Neuroglial Cells and Schizophrenia

신경아교세포와 조현병

  • Won, Seunghee (Department of Psychiatry, Kyungpook National University School of Medicine)
  • 원승희 (경북대학교 의학전문대학원 정신건강의학교실)
  • Received : 2015.04.10
  • Accepted : 2015.05.21
  • Published : 2015.05.31

Abstract

In the past decade, structural, molecular, and functional changes in glial cells have become a major focus in the search for the neurobiological foundations of schizophrenia. Glial cells, consisting of oligodendrocytes, astrocytes, microglia, and nerve/glial antigen 2-positive cells, constitute a major cell population in the central nervous system. There is accumulating evidence of reduced numbers of oligodendrocytes and altered expression of myelin/oligodendrocyte-related genes that might explain the white matter abnormalities and altered inter- and intra-hemispheric connectivities that are characteristic signs of schizophrenia. Astrocytes play a key role in the synaptic metabolism of neurotransmitters ; thus, astrocyte dysfunction may contribute to certain aspects of altered neurotransmission in schizophrenia. Increased densities of microglial cells and aberrant expression of microglia-related surface markers in schizophrenia suggest that immunological/inflammatory factors are of considerable relevance to the pathophysiology of psychosis. This review describes current evidence for the multifaceted role of glial cells in schizophrenia and discusses efforts to develop glia-directed therapies for the treatment of the disease.

Keywords

References

  1. Graeber MB. Changing face of microglia. Science 2010;330:783-788. https://doi.org/10.1126/science.1190929
  2. Nishiyama A, Komitova M, Suzuki R, Zhu X. Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat Rev Neurosci 2009;10:9-22.
  3. Kubicki M, McCarley RW, Shenton ME. Evidence for white matter abnormalities in schizophrenia. Curr Opin Psychiatry 2005;18:121-134. https://doi.org/10.1097/00001504-200503000-00004
  4. Rubinov M, Bullmore E. Schizophrenia and abnormal brain network hubs. Dialogues Clin Neurosci 2013;15:339-349.
  5. Konrad A, Winterer G. Disturbed structural connectivity in schizophrenia primary factor in pathology or epiphenomenon? Schizophr Bull 2008;34:72-92.
  6. Dwork AJ, Mancevski B, Rosoklija G. White matter and cognitive function in schizophrenia. Int J Neuropsychopharmacol 2007;10: 513-536. https://doi.org/10.1017/S1461145707007638
  7. Uranova NA, Vostrikov VM, Vikhreva OV, Zimina IS, Kolomeets NS, Orlovskaya DD. The role of oligodendrocyte pathology in schizophrenia. Int J Neuropsychopharmacol 2007;10:537-545. https://doi.org/10.1017/S1461145707007626
  8. Rosenbluth J, Bobrowski-Khoury N. Structural bases for central nervous system malfunction in the quaking mouse: dysmyelination in a potential model of schizophrenia. J Neurosci Res 2013;91:374-381. https://doi.org/10.1002/jnr.23167
  9. Haroutunian V, Davis KL. Introduction to the special section: Myelin and oligodendrocyte abnormalities in schizophrenia. Int J Neuropsychopharmacol 2007;10:499-502. https://doi.org/10.1017/S1461145706007449
  10. Martins-de-Souza D, Gattaz WF, Schmitt A, Maccarrone G, Hunyadi-Gulyas E, Eberlin MN, et al. Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia. J Psychiatr Res 2009;43:978-986. https://doi.org/10.1016/j.jpsychires.2008.11.006
  11. Zai G, King N, Wigg K, Couto J, Wong GW, Honer WG, et al. Genetic study of the myelin oligodendrocyte glycoprotein (MOG) gene in schizophrenia. Genes Brain Behav 2005;4:2-9.
  12. Wan C, Yang Y, Feng G, Gu N, Liu H, Zhu S, et al. Polymorphisms of myelin-associated glycoprotein gene are associated with schizophrenia in the Chinese Han population. Neurosci Lett 2005;388:126-131. https://doi.org/10.1016/j.neulet.2005.06.051
  13. Voineskos AN, de Luca V, Bulgin NL, van Adrichem Q, Shaikh S, Lang DJ, et al. A family-based association study of the myelin-associated glycoprotein and 2',3'-cyclic nucleotide 3'-phosphodiesterase genes with schizophrenia. Psychiatr Genet 2008;18:143-146. https://doi.org/10.1097/YPG.0b013e3282fa1874
  14. Qu M, Yue W, Tang F, Wang L, Han Y, Zhang D. Polymorphisms of Transferrin gene are associated with schizophrenia in Chinese Han population. J Psychiatr Res 2008;42:877-883. https://doi.org/10.1016/j.jpsychires.2007.10.005
  15. Novak G, Tallerico T. Nogo A, B and C expression in schizophrenia, depression and bipolar frontal cortex, and correlation of Nogo expression with CAA/TATC polymorphism in 3'-UTR. Brain Res 2006; 1120:161-171. https://doi.org/10.1016/j.brainres.2006.08.071
  16. Cannon DM, Walshe M, Dempster E, Collier DA, Marshall N, Bramon E, et al. The association of white matter volume in psychotic disorders with genotypic variation in NRG1, MOG and CNP: a voxel-based analysis in affected individuals and their unaffected relatives. Transl Psychiatry 2012;2:e167. https://doi.org/10.1038/tp.2012.82
  17. Schmandke A, Schmandke A, Schwab ME. Nogo-A: Multiple Roles in CNS Development, Maintenance, and Disease. Neuroscientist 2014;20:372-386. https://doi.org/10.1177/1073858413516800
  18. Stroman PW, Bosma RL, Kornelsen J, Lawrence-Dewar J, Wheeler-Kingshott C, Cadotte D, et al. Advanced MR imaging techniques and characterization of residual anatomy. Clin Neurol Neurosurg 2012; 114:460-470. https://doi.org/10.1016/j.clineuro.2012.01.003
  19. Uranova NA, Orlovskaia DD, Vikhreva OV, Zimina IS, Rakhmanova VI. [Morphometric study of ultrastructural changes in oligodendroglial cells in the postmortem brain in endogenous psychoses]. Vestn Ross Akad Med Nauk 2001;(7):42-48.
  20. Hof PR, Haroutunian V, Friedrich VL Jr, Byne W, Buitron C, Perl DP, et al. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 2003; 53:1075-1085. https://doi.org/10.1016/S0006-3223(03)00237-3
  21. Vostrikov VM, Uranova NA, Orlovskaya DD. Deficit of perineuronal oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders. Schizophr Res 2007;94:273-280. https://doi.org/10.1016/j.schres.2007.04.014
  22. Vostrikov V, Orlovskaya D, Uranova N. Deficit of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenia. World J Biol Psychiatry 2008;9:34-42. https://doi.org/10.1080/15622970701210247
  23. Gutierrez-Fernandez A, Gonzalez-Pinto A, Vega P, Barbeito S, Matute C. Expression of oligodendrocyte and myelin genes is not altered in peripheral blood cells of patients with first-episode schizophrenia and bipolar disorder. Bipolar Disord 2010;12:107-109. https://doi.org/10.1111/j.1399-5618.2009.00776.x
  24. Takahashi N, Sakurai T. Roles of glial cells in schizophrenia: possible targets for therapeutic approaches. Neurobiol Dis 2013;53:49-60. https://doi.org/10.1016/j.nbd.2012.11.001
  25. Bernstein HG, Steiner J, Guest PC, Dobrowolny H, Bogerts B. Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy. Schizophr Res 2015;161:4-18. https://doi.org/10.1016/j.schres.2014.03.035
  26. Hempel KJ, Treff WM. Die Gliazelldichte bei klinisch Gesunden und Schizophrenen. J Hirnforsch 1959;4:371-411.
  27. Stevens JR. Neuropathology of schizophrenia. Arch Gen Psychiatry 1982;39:1131-1139. https://doi.org/10.1001/archpsyc.1982.04290100011003
  28. Bruton CJ, Crow TJ, Frith CD, Johnstone EC, Owens DG, Roberts GW. Schizophrenia and the brain: a prospective clinico-neuropathological study. Psychol Med 1990;20:285-304. https://doi.org/10.1017/S0033291700017608
  29. Falkai P, Honer WG, David S, Bogerts B, Majtenyi C, Bayer TA. No evidence for astrogliosis in brains of schizophrenic patients. A postmortem study. Neuropathol Appl Neurobiol 1999;25:48-53.
  30. Rajkowska G, Miguel-Hidalgo JJ, Makkos Z, Meltzer H, Overholser J, Stockmeier C. Layer-specific reductions in GFAP-reactive astroglia in the dorsolateral prefrontal cortex in schizophrenia. Schizophr Res 2002;57:127-138. https://doi.org/10.1016/S0920-9964(02)00339-0
  31. Williams MR, Hampton T, Pearce RK, Hirsch SR, Ansorge O, Thom M, et al. Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia. Eur Arch Psychiatry Clin Neurosci 2013;263: 41-52. https://doi.org/10.1007/s00406-012-0328-5
  32. Steffek AE, McCullumsmith RE, Haroutunian V, Meador-Woodruff JH. Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia. Schizophr Res 2008; 103:71-82. https://doi.org/10.1016/j.schres.2008.04.032
  33. Hertz L, Schousboe I, Hertz L, Schousboe A. Receptor expression in primary cultures of neurons or astrocytes. Prog Neuropsychopharmacol Biol Psychiatry 1984;8:521-527. https://doi.org/10.1016/0278-5846(84)90010-1
  34. Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson AR, et al. Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry 2008;63:759-765. https://doi.org/10.1016/j.biopsych.2007.08.018
  35. Bernstein HG, Kirschke H, Wiederanders B, Khudoerkov RM, Hinz W, Rinne A. Lysosomal proteinases as putative diagnostic tools in human neuropathology: Alzheimer disease (AD) and schizophrenia. Acta Histochem Suppl 1992;42:19-24.
  36. Merenlender-Wagner A, Malishkevich A, Shemer Z, Udawela M, Gibbons A, Scarr E, et al. Autophagy has a key role in the pathophysiology of schizophrenia. Mol Psychiatry 2015;20:126-132. https://doi.org/10.1038/mp.2013.174
  37. Oifa AI, Uranova NA. [Electron-microscopic analysis of cytoarchitectonic disorders in the cerebral cortex in schizophrenia]. Zh Nevropatol Psikhiatr Im S S Korsakova 1991;91:48-52.
  38. Kolomeets NS, Uranova N. Ultrastructural abnormalities of astrocytes in the hippocampus in schizophrenia and duration of illness: a postortem morphometric study. World J Biol Psychiatry 2010;11(2 Pt 2):282-292. https://doi.org/10.3109/15622970902806124
  39. Amar S, Belmaker RH, Agam G. The possible involvement of glycogen synthase kinase-3 (GSK-3) in diabetes, cancer and central nervous system diseases. Curr Pharm Des 2011;17:2264-2277. https://doi.org/10.2174/138161211797052484
  40. Allaman I, Belanger M, Magistretti PJ. Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 2011;34: 76-87. https://doi.org/10.1016/j.tins.2010.12.001
  41. Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, et al. Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 2003;60:572-576. https://doi.org/10.1001/archpsyc.60.6.572
  42. Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H, et al. A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. Schizophr Res 2007;90:41-51. https://doi.org/10.1016/j.schres.2006.10.010
  43. Roussos P, Giakoumaki SG, Adamaki E, Georgakopoulos A, Robakis NK, Bitsios P. The association of schizophrenia risk D-amino acid oxidase polymorphisms with sensorimotor gating, working memory and personality in healthy males. Neuropsychopharmacology 2011;36:1677-1688. https://doi.org/10.1038/npp.2011.49
  44. Labrie V, Fukumura R, Rastogi A, Fick LJ, Wang W, Boutros PC, et al. Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model. Hum Mol Genet 2009;18:3227-3243. https://doi.org/10.1093/hmg/ddp261
  45. Erhardt S, Olsson SK, Engberg G. Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders. CNS Drugs 2009;23:91-101. https://doi.org/10.2165/00023210-200923020-00001
  46. Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE, et al. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Arch Gen Psychiatry 2011;68:665-674. https://doi.org/10.1001/archgenpsychiatry.2011.71
  47. Torrey EF, Bartko JJ, Lun ZR, Yolken RH. Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. Schizophr Bull 2007;33:729-736. https://doi.org/10.1093/schbul/sbl050
  48. Matute C, Melone M, Vallejo-Illarramendi A, Conti F. Increased expression of the astrocytic glutamate transporter GLT-1 in the prefrontal cortex of schizophrenics. Glia 2005;49:451-455. https://doi.org/10.1002/glia.20119
  49. Cohen-Cory S, Kidane AH, Shirkey NJ, Marshak S. Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Dev Neurobiol 2010;70:271-288.
  50. Schnieder TP, Dwork AJ. Searching for neuropathology: gliosis in schizophrenia. Biol Psychiatry 2011;69:134-139. https://doi.org/10.1016/j.biopsych.2010.08.027
  51. Kondziella D, Brenner E, Eyjolfsson EM, Sonnewald U. How do glial-neuronal interactions fit into current neurotransmitter hypotheses of schizophrenia? Neurochem Int 2007;50:291-301. https://doi.org/10.1016/j.neuint.2006.09.006
  52. Kalkman HO. Circumstantial evidence for a role of glutamine-synthetase in suicide. Med Hypotheses 2011;76:905-907. https://doi.org/10.1016/j.mehy.2011.03.005
  53. Tanahashi S, Yamamura S, Nakagawa M, Motomura E, Okada M. Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes. Br J Pharmacol 2012;165:1543-1555. https://doi.org/10.1111/j.1476-5381.2011.01638.x
  54. Muller N, Schwarz M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res 2006; 10:131-148. https://doi.org/10.1007/BF03033242
  55. Mednick SA, Machon RA, Huttunen MO, Bonett D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 1988;45:189-192. https://doi.org/10.1001/archpsyc.1988.01800260109013
  56. Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry 2011;168:1303-1310. https://doi.org/10.1176/appi.ajp.2011.11030516
  57. Steiner J, Mawrin C, Ziegeler A, Bielau H, Ullrich O, Bernstein HG, et al. Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization. Acta Neuropathol 2006; 112:305-316. https://doi.org/10.1007/s00401-006-0090-8
  58. van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 2008;64:820-822. https://doi.org/10.1016/j.biopsych.2008.04.025
  59. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Metaanalysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2011;70:663-671. https://doi.org/10.1016/j.biopsych.2011.04.013
  60. Abazyan B, Nomura J, Kannan G, Ishizuka K, Tamashiro KL, Nucifora F, et al. Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biol Psychiatry 2010; 68:1172-1181. https://doi.org/10.1016/j.biopsych.2010.09.022
  61. Powell SB, Sejnowski TJ, Behrens MM. Behavioral and neurochemical consequences of cortical oxidative stress on parvalbumin-interneuron maturation in rodent models of schizophrenia. Neuropharmacology 2012;62:1322-1331. https://doi.org/10.1016/j.neuropharm.2011.01.049
  62. Lai AY, Todd KG. Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclines. Glia 2006; 53:809-816. https://doi.org/10.1002/glia.20335
  63. Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 2010;71:138-149. https://doi.org/10.4088/JCP.08m04666yel
  64. Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol 2012;26:1185-1193. https://doi.org/10.1177/0269881112444941
  65. Muller N, Riedel M, Scheppach C, Brandstatter B, Sokullu S, Krampe K, et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 2002;159:1029-1034. https://doi.org/10.1176/appi.ajp.159.6.1029
  66. Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B. Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res 2007;90:179-185. https://doi.org/10.1016/j.schres.2006.11.016
  67. Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D. Celecoxib augmentation of continuously ill patients with schizophrenia. Biol Psychiatry 2005;57:1594-1596. https://doi.org/10.1016/j.biopsych.2005.02.024