Skip to main content Accessibility help
Hostname: page-component-65dc7cd545-7xdgm Total loading time: 0.367 Render date: 2021-07-26T01:29:30.050Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": true, "newCiteModal": false, "newCitedByModal": true, "newEcommerce": true, "newUsageEvents": true }

Glial cells as key elements in the pathophysiology and treatment of bipolar disorder

Published online by Cambridge University Press:  24 October 2016

Mojtaba Keshavarz
Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
E-mail address:



The exact pathophysiology of bipolar disorder (BD) is not yet fully understood, and there are many questions in this area which should be answered. This review aims to discuss the roles of glial cells in the pathophysiology of BD and their contribution to the mechanism of action of mood-stabilising drugs.


We critically reviewed the most recent advances regarding glial cell roles in the pathophysiology and treatment of BD and the neuroprotective and neurotrophic effects of these cells.


Postmortem studies revealed a decrease in the glial cell number or density in the specific layers of prefrontal and anterior cingulate cortex in the patients with BD, whereas there was no difference in other brain regions, such as entorhinal cortex, amygdala and hippocampus. Astrocytes and oligodendrocytes were the most important glial types that were responsible for the glial reduction, but microglia activation rather than loss may be implicated in BD. The decreased number or density of glial cells may contribute to the pathological changes observed in neurons in the patients with BD. Alteration of specific neurotrophic factors such as glial cell line-derived neurotrophic factor and S100B may be an important feature of BD. Glial cells mediate the therapeutic effects of mood-stabilising agents in the treatment of BD.


Recent studies provide important evidence on the impairment of glial cells in the pathophysiology and treatment of BD. However, future controlled studies are necessary to elucidate different aspects of glial cells contribution to BD, and the mechanism of action of mood-stabilising drugs.

Review Article
© Scandinavian College of Neuropsychopharmacology 2016 

Access options

Get access to the full version of this content by using one of the access options below.


1. Belmaker, R. Bipolar disorder. New Engl J Med 2004;351:476486.CrossRefGoogle Scholar
2. Oswald, P, Souery, D, Kasper, S et al. Current issues in bipolar disorder: a critical review. Eur Neuropsychopharmacol 2007;17:687695.CrossRefGoogle Scholar
3. Pini, S, de Queiroz, V, Pagnin, D et al. Prevalence and burden of bipolar disorders in European countries. Eur Neuropsychopharmacol 2005;15:425434.CrossRefGoogle ScholarPubMed
4. Angst, J, Azorin, J-M, Bowden, CL et al. Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study. Arch Gen Psychiat 2011;68:791799.CrossRefGoogle ScholarPubMed
5. Ghaemi, SN, Boiman, EE, Goodwin, FK. Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiat 2000;61:804808.CrossRefGoogle Scholar
6. Schloesser, RJ, Huang, J, Klein, PS, Manji, HK. Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacol 2008;33:110133.CrossRefGoogle ScholarPubMed
7. Kapczinski, F, Frey, BN, Kauer-Sant’Anna, M, Grassi-Oliveira, R. Brain-derived neurotrophic factor and neuroplasticity in bipolar disorder. Expert Rev Neurother 2008;8:11011113.CrossRefGoogle ScholarPubMed
8. Carlson, PJ, Singh, JB, Zarate, CA, Drevets, WC, Manji, HK. Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx 2006;3:2241.CrossRefGoogle ScholarPubMed
9. Czeh, B, Fuchs, E, Flugge, G. Altered glial plasticity in animal models for mood disorders. Curr Drug Targets 2013;14:12491261.CrossRefGoogle ScholarPubMed
10. Abbott, NJ, Rönnbäck, L, Hansson, E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 2006;7:4153.CrossRefGoogle ScholarPubMed
11. Acosta, MT, Gioia, GA, Silva, AJ. Neurofibromatosis type 1: new insights into neurocognitive issues. Curr Neurol Neurosci Rep 2006;6:136143.CrossRefGoogle ScholarPubMed
12. Araque, A, Parpura, V, Sanzgiri, RP, Haydon, PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 1999;22:208215.CrossRefGoogle Scholar
13. Cotter, DR, Pariante, CM, Everall, IP. Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull 2001;55:585595.CrossRefGoogle ScholarPubMed
14. Rajkowska, G, Miguel-Hidalgo, J. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 2007;6:219.CrossRefGoogle ScholarPubMed
15. Eroglu, C, Barres, BA. Regulation of synaptic connectivity by glia. Nature 2010;468:223231.CrossRefGoogle ScholarPubMed
16. Verkhratsky, A, Orkand, RK, Kettenmann, H. Glial calcium: homeostasis and signaling function. Physiol Rev 1998;78:99141.Google ScholarPubMed
17. Mennerick, S, Zorumski, CF. Glial contributions to excitatory neurotransmission in cultured hippocampal cells. Nature 1994;368:5962.CrossRefGoogle ScholarPubMed
18. Tsacopoulos, M, Magistretti, PJ. Metabolic coupling between glia and neurons. J Neurosci 1996;16:877885.Google ScholarPubMed
19. Magistretti, PJ. Role of glutamate in neuron-glia metabolic coupling. Am J Clin Nutr 2009;90:875S880S.CrossRefGoogle ScholarPubMed
20. Anton, ES, Cameron, RS, Rakic, P. Role of neuron-glial junctional domain proteins in the maintenance and termination of neuronal migration across the embryonic cerebral wall. J Neurosci 1996;16:22832293.Google Scholar
21. Lin, LF, Doherty, DH, Lile, JD, Bektesh, S, Collins, F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 1993;260:11301132.CrossRefGoogle ScholarPubMed
22. Pont-Lezica, L, Béchade, C, Belarif‐Cantaut, Y, Pascual, O, Bessis, A. Physiological roles of microglia during development. J Neurochem 2011;119:901908.CrossRefGoogle Scholar
23. Tremblay, M-È, Stevens, B, Sierra, A, Wake, H, Bessis, A, Nimmerjahn, A. The role of microglia in the healthy brain. J Neurosci 2011;31:1606416069.CrossRefGoogle Scholar
24. Baumann, N, Pham-Dinh, D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 2001;81:871927.Google Scholar
25. Chen, PS, Peng, G, Li, G et al. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry 2006;11:11161125.CrossRefGoogle ScholarPubMed
26. Barbosa, IG, Huguet, RB, Sousa, LP et al. Circulating levels of GDNF in bipolar disorder. Neurosci Lett 2011;502:103106.CrossRefGoogle ScholarPubMed
27. Dhandapani, KM, Hadman, M, De Sevilla, L, Wade, MF, Mahesh, VB, Brann, DW. Astrocyte protection of neurons: role of transforming growth factor-β signaling via Ac-Jun-AP-1 protective pathway. J Biol Chem 2003;278:4332943339.CrossRefGoogle ScholarPubMed
28. Largo, C, Cuevas, P, Herreras, O. Is glia disfunction the initial cause of neuronal death in ischemic penumbra? Neurol Res 1996;18:445448.CrossRefGoogle ScholarPubMed
29. Nawashiro, H, Brenner, M, Fukui, S, Shima, K, Hallenbeck, JM. High susceptibility to cerebral ischemia in GFAP-null mice. J Cereb Blood Flow Metab 2000;20:10401044.CrossRefGoogle ScholarPubMed
30. Cui, W, Allen, ND, Skynner, M, Gusterson, B, Clark, AJ. Inducible ablation of astrocytes shows that these cells are required for neuronal survival in the adult brain. Glia 2001;34:272282.CrossRefGoogle Scholar
31. Connor, B, Dragunow, M. The role of neuronal growth factors in neurodegenerative disorders of the human brain. Brain Res Rev 1998;27:139.CrossRefGoogle ScholarPubMed
32. Desagher, S, Glowinski, J, Premont, J. Astrocytes protect neurons from hydrogen peroxide toxicity. J Neurosci 1996;16:25532562.Google ScholarPubMed
33. Cotter, D, Mackay, D, Landau, S, Kerwin, R, Everall, I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry 2001;58:545553.CrossRefGoogle ScholarPubMed
34. Peuchen, S, Bolaños, JP, Heales, SJ, Almeida, A, Duchen, MR, Clark, JB. Interrelationships between astrocyte function, oxidative stress and antioxidant status within the central nervous system. Prog Neurobiol 1997;52:261281.CrossRefGoogle ScholarPubMed
35. Dringen, R, Gutterer, JM, Hirrlinger, J. Glutathione metabolism in brain. Eur J Biochem 2000;267:49124916.CrossRefGoogle ScholarPubMed
36. Tanaka, J, Toku, K, Zhang, B, Ishihara, K, Sakanaka, M, Maeda, N. Astrocytes prevent neuronal death induced by reactive oxygen and nitrogen species. Glia 1999;28:8596.3.0.CO;2-Y>CrossRefGoogle ScholarPubMed
37. Rothstein, JD, Dykes-Hoberg, M, Pardo, CA et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996;16:675686.CrossRefGoogle Scholar
38. Ellison-Wright, I, Bullmore, E. Anatomy of bipolar disorder and schizophrenia: a meta-analysis. Schizophr Res 2010;117:112.CrossRefGoogle ScholarPubMed
39. Arnone, D, Cavanagh, J, Gerber, D, Lawrie, S, Ebmeier, K, McIntosh, A. Magnetic resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis. Br J Psychiatry 2009;195:194201.CrossRefGoogle ScholarPubMed
40. Kempton, MJ, Geddes, JR, Ettinger, U, Williams, SC, Grasby, PM. Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. Arch Gen Psychiatry 2008;65:10171032.CrossRefGoogle Scholar
41. McDonald, C, Zanelli, J, Rabe-Hesketh, S et al. Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biol Psychiatry 2004;56:411417.CrossRefGoogle ScholarPubMed
42. Hajek, T, Kopecek, M, Kozeny, J, Gunde, E, Alda, M, Höschl, C. Amygdala volumes in mood disorders – meta-analysis of magnetic resonance volumetry studies. J Affect Disord 2009;115:395410.CrossRefGoogle Scholar
43. Öngür, D, Bechtholt, AJ, Carlezon, WA Jr, Cohen, BM. Glial abnormalities in mood disorders. Harv Rev Psychiatry 2013;22:334337.CrossRefGoogle ScholarPubMed
44. Rajkowska, G. Cell pathology in bipolar disorder. Bipolar Disord 2002;4:105116.CrossRefGoogle ScholarPubMed
45. Öngür, D, Drevets, WC, Price, JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 1998;95:1329013295.CrossRefGoogle ScholarPubMed
46. Rajkowska, G, Halaris, A, Selemon, LD. Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry 2001;49:741752.CrossRefGoogle ScholarPubMed
47. Brauch, RA, Adnan El-Masri, M, Parker, JC Jr, El-Mallakh, RS. Glial cell number and neuron/glial cell ratios in postmortem brains of bipolar individuals. J Affect Disord 2006;91:8790.CrossRefGoogle ScholarPubMed
48. Cotter, D, Mackay, D, Chana, G, Beasley, C, Landau, S, Everall, IP. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex 2002;12:386394.CrossRefGoogle Scholar
49. Webster, M, Knable, M, Johnston-Wilson, N, Nagata, K, Inagaki, M, Yolken, R. Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav Immun 2001;15:388400.CrossRefGoogle ScholarPubMed
50. Gittins, RA, Harrison, PJ. A morphometric study of glia and neurons in the anterior cingulate cortex in mood disorder. J Affect Disord 2011;133:328332.CrossRefGoogle ScholarPubMed
51. Chana, G, Landau, S, Beasley, C, Everall, IP, Cotter, D. Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density. Biol Psychiatry 2003;53:10861098.CrossRefGoogle ScholarPubMed
52. Benes, FM, Vincent, SL, Todtenkopf, M. The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects. Biol Psychiatry 2001;50:395406.CrossRefGoogle ScholarPubMed
53. Hamidi, M, Drevets, WC, Price, JL. Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol Psychiatry 2004;55:563569.CrossRefGoogle ScholarPubMed
54. Altshuler, LL, Abulseoud, OA, Foland-Ross, L et al. Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. Bipolar Disord 2010;12:541549.CrossRefGoogle Scholar
55. Bowley, MP, Drevets, WC, Öngür, D, Price, JL. Low glial numbers in the amygdala in major depressive disorder. Biol Psychiatry 2002;52:404412.CrossRefGoogle ScholarPubMed
56. Czéh, B, Müller-Keuker, JI, Rygula, R et al. Chronic social stress inhibits cell proliferation in the adult medial prefrontal cortex: hemispheric asymmetry and reversal by fluoxetine treatment. Neuropsychopharmacology 2007;32:14901503.CrossRefGoogle ScholarPubMed
57. Brietzke, E, Kapczinski, F. TNF-α as a molecular target in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:13551361.CrossRefGoogle ScholarPubMed
58. Murphy, GM, Lee, YL, Jia, XC et al. Tumor necrosis factor‐α and basic fibroblast growth factor decrease glial fibrillary acidic protein and its encoding mRNA in astrocyte cultures and glioblastoma cells. J Neurochem 1995;65:27162724.CrossRefGoogle ScholarPubMed
59. Dewar, D, Underhill, SM, Goldberg, MP. Oligodendrocytes and ischemic brain injury. J Cereb Blood Flow Metab 2003;23:263274.CrossRefGoogle ScholarPubMed
60. McDonald, JW, Levine, JM, Qu, Y. Multiple classes of the oligodendrocyte lineage are highly vulnerable to excitotoxicity. Neuroreport 1998;9:27572762.CrossRefGoogle ScholarPubMed
61. Juurlink, BH, Thorburne, SK, Hertz, L. Peroxide‐scavenging deficit underlies oligodendrocyte susceptibility to oxidative stress. Glia 1998;22:371378.3.0.CO;2-6>CrossRefGoogle Scholar
62. Danilov, CA, Chandrasekaran, K, Racz, J, Soane, L, Zielke, C, Fiskum, G. Sulforaphane protects astrocytes against oxidative stress and delayed death caused by oxygen and glucose deprivation. Glia 2009;57:645656.CrossRefGoogle ScholarPubMed
63. Sugawara, T, Lewén, A, Noshita, N, Gasche, Y, Chan, PH. Effects of global ischemia duration on neuronal, astroglial, oligodendroglial, and microglial reactions in the vulnerable hippocampal CA1 subregion in rats. J Neurotrauma 2002;19:8598.CrossRefGoogle Scholar
64. Matute, C, Alberdi, E, Domercq, Ma, Pérez-Cerdá, F, Pérez-Samartı́n, A, Sánchez-Gómez, MaV. The link between excitotoxic oligodendroglial death and demyelinating diseases. Trends Neurosci 2001;24:224230.CrossRefGoogle ScholarPubMed
65. Rajkowska, G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry 2000;48:766777.CrossRefGoogle ScholarPubMed
66. Henn, F. Neurotransmitters and astroglia lead to neuromodulation. Prog Brain Res 1982;55:241252.CrossRefGoogle ScholarPubMed
67. Millan, MJ. The role of monoamines in the actions of established and ‘novel’ antidepressant agents: a critical review. Eur J Pharmacol 2004;500:371384.CrossRefGoogle ScholarPubMed
68. Maeng, S, Zarate, CA. The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr Psychiatry Rep 2007;9:467474.CrossRefGoogle ScholarPubMed
69. Riedel, G, Platt, B, Micheau, J. Glutamate receptor function in learning and memory. Behav Brain Res 2003;140:147.CrossRefGoogle ScholarPubMed
70. Anderson, CM, Swanson, RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 2000;32:114.3.0.CO;2-W>CrossRefGoogle Scholar
71. Pfrieger, FW, Barres, BA. Synaptic efficacy enhanced by glial cells in vitro . Science 1997;277:16841687.CrossRefGoogle Scholar
72. Watkins, C, Sawa, A, Pomper, M. Glia and immune cell signaling in bipolar disorder: insights from neuropharmacology and molecular imaging to clinical application. Transl Psychiatry 2014;4:e350.CrossRefGoogle Scholar
73. Sofroniew, MV, Vinters, HV. Astrocytes: biology and pathology. Acta Neuropathol 2010;119:735.CrossRefGoogle ScholarPubMed
74. Volterra, A, Meldolesi, J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 2005;6:626640.CrossRefGoogle ScholarPubMed
75. Miller, G. The dark side of glia. Science 2005;308:778781.CrossRefGoogle ScholarPubMed
76. Seifert, G, Schilling, K, Steinhäuser, C. Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 2006;7:194206.CrossRefGoogle ScholarPubMed
77. Johnston-Wilson, N, Sims, C, Hofmann, J et al. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. Mol Psychiatry 2000;5:142149.CrossRefGoogle ScholarPubMed
78. Gos, T, Schroeter, ML, Lessel, W et al. S100B-immunopositive astrocytes and oligodendrocytes in the hippocampus are differentially afflicted in unipolar and bipolar depression: a postmortem study. J Psychiat Res 2013;47:16941699.CrossRefGoogle ScholarPubMed
79. Toro, CT, Hallak, JE, Dunham, JS, Deakin, JF. Glial fibrillary acidic protein and glutamine synthetase in subregions of prefrontal cortex in schizophrenia and mood disorder. Neurosci Lett 2006;404:276281.CrossRefGoogle ScholarPubMed
80. Tkachev, D, Mimmack, ML, Ryan, MM et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 2003;362:798805.CrossRefGoogle ScholarPubMed
81. Damadzic, R, Bigelow, LB, Krimer, LS et al. A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis. Brain Res Bull 2001;55:611618.CrossRefGoogle Scholar
82. Bernstein, H-G, Meyer-Lotz, G, Dobrowolny, H et al. Reduced density of glutamine synthetase immunoreactive astrocytes in different cortical areas in major depression but not in bipolar I disorder. Front Cell Neurosci 2015;9:273.CrossRefGoogle ScholarPubMed
83. Rocha, E, Rodnight, R. Chronic administration of lithium chloride increases immunodetectable glial fibrillary acidic protein in the rat hippocampus. J Neurochem 1994;63:15821584.CrossRefGoogle ScholarPubMed
84. Rocha, E, Achaval, M, Santos, P, Rodnight, R. Lithium treatment causes gliosis and modifies the morphology of hippocampal astrocytes in rats. Neuroreport 1998;9:39713974.CrossRefGoogle Scholar
85. Uranova, N, Orlovskaya, D, Vikhreva, O et al. Electron microscopy of oligodendroglia in severe mental illness. Brain Res Bull 2001;55:597610.CrossRefGoogle ScholarPubMed
86. Regenold, WT, Phatak, P, Marano, CM, Gearhart, L, Viens, CH, Hisley, KC. Myelin staining of deep white matter in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and unipolar major depression. Psychiatry Res 2007;151:179188.CrossRefGoogle Scholar
87. Munkholm, K, Braüner, JV, Kessing, LV, Vinberg, M. Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatr Res 2013;47:11191133.CrossRefGoogle ScholarPubMed
88. Brietzke, E, Stertz, L, Fernandes, BS et al. Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord 2009;116:214217.CrossRefGoogle ScholarPubMed
89. Söderlund, J, Olsson, SK, Samuelsson, M et al. Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder. J Psychiatry Neurosci 2011;36:114.CrossRefGoogle Scholar
90. Takeuchi, H, Jin, S, Wang, J et al. Tumor necrosis factor-α induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 2006;281:2136221368.CrossRefGoogle Scholar
91. Berk, M, Kapczinski, F, Andreazza, A et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 2011;35:804817.CrossRefGoogle Scholar
92. Pochon, NM, Menoud, A, Tseng, J, Zurn, A, Aebischer, P. Neuronal GDNF expression in the adult rat nervous system identified by in situ hybridization. Eur J Neurosci 1997;9:463471.CrossRefGoogle Scholar
93. Airaksinen, MS, Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 2002;3:383394.CrossRefGoogle ScholarPubMed
94. Quintero, E, Willis, L, Zaman, V et al. Glial cell line-derived neurotrophic factor is essential for neuronal survival in the locus coeruleus–hippocampal noradrenergic pathway. Neuroscience 2004;124:137146.CrossRefGoogle ScholarPubMed
95. Cheng, H, Fu, YS, Guo, JW. Ability of GDNF to diminish free radical production leads to protection against kainate-induced excitotoxicity in hippocampus. Hippocampus 2004;14:7786.CrossRefGoogle ScholarPubMed
96. Gratacòs, E, Pérez-Navarro, E, Tolosa, E, Arenas, E, Alberch, J. Neuroprotection of striatal neurons against kainate excitotoxicity by neurotrophins and GDNF family members. J Neurochem 2001;78:12871296.CrossRefGoogle ScholarPubMed
97. Takebayashi, M, Hisaoka, K, Nishida, A et al. Decreased levels of whole blood glial cell line-derived neurotrophic factor (GDNF) in remitted patients with mood disorders. Int J Neuropsychopharmacol 2006;9:607612.CrossRefGoogle ScholarPubMed
98. Zhang, X, Zhang, Z, Sha, W et al. Effect of treatment on serum glial cell line-derived neurotrophic factor in bipolar patients. J Affect Disord 2010;126:326329.CrossRefGoogle ScholarPubMed
99. Rosa, AR, Frey, BN, Andreazza, AC et al. Increased serum glial cell line-derived neurotrophic factor immunocontent during manic and depressive episodes in individuals with bipolar disorder. Neurosci Lett 2006;407:146150.CrossRefGoogle ScholarPubMed
100. Otsuki, K, Uchida, S, Watanuki, T et al. Altered expression of neurotrophic factors in patients with major depression. J Psychiatr Res 2008;42:11451153.CrossRefGoogle ScholarPubMed
101. Tunca, Z, Ozerdem, A, Ceylan, D et al. Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: the role of lithium. J Affect Disord 2014;166:193200.CrossRefGoogle Scholar
102. Rybakowski, JK, Permoda-Osip, A, Skibinska, M, Adamski, R, Bartkowska‐Sniatkowska, A. Single ketamine infusion in bipolar depression resistant to antidepressants: are neurotrophins involved? Hum Psychopharmacol Clin Exp 2013;28:8790.CrossRefGoogle Scholar
103. Albeck, DS, Hoffer, BJ, Quissell, D, Sanders, LA, Zerbe, G, Granholm, A-CE. A non‐invasive transport system for GDNF across the blood–brain barrier. Neuroreport 1997;8:22932298.CrossRefGoogle Scholar
104. Kastin, AJ, Akerstrom, V, Pan, W. Glial cell line-derived neurotrophic factor does not enter normal mouse brain. Neurosci Lett 2003;340:239241.CrossRefGoogle Scholar
105. Scola, G, Andreazza, AC. The role of neurotrophins in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2015;56:122128.CrossRefGoogle ScholarPubMed
106. Schäfer, BW, Heizmann, CW. The S100 family of EF-hand calcium-binding proteins: functions and pathology. Trends Biochem Sci 1996;21:134140.CrossRefGoogle ScholarPubMed
107. Schroeter, ML, Abdul-Khaliq, H, Diefenbacher, A, Blasig, IE. S100B is increased in mood disorders and may be reduced by antidepressive treatment. Neuroreport 2002;13:16751678.CrossRefGoogle ScholarPubMed
108. Zimmer, D, Chaplin, J, Baldwin, A, Rast, M. S100-mediated signal transduction in the nervous system and neurological diseases. Cell Mol Biol 2005;51:201214.Google ScholarPubMed
109. Van Eldik, LJ, Wainwright, MS. The Janus face of glial-derived S100B: beneficial and detrimental functions in the brain. Restor Neurol Neurosci 2003;21:97108.Google Scholar
110. Schroeter, ML, Abdul-Khaliq, H, Krebs, M, Diefenbacher, A, Blasig, IE. Serum markers support disease-specific glial pathology in major depression. J Affect Disord 2008;111:271280.CrossRefGoogle Scholar
111. Schroeter, ML, Steiner, J. Elevated serum levels of the glial marker protein S100B are not specific for schizophrenia or mood disorders. Mol Psychiatry 2009;14:235237.CrossRefGoogle Scholar
112. Grabe, HJ, Ahrens, N, Rose, H-J, Kessler, C, Freyberger, HJ. Neurotrophic factor S100beta in major depression. Neuropsychobiology 2001;44:8890.CrossRefGoogle Scholar
113. Machado-Vieira, R, Schmidt, AP, Ávila, TT et al. Increased cerebrospinal fluid levels of S100B protein in rat model of mania induced by ouabain. Life Sci 2004;76:805811.CrossRefGoogle Scholar
114. Machado-Vieira, R, Lara, D, Portela, L et al. Elevated serum S100B protein in drug-free bipolar patients during first manic episode: a pilot study. Eur Neuropsychopharmacol 2002;12:269272.CrossRefGoogle ScholarPubMed
115. Andreazza, AC, Cassini, C, Rosa, AR et al. Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res 2007;41:523529.CrossRefGoogle ScholarPubMed
116. Schroeter, ML, Steiner, J, Mueller, K. Glial pathology is modified by age in mood disorders – a systematic meta-analysis of serum S100B in vivo studies. J Affect Disord 2011;134:3238.CrossRefGoogle ScholarPubMed
117. Dean, B, Gray, L, Scarr, E. Regionally specific changes in levels of cortical S100β in bipolar 1 disorder but not schizophrenia. Aust NZ J Psychiatry 2006;40:217224.Google Scholar
118. Hetzel, G, Moeller, O, Evers, S et al. The astroglial protein S100B and visually evoked event-related potentials before and after antidepressant treatment. Psychopharmacology 2005;178:161166.CrossRefGoogle Scholar
119. Allore, R, O’Hanlon, D, Price, R et al. Gene encoding the beta subunit of S100 protein is on chromosome 21: implications for Down syndrome. Science 1988;239:13111313.CrossRefGoogle Scholar
120. McQuillin, A, Bass, N, Kalsi, G et al. Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22. 3. Mol Psychiatry 2006;11:134142.CrossRefGoogle ScholarPubMed
121. Roche, S, Cassidy, F, Zhao, C et al. Candidate gene analysis of 21q22: support for S100B as a susceptibility gene for bipolar affective disorder with psychosis. Am J Med Genet B Neuropsychiatr Genet 2007;144:10941096.CrossRefGoogle Scholar
122. Dagdan, E, Morris, DW, Campbell, M et al. Functional assessment of a promoter polymorphism in S100B, a putative risk variant for bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2011;156:691699.CrossRefGoogle Scholar
123. Schroeter, ML, Steiner, J, Schönknecht, P, Mueller, K. Further evidence for a role of S100B in mood disorders: a human gene expression mega-analysis. J Psychiatr Res 2014;53:8486.CrossRefGoogle ScholarPubMed
124. Bora, E, Fornito, A, Yücel, M, Pantelis, C. Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder. Biol Psychiatry 2010;67:10971105.CrossRefGoogle ScholarPubMed
125. Moore, GJ, Bebchuk, JM, Wilds, IB, Chen, G, Manji, HK. Lithium-induced increase in human brain grey matter. Lancet 2000;356:12411242.CrossRefGoogle ScholarPubMed
126. Moore, GJ, Bebchuk, JM, Hasanat, K et al. Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry 2000;48:18.CrossRefGoogle Scholar
127. Machado-Vieira, R, Manji, HK, Zarate, CA Jr. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord 2009;11(Suppl. 2):92109.CrossRefGoogle ScholarPubMed
128. Rajkowska, G, Clarke, G, Mahajan, G et al. Differential effect of lithium on cell number in the hippocampus and prefrontal cortex in adult mice: a stereological study. Bipolar Disord 2016;18:4151.CrossRefGoogle ScholarPubMed
129. Keshavarz, M, Emamghoreishi, M, Nekooeian, AA, Warsh, JJ, Zare, HR. Increased bcl-2 protein levels in rat primary astrocyte culture following chronic lithium treatment. Iran J Med Sci 2013;38:255.Google ScholarPubMed
130. Manji, HK, Moore, GJ, Chen, G. Lithium up-regulates the cytoprotective protein Bcl-2 in the CNS in vivo: a role for neurotrophic and neuroprotective effects in manic depressive illness. J Clin Psychiatry 2000;61(Suppl. 9):14781496.Google Scholar
131. Emamghoreishi, M, Keshavarz, M, Nekooeian, AA. Acute and chronic effects of lithium on BDNF and GDNF mRNA and protein levels in rat primary neuronal, astroglial and neuroastroglia cultures. Iran J Basic Med Sci 2015;18:240.Google ScholarPubMed
132. Angelucci, F, Aloe, L, Jiménez-Vasquez, P, Mathé, AA. Lithium treatment alters brain concentrations of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in a rat model of depression. Int J Neuropsychopharmacol 2003;6:225231.CrossRefGoogle Scholar
133. Fukumoto, T, Morinobu, S, Okamoto, Y, Kagaya, A, Yamawaki, S. Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology 2001;158:100106.CrossRefGoogle ScholarPubMed
134. Su, H, Chu, T-H, Wu, W. Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord. Exp Neurol 2007;206:296307.CrossRefGoogle ScholarPubMed
135. Qu, Z, Sun, D, Young, W. Lithium promotes neural precursor cell proliferation: evidence for the involvement of the non-canonical GSK-3β-NF-AT signaling. Cell Biosci 2011;1:1.CrossRefGoogle ScholarPubMed
136. Emamghoreishi, M, Keshavarz, M, Nekooeian, AA. Chronic lithium treatment increased intracellular s100ß levels in rat primary neuronal culture. Acta Med Iranica 2015;53:8996.Google ScholarPubMed
137. Uranova, NA, Vostrikov, VM, Orlovskaya, DD, Rachmanova, VI. Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res 2004;67:269275.CrossRefGoogle ScholarPubMed
Cited by

Send article to Kindle

To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Glial cells as key elements in the pathophysiology and treatment of bipolar disorder
Available formats

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

Glial cells as key elements in the pathophysiology and treatment of bipolar disorder
Available formats

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

Glial cells as key elements in the pathophysiology and treatment of bipolar disorder
Available formats

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *