case study. Psychiatry Res 69(2–3):197–202PubMedGoogle Scholar
  175. Soares JC, Mallinger AG, Dippold CS, Frank E, Kupfer DJ (1999) Platelet membrane phospholipids in euthymic bipolar disorder patients: are they affected by lithium treatment? Biol Psychiatry 45(4):453–457PubMedGoogle Scholar
  176. Soares JC, Chen G, Dippold CS, Wells KF, Frank E, Kupfer DJ et al (2000) Concurrent measures of protein kinase C and phosphoinositides in lithium-treated bipolar patients and healthy individuals: a preliminary study. Psychiatry Res 95(2):109–118PubMedGoogle Scholar
  177. Spaulding GF, Jessup JM, Goodwin TJ (1993) Advances in cellular construction. J Cell Biochem 51(3):249–251PubMedGoogle Scholar
  178. Spleiss O, van Calker D, Scharer L, Adamovic K, Rcrgcr M, Gcbickc-Haerter PJ (1998) Abnormal G protein alpha(s) - and alpha(i2)-subunit mRNA expression in bipolar affective disorder. Mol Psychiatry 3(6):512–520PubMedGoogle Scholar
  179. Spiliotaki M, Salpeas V, Malitas P, Alevizos V, Moutsalsou P (2006) Altered glucocorticoid receptor signaling cascade in lymphocytes of bipolar disorder patients. Psychoneurocndocrin 31(6):748–760Google Scholar
  180. Sulser F (2002) The role of CREB and other transcription factors in the pharmacotherapy and etiology of depression. Ann Med 34(5):348–356PubMedGoogle Scholar
  181. Szczepankiewicz A, Rybakowski JK, Suwalska A, Skibinska M, Leszczynska-Rodziewicz A, Dmitrzak-Weglarz M et al (2006) Association study of the glycogen synthase kinase-3beta gene polymorphism with prophylactic lithium response in bipolar patients. World J Biol Psychiatry 7(3):158–161PubMedGoogle Scholar
  182. Tardito D, Mori S, Racagni G, Smeraldi E, Zanardi R, Perez J (2003) Protein kinase A activity in platelets from patients with bipolar disorder. J Affect Disord 76(1–3):249–253PubMedGoogle Scholar
  183. Taylor SJ, Exton JH (1991) Two alpha subunits of the Gq class of G proteins stimulate phosphoinositide phospholipase C-beta 1 activity. FEBS Lett 286(1–2):214–216PubMedGoogle Scholar
  184. Wang HY, Friedman E (1996) Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol Psychiatry 40(7):568–575PubMedGoogle Scholar
  185. Wang JF, Bown CD, Chen B, Young LT (2001) Identification of mood stabilizer-regulated genes by differential-display PCR. Int J Neuropsychopharmacol 4(1):65–74PubMedGoogle Scholar
  186. Wasserman MJ, Corson TW, Sibony D, Cooke RG, Parikh SV, Pennefather PS et al (2004) Chronic lithium treatment attenuates intracellular calcium mobilization. Neuropsychopharmacology 29(4):759–769PubMedGoogle Scholar
  187. Wodarz A, Nusse R (1998) Mechanisms of Wnt signaling in development. Annu Rev Cell Biol 14:59–88Google Scholar
  188. Wong DF, Pearlson GD, Tune LE, Young LT, Meltzer CC, Dannals RF et al (1997) Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness. J Cereb Blood Flow Metab 17(3):331–342PubMedGoogle Scholar
  189. Xavier IJ, Mercier PA, McLoughlin CM, Ali A, Woodgett JR, Ovsenck N (2000) Glycogen synthase kinase 3beta negatively regulates both DNA-binding and transcriptional activities of heat shock factor 1. J Biol Chem 275(37):29147–29152PubMedGoogle Scholar
  190. Yildiz-Yesilogki A, Ankerst DP (2006) Ncurochcmical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings. Prog Neuropsychopharmacol Biol Psychiatry 30(6):969–995Google Scholar
  191. Yoon IS, Li PP, Siu KP, Kennedy JL, Cooke RG, Parikh SV et al (2001) Altered IMPA2 gene expression and calcium homeostasis in bipolar disorder. Mol Psychiatry 6(6):678–683PubMedGoogle Scholar
  192. Young LT, Li PP, Kish SJ, Siu KP, Warsh JJ (1991) Postmortem cerebral cortex Gs alpha-subunit levels are elevated in bipolar affective disorder. Brain Res 553(2):323–326PubMedGoogle Scholar
  193. Young LT, Li PP, Kish SJ, Siu KP, Kamble A, Hornykiewicz O et al (1993) Cerebral cortex Gs alpha protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. J Neurochem 61(3):890–898PubMedGoogle Scholar
  194. Young LT, Asghari V, Li PP, Kish SJ, Fahnestock M, Warsh JJ (1996) Stimulatory G-protein alpha-subunit mRNA levels are not increased in autopsied cerebral cortex from patients with bipolar disorder. Brain Res Mol Brain Res 42(1):45–50PubMedGoogle Scholar
  195. Young LT, Li PP, Kamble A, Siu KP, Warsh JJ (1994) Mononuclear leukocyte levels of G proteins in depressed patients with bipolar disorder or major depressive disorder. Am J Psychiatry 151(4):594–596PubMedGoogle Scholar
  196. Zanardi R, Racagni G, Smeraldi E, Perez J (1997) Differential effects of lithium on platelet protein phosphorylation in bipolar patients and healthy subjects. Psychopharmacology 129(1):44–47PubMedGoogle Scholar
  197. Zarate CA, Manji HK (2008) Bipolar disorder: candidate drug targets. Mt Sinai J Med 75(3):226–247PubMedPubMedCentralGoogle Scholar
  198. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14–3-3 not BCL-X(L). Cell 87(4):619–628PubMedGoogle Scholar
  199. Zubenko GS, Hughes HB, Maher BS, Stiffler JS, Zubenko WN, Marazita ML (2002) Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early-onset, major depression. Am J Med Genet 114(8):980–987PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of PsychiatryUniversity of British ColumbiaVancouverCanada

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