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Glial Cells

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The Neuropathology of Schizophrenia

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Abstract

Glial cells, discovered over a century ago and examined for several decades in neuropathological studies of schizophrenia, have often been limited to simple counts published as total glia density or number. In recent decades, it has become clear that the differing primary glial cell types, oligodendrocytes, astrocytes and microglia and macrophages have very different functions in the brain and make up very different proportions of the total glial numbers. These glial cell types are now well understood to have very different biological roles, neurodevelopmental origins, lifespans and fates, and in recent years have been studied as distinct cell populations with differing potential roles in schizophrenia. Whilst there is much to be learned still about both the fundamental biology of these cells types and their role in schizophrenia, the data strongly suggest that future neuropathological studies should take these glial morphological and biochemical characteristics into account in their experimental designs.

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References

  1. Virchow R. Gesammelte abhandlungen zur wissenschaftlichen medicin (collected papers on scientific medicine). Virchows Archives. 1856;8:537–40.

    Article  Google Scholar 

  2. Dieters O. Untersuchungen uber Gehirn und R € uckenmark (Investigations on brain and spinal cord) (Vieweg); 1865.

    Google Scholar 

  3. Somjen GG. Nervenkitt: notes on the history of the concept of neuroglia. Glia. 1988;1(1):2–9.

    Article  CAS  PubMed  Google Scholar 

  4. von Lenhossek M. Der feinere Bau des Nervensystems im Lichte neuester Forschungen (Fischer’s Medicinische Buchhandlung); 1995.

    Google Scholar 

  5. Williams M, Pearce RK, Hirsch SR, Ansorge O, Thom M, Maier M. Fibrillary astrocytes are decreased in the subgenual cingulate in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2014a;264(4):357–62.

    Article  PubMed  Google Scholar 

  6. Williams MR, Galvin K, O'Sullivan B, MacDonald CD, Ching EW, Turkheimer F, Howes OD, Pearce RK, Hirsch SR, Maier M. Neuropathological changes in the substantia nigra in schizophrenia but not depression. Eur Arch Psychiatry Clin Neurosci. 2014b;264(4):285–96.

    Article  CAS  PubMed  Google Scholar 

  7. Williams MR, Hampton T, Pearce RK, Hirsch SR, Ansorge O, Thom M, Maier M. Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2013a;263(1):41–52.

    Article  PubMed  Google Scholar 

  8. Kanakis D, Lendeckel U, Theodosiou P, Dobrowolny H, Mawrin C, Keilhoff G, Bukowska A, Dietzmann K, Bogerts B, Bernstein HG. ADAM 12: a putative marker of oligodendrogliomas? Dis Markers. 2013;34(2):81–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Busse S, Busse M, Schiltz K, Bielau H, Gos T, Brisch R, Mawrin C, Schmitt A, Jordan W, Muller UJ, Bernstein HG, Bogerts B, Steiner J. Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations? Brain Behav Immun. 2012;26(8):1273–9.

    Article  CAS  PubMed  Google Scholar 

  10. Munn NA. Microglia dysfunction in schizophrenia: an integrative theory. Med Hypotheses. 2000;54(2):198–202.

    Article  CAS  PubMed  Google Scholar 

  11. Steiner J, Mawrin C, Ziegeler A, Bielau H, Ullrich O, Bernstein HG, Bogerts B. Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization. Acta Neuropathol. 2006;112(3):305–16.

    Article  CAS  PubMed  Google Scholar 

  12. van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, Luurtsema G, Windhorst AD, Cahn W, Lammertsma AA, Kahn RS. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry. 2008;64(9):820–2.

    Article  PubMed  Google Scholar 

  13. Chew LJ, Fusar-Poli P, Schmitz T. Oligodendroglial alterations and the role of microglia in white matter injury: relevance to schizophrenia. Dev Neurosci. 2013;35(2–3):102–29.

    Article  CAS  PubMed  Google Scholar 

  14. Mattei D, Djodari-Irani A, Hadar R, Pelz A, de Cossio LF, Goetz T, Matyash M, Kettenmann H, Winter C, Wolf SA. Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia. Brain Behav Immun. 2014;38:175–84.

    Article  CAS  PubMed  Google Scholar 

  15. Monji A, Kato T, Kanba S. Cytokines and schizophrenia: microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009;63(3):257–65.

    Article  CAS  PubMed  Google Scholar 

  16. O'Donnell P, Grace AA. Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters. Schizophr Bull. 1998;24(2):267–83.

    Article  CAS  PubMed  Google Scholar 

  17. Sofroniew MV. Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci. 2015;16(5):249–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119(1):7–35.

    Article  PubMed  Google Scholar 

  19. Hui SP, Dutta A, Ghosh S. Cellular response after crush injury in adult zebrafish spinal cord. Dev Dyn. 2010;239(11):2962–79.

    Article  PubMed  Google Scholar 

  20. Hung YH, Stelzner DJ. Frog tectal efferent axons fail to regenerate within the CNS but grow within peripheral nerve implants. Exp Neurol. 1991;112(3):273–83.

    Article  CAS  PubMed  Google Scholar 

  21. Kálmán M, Somiya H, Lazarevic L, Milosevic I, Ari C, Majorossy K. Absence of post-lesion reactive gliosis in elasmobranchs and turtles and its bearing on the evolution of astroglia. J Exp Zool B Mol Dev Evol. 2013;320(6):351–67.

    Article  PubMed  CAS  Google Scholar 

  22. Lang DM, Monzon-Mayor M, Del Mar Romero-Aleman M, Yanes C, Santos E, Pesheva P. Tenascin-R and axon growth-promoting molecules are up-regulated in the regenerating visual pathway of the lizard (Gallotia galloti). Dev Neurobiol. 2008;68(7):899–916.

    Article  CAS  PubMed  Google Scholar 

  23. MacDonald JM, Beach MG, Porpiglia E, Sheehan AE, Watts RJ, Freeman MR. The drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons. Neuron. 2006;50(6):869–81.

    Article  CAS  PubMed  Google Scholar 

  24. Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr. 2000;130(4S Suppl):1007S–15S.

    Article  CAS  PubMed  Google Scholar 

  25. Howes O, McCutcheon R, Stone J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol. 2015;29(2):97–115.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Bar-Peled O, Ben-Hur H, Biegon A, Groner Y, Dewhurst S, Furuta A, Rothstein JD. Distribution of glutamate transporter subtypes during human brain development. J Neurochem. 1997;69(6):2571–80.

    Article  CAS  PubMed  Google Scholar 

  27. Furuta A, Martin LJ, Lin CL, Dykes-Hoberg M, Rothstein JD. Cellular and synaptic localization of the neuronal glutamate transporters excitatory amino acid transporter 3 and 4. Neuroscience. 1997;81(4):1031–42.

    Article  CAS  PubMed  Google Scholar 

  28. Kanai Y, Clemencon B, Simonin A, Leuenberger M, Lochner M, Weisstanner M, Hediger MA. The SLC1 high-affinity glutamate and neutral amino acid transporter family. Mol Asp Med. 2013;34(2–3):108–20.

    Article  CAS  Google Scholar 

  29. Nakagawa T, Kaneko S. SLC1 glutamate transporters and diseases: psychiatric diseases and pathological pain. Curr Mol Pharmacol. 2013;6(2):66–73.

    Article  CAS  PubMed  Google Scholar 

  30. Barbour B, Brew H, Attwell D. Electrogenic glutamate uptake in glial cells is activated by intracellular potassium. Nature. 1988;335(6189):433–5.

    Article  CAS  PubMed  Google Scholar 

  31. Kanai Y, Hediger MA. The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects. Pflugers Arch. 2004;447(5):469–79.

    Article  CAS  PubMed  Google Scholar 

  32. Slotboom DJ, Konings WN, Lolkema JS. The structure of glutamate transporters shows channel-like features. FEBS Lett. 2001;492(3):183–6.

    Article  CAS  PubMed  Google Scholar 

  33. Grewer C, Gameiro A, Rauen T. SLC1 glutamate transporters. Pflugers Arch. 2014;466(1):3–24.

    Article  CAS  PubMed  Google Scholar 

  34. Nothmann D, Leinenweber A, Torres-Salazar D, Kovermann P, Hotzy J, Gameiro A, Grewer C, Fahlke C. Hetero-oligomerization of neuronal glutamate transporters. J Biol Chem. 2011;286(5):3935–43.

    Article  CAS  PubMed  Google Scholar 

  35. Gegelashvili G, Schousboe A. Cellular distribution and kinetic properties of high-affinity glutamate transporters. Brain Res Bull. 1998;45(3):233–8.

    Article  CAS  PubMed  Google Scholar 

  36. Zhou Y, Danbolt NC. GABA and glutamate transporters in brain. Front Endocrinol (Lausanne). 2013;4:165.

    Article  Google Scholar 

  37. Jimenez E, Nunez E, Ibanez I, Draffin JE, Zafra F, Gimenez C. Differential regulation of the glutamate transporters GLT-1 and GLAST by GSK3beta. Neurochem Int. 2014;79:33–43.

    Article  CAS  PubMed  Google Scholar 

  38. Uwechue NM, Marx MC, Chevy Q, Billups B. Activation of glutamate transport evokes rapid glutamine release from perisynaptic astrocytes. J Physiol. 2012;590(Pt 10):2317–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Piet R, Poulain DA, Oliet SH. Contribution of astrocytes to synaptic transmission in the rat supraoptic nucleus. Neurochem Int. 2004a;45(2–3):251–7.

    Article  CAS  PubMed  Google Scholar 

  40. Piet R, Vargova L, Sykova E, Poulain DA, Oliet SH. Physiological contribution of the astrocytic environment of neurons to intersynaptic crosstalk. Proc Natl Acad Sci U S A. 2004b;101(7):2151–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Matsugami TR, Tanemura K, Mieda M, Nakatomi R, Yamada K, Kondo T, Ogawa M, Obata K, Watanabe M, Hashikawa T, Tanaka K. From the cover: indispensability of the glutamate transporters GLAST and GLT1 to brain development. Proc Natl Acad Sci U S A. 2006;103(32):12161–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Karlsson RM, Tanaka K, Saksida LM, Bussey TJ, Heilig M, Holmes A. Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology. 2009;34(6):1578–89.

    Article  CAS  PubMed  Google Scholar 

  43. Spangaro M, Bosia M, Zanoletti A, Bechi M, Mariachiara B, Pirovano A, Lorenzi C, Bramanti P, Smeraldi E, Cavallaro R. Exploring effects of EAAT polymorphisms on cognitive functions in schizophrenia. Pharmacogenomics. 2014;15(7):925–32.

    Article  CAS  PubMed  Google Scholar 

  44. Karki P, Smith K, Johnson J Jr, Lee E. Astrocyte-derived growth factors and estrogen neuroprotection: role of transforming growth factor-alpha in estrogen-induced upregulation of glutamate transporters in astrocytes. Mol Cell Endocrinol. 2014;389(1–2):58–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu X, Kihara T, Akaike A, Niidome T, Sugimoto H. PI3K/Akt/mTOR signaling regulates glutamate transporter 1 in astrocytes. Biochem Biophys Res Commun. 2010;393(3):514–8.

    Article  CAS  PubMed  Google Scholar 

  46. Unger T, Lakowa N, Bette S, Engele J. Transcriptional regulation of the GLAST/EAAT-1 gene in rat and man. Cell Mol Neurobiol. 2012;32(4):539–47.

    Article  CAS  PubMed  Google Scholar 

  47. Figiel M, Engele J. Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuron-derived peptide regulating glial glutamate transport and metabolism. J Neurosci. 2000;20(10):3596–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sidoryk-Wegrzynowicz M, Lee E, Aschner M. Mechanism of Mn(II)-mediated dysregulation of glutamine-glutamate cycle: focus on glutamate turnover. J Neurochem. 2012;122(4):856–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Thierry-Mieg D, Thierry-Mieg J. AceView: a comprehensive cDNA-supported gene and transcripts annotation. Genome Biol. 2006;7(Suppl 1):S12.1–14.

    Article  Google Scholar 

  50. Karki P, Smith K, Johnson J Jr, Aschner M, Lee EY. Genetic dys-regulation of astrocytic glutamate transporter EAAT2 and its implications in neurological disorders and manganese toxicity. Neurochem Res. 2015;40(2):380–8.

    Article  CAS  PubMed  Google Scholar 

  51. Morel L, Regan M, Higashimori H, Ng SK, Esau C, Vidensky S, Rothstein J, Yang Y. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem. 2013;288(10):7105–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Martinez-Villarreal J, Garcia Tardon N, Ibanez I, Gimenez C, Zafra F. Cell surface turnover of the glutamate transporter GLT-1 is mediated by ubiquitination/deubiquitination. Glia. 2012;60(9):1356–65.

    Article  PubMed  Google Scholar 

  53. Butchbach ME, Tian G, Guo H, Lin CL. Association of excitatory amino acid transporters, especially EAAT2, with cholesterol-rich lipid raft microdomains: importance for excitatory amino acid transporter localization and function. J Biol Chem. 2004;279(33):34388–96.

    Article  CAS  PubMed  Google Scholar 

  54. Roberts RC, Roche JK, McCullumsmith RE. Localization of excitatory amino acid transporters EAAT1 and EAAT2 in human postmortem cortex: a light and electron microscopic study. Neuroscience. 2014;277:522–40.

    Article  CAS  PubMed  Google Scholar 

  55. Hu WH, Walters WM, Xia XM, Karmally SA, Bethea JR. Neuronal glutamate transporter EAAT4 is expressed in astrocytes. Glia. 2003;44(1):13–25.

    Article  PubMed  Google Scholar 

  56. Dall'Igna OP, Bobermin LD, Souza DO, Quincozes-Santos A. Riluzole increases glutamate uptake by cultured C6 astroglial cells. Int J Dev Neurosci. 2013;31(7):482–6.

    Article  CAS  PubMed  Google Scholar 

  57. Perego C, Vanoni C, Bossi M, Massari S, Basudev H, Longhi R, Pietrini G. The GLT-1 and GLAST glutamate transporters are expressed on morphologically distinct astrocytes and regulated by neuronal activity in primary hippocampal cocultures. J Neurochem. 2000;75(3):1076–84.

    Article  CAS  PubMed  Google Scholar 

  58. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci. 2008;28(1):264–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hatten ME, Liem RK, Shelanski ML, Mason CA. Astroglia in CNS injury. Glia. 1991;4(2):233–43.

    Article  CAS  PubMed  Google Scholar 

  60. Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001;81(2):807–69.

    Article  CAS  PubMed  Google Scholar 

  61. Neary JT, Zimmermann H. Trophic functions of nucleotides in the central nervous system. Trends Neurosci. 2009;32(4):189–98.

    Article  CAS  PubMed  Google Scholar 

  62. Wanner IB, Anderson MA, Song B, Levine J, Fernandez A, Gray-Thompson Z, Ao Y, Sofroniew MV. Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci. 2013;33(31):12870–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46(6):957–67.

    Article  CAS  PubMed  Google Scholar 

  64. Pirici D, Mogoanta L, Margaritescu O, Pirici I, Tudorica V, Coconu M. Fractal analysis of astrocytes in stroke and dementia. Romanian J Morphol Embryol. 2009;50(3):381–90.

    CAS  Google Scholar 

  65. Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002;22(1):183–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Halassa MM, Fellin T, Takano H, Dong JH, Haydon PG. Synaptic islands defined by the territory of a single astrocyte. J Neurosci. 2007;27(24):6473–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Raponi E, Agenes F, Delphin C, Assard N, Baudier J, Legraverend C, Deloulme JC. S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage. Glia. 2007;55(2):165–77.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Brozzi F, Arcuri C, Giambanco I, Donato R. S100B protein regulates astrocyte shape and migration via interaction with Src kinase: implications for astrocyte development, activation, and tumor growth. J Biol Chem. 2009;284(13):8797–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pekny M, Johansson CB, Eliasson C, Stakeberg J, Wallen A, Perlmann T, Lendahl U, Betsholtz C, Berthold CH, Frisen J. Abnormal reaction to central nervous system injury in mice lacking glial fibrillary acidic protein and vimentin. J Cell Biol. 1999;145(3):503–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Stevens JR. Neuropathology of schizophrenia. Arch Gen Psychiatry. 1982;39(10):1131–9.

    Article  CAS  PubMed  Google Scholar 

  71. 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(2):285–304.

    Article  CAS  PubMed  Google Scholar 

  72. Roberts GW, Bruton CJ. Notes from the graveyard: neuropathology and schizophrenia. Neuropathol Appl Neurobiol. 1990;16(1):3–16.

    Article  CAS  PubMed  Google Scholar 

  73. Roberts GW, Colter N, Lofthouse R, Johnstone EC, Crow TJ. Is there gliosis in schizophrenia? Investigation of the temporal lobe. Biol Psychiatry. 1987;22(12):1459–68.

    Article  CAS  PubMed  Google Scholar 

  74. Hercher C, Chopra V, Beasley CL. Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder. J Psychiatry Neurosci. 2014;39(6):376–85.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Zhang Y, Barres BA. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol. 2010;20(5):588–94.

    Article  CAS  PubMed  Google Scholar 

  76. Tomassy GS, Dershowitz LB, Arlotta P. Diversity matters: a revised guide to myelination. Trends Cell Biol. 2016;26(2):135–47.

    Article  CAS  PubMed  Google Scholar 

  77. Snaidero N, Möbius W, Czopka T, Hekking LH, Mathisen C, Verkleij D, Goebbels S, Edgar J, Merkler D, Lyons DA, Nave KA, Simons M. Myelin membrane wrapping of CNS axons by PI(3,4,5)P3-dependent polarized growth at the inner tongue. Cell. 2014;156(1–2):277–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Snaidero N, Velte C, Myllykoski M, Raasakka A, Ignatev A, Werner HB, Erwig MS, Möbius W, Kursula P, Nave KA, Simons M. Antagonistic functions of MBP and CNP establish cytosolic channels in CNS myelin. Cell Rep. 2017;18(2):314–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pérez-Cerdá F, Sánchez-Gómez MV, Matute C. Pío del Río Hortega and the discovery of the oligodendrocytes. Front Neuroanat. 2015;9:92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Nave KA, Trapp BD. Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci. 2008;31:535–61.

    Article  CAS  PubMed  Google Scholar 

  81. Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell. 1989;57(1):167–75.

    Article  CAS  PubMed  Google Scholar 

  82. Pillai A, Veeranan-Karmegam R, Dhandapani KM, Mahadik SP. Cystamine prevents haloperidol-induced decrease of BDNF/TrkB signaling in mouse frontal cortex. J Neurochem. 2008;107(4):941–51.

    CAS  PubMed  Google Scholar 

  83. Whitman M, Downes CP, Keeler M, Keller T, Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988;332(6165):644–6.

    Article  CAS  PubMed  Google Scholar 

  84. Peirce TR, Bray NJ, Williams NM, Norton N, Moskvina V, Preece A, Haroutunian V, Buxbaum JD, Owen MJ, O'Donovan MC. Convergent evidence for 2′,3′-cyclic nucleotide 3′-phosphodiesterase as a possible susceptibility gene for schizophrenia. Arch Gen Psychiatry. 2006;63(1):18–24.

    Article  CAS  PubMed  Google Scholar 

  85. Mitkus SN, Hyde TM, Vakkalanka R, Kolachana B, Weinberger DR, Kleinman JE, Lipska BK. Expression of oligodendrocyte-associated genes in dorsolateral prefrontal cortex of patients with schizophrenia. Schizophr Res. 2008;98(1–3):129–38.

    Article  PubMed  Google Scholar 

  86. Yu Y, Chen Y, Kim B, Wang H, Zhao C, He X, Liu L, Liu W, Wu LM, Mao M, Chan JR, Wu J, Lu QR. Olig2 targets chromatin remodelers to enhancers to initiate oligodendrocyte differentiation. Cell. 2013;152(1–2):248–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Beasley CL, Honavar M, Everall IP, Cotter D. Two-dimensional assessment of cytoarchitecture in the superior temporal white matter in schizophrenia, major depressive disorder and bipolar disorder. Schizophr Res. 2009;115(2–3):156–62.

    Article  PubMed  Google Scholar 

  88. Chana G, Landau S, Everall I, Cotter D. Glial cell number and nuclear size in the mediodorsal thalamic nucleus (MDNT) in schizophrenia. Schizophr Res. 2008;102(1–3):344–5.

    Article  PubMed  Google Scholar 

  89. Cotter D, Kerwin R, al-Sarraji S, Brion JP, Chadwich A, Lovestone S, Anderton B, Everall I. Abnormalities of Wnt signalling in schizophrenia--evidence for neurodevelopmental abnormality. Neuroreport. 1998;9(7):1379–83.

    Article  CAS  PubMed  Google Scholar 

  90. 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. 2001a;58(6):545–53.

    Article  CAS  PubMed  Google Scholar 

  91. Cotter DR, Pariante CM, Everall IP. Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull. 2001b;55(5):585–95.

    Article  CAS  PubMed  Google Scholar 

  92. Drevets WC. Prefrontal cortical-amygdalar metabolism in major depression. Ann N Y Acad Sci. 1999;877:614–37.

    Article  CAS  PubMed  Google Scholar 

  93. Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, Vannier M, Raichle ME. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386(6627):824–7.

    Article  CAS  PubMed  Google Scholar 

  94. Ongür D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A. 1998;95(22):13290–5.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Williams MR, Harb H, Pearce RK, Hirsch SR, Maier M. Oligodendrocyte density is changed in the basolateral amygdala in schizophrenia but not depression. Schizophr Res. 2013b;147(2–3):402–3.

    Article  CAS  PubMed  Google Scholar 

  96. Williams MR, Marsh R, Macdonald CD, Jain J, Pearce RK, Hirsch SR, Ansorge O, Gentleman SM, Maier M. Neuropathological changes in the nucleus basalis in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2013c;263(6):485–95.

    Article  CAS  PubMed  Google Scholar 

  97. Vikhreva OV, Rakhmanova VI, Orlovskaya DD, Uranova NA. Ultrastructural alterations of oligodendrocytes in prefrontal white matter in schizophrenia: a post-mortem morphometric study. Schizophr Res. 2016;177(1–3):28–36.

    Article  CAS  PubMed  Google Scholar 

  98. Cooper MD, Alder MN. The evolution of adaptive immune systems. Cell. 2006;124(4):815–22.

    Article  CAS  PubMed  Google Scholar 

  99. Tauber AI. Metchnikoff and the phagocytosis theory. Nat Rev Mol Cell Biol. 2003;4(11):897–901.

    Article  CAS  PubMed  Google Scholar 

  100. Denker SP, Ji S, Dingman A, Lee SY, Derugin N, Wendland MF, Vexler ZS. Macrophages are comprised of resident brain microglia not infiltrating peripheral monocytes acutely after neonatal stroke. J Neurochem. 2007;100(4):893–904.

    Article  CAS  PubMed  Google Scholar 

  101. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooijen N, García-Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38(4):792–804.

    Article  CAS  PubMed  Google Scholar 

  103. Jakubzick C, Gautier EL, Gibbings SL, Sojka DK, Schlitzer A, Johnson TE, Ivanov S, Duan Q, Bala S, Condon T, van Rooijen N, Grainger JR, Belkaid Y, Ma'ayan A, Riches DW, Yokoyama WM, Ginhoux F, Henson PM, Randolph GJ. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity. 2013;39(3):599–610.

    Article  CAS  PubMed  Google Scholar 

  104. Sevenich L. Brain-resident microglia and blood-borne macrophages orchestrate central nervous system inflammation in neurodegenerative disorders and brain cancer. Front Immunol. 2018;9:697.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Waisman A, Ginhoux F, Greter M, Bruttger J. Homeostasis of microglia in the adult brain: review of novel microglia depletion systems. Trends Immunol. 2015;36(10):625–36.

    Article  CAS  PubMed  Google Scholar 

  106. Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity. 2014;41(1):21–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hu K, Jin Y, Chroneos Z, Han X, Liu H, Lin L. Macrophage functions and regulation: roles in diseases and implications in therapeutics. J Immunol Res. 2018;2018:7590350.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Nayak D, Roth TL, McGavern DB. Microglia development and function. Annu Rev Immunol. 2014;32:367–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 2009;29(13):3974–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Olson JK. Immune response by microglia in the spinal cord. Ann N Y Acad Sci. 2010;1198:271–8.

    Article  CAS  PubMed  Google Scholar 

  111. Ormel PR, van Mierlo HC, Litjens M, Strien MEV, Hol EM, Kahn RS, de Witte LD. Characterization of macrophages from schizophrenia patients. NPJ Schizophr. 2017;3(1):41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Brown GC, Neher JJ. Microglial phagocytosis of live neurons. Nat Rev Neurosci. 2014;15(4):209–16.

    Article  CAS  PubMed  Google Scholar 

  113. Kawabori M, Yenari MA. The role of the microglia in acute CNS injury. Metab Brain Dis. 2015;30(2):381–92.

    Article  CAS  PubMed  Google Scholar 

  114. Mizee MR, Miedema SS, van der Poel M, Adelia KGS, van Strien ME, Melief J, Smolders J, Hendrickx DA, Heutinck KM, Hamann J, Huitinga I. Isolation of primary microglia from the human post-mortem brain: effects of ante- and post-mortem variables. Acta Neuropathol Commun. 2017;5(1):16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Tsuda M. Microglia in the CNS and neuropathic pain. Adv Exp Med Biol. 2018;1099:77–91.

    Article  CAS  PubMed  Google Scholar 

  116. Colonna M, Butovsky O. Microglia function in the central nervous system during health and Neurodegeneration. Annu Rev Immunol. 2017;35:441–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Garaschuk O, Verkhratsky A. Physiology of microglia. Methods Mol Biol. 2019;2034:27–40.

    Article  CAS  PubMed  Google Scholar 

  118. Horváth S, Mirnics K. Immune system disturbances in schizophrenia. Biol Psychiatry. 2014;75(4):316–23.

    Article  PubMed  CAS  Google Scholar 

  119. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91(2):461–553.

    Article  CAS  PubMed  Google Scholar 

  120. Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron. 2013;77(1):10–8.

    Article  CAS  PubMed  Google Scholar 

  121. Lucin KM, Wyss-Coray T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron. 2009;64(1):110–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tremblay M, Lowery RL, Majewska AK. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 2010;8(11):e1000527.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Volk DW. Role of microglia disturbances and immune-related marker abnormalities in cortical circuitry dysfunction in schizophrenia. Neurobiol Dis. 2017;99:58–65.

    Article  CAS  PubMed  Google Scholar 

  124. Wohleb ES, Delpech JC. Dynamic cross-talk between microglia and peripheral monocytes underlies stress-induced neuroinflammation and behavioral consequences. Prog Neuropsychopharmacol Biol Psychiatry. 2017;79(Pt A):40–8.

    Article  CAS  PubMed  Google Scholar 

  125. Hempel C, Nörenberg W, Sobottka H, Urban N, Nicke A, Fischer W, Schaefer M. The phenothiazine-class antipsychotic drugs prochlorperazine and trifluoperazine are potent allosteric modulators of the human P2X7 receptor. Neuropharmacology. 2013;75:365–79.

    Article  CAS  PubMed  Google Scholar 

  126. Andrejew R, Oliveira-Giacomelli Á, Ribeiro DE, Glaser T, Arnaud-Sampaio VF, Lameu C, Ulrich H. The P2X7 receptor: central hub of brain diseases. Front Mol Neurosci. 2020;13:124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, Fu T, Worringer K, Brown HE, Wang J, Kaykas A, Karmacharya R, Goold CP, Sheridan SD, Perlis RH. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019;22(3):374–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Coughlin JM, Wang Y, Ambinder EB, Ward RE, Minn I, Vranesic M, Kim PK, Ford CN, Higgs C, Hayes LN, Schretlen DJ, Dannals RF, Kassiou M, Sawa A, Pomper MG. In vivo markers of inflammatory response in recent-onset schizophrenia: a combined study using [(11)C]DPA-713 PET and analysis of CSF and plasma. Transl Psychiatry. 2016;6(4):e777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Trépanier MO, Hopperton KE, Mizrahi R, Mechawar N, Bazinet RP. Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review. Mol Psychiatry. 2016;21(8):1009–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7.

    Article  PubMed Central  CAS  Google Scholar 

  131. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE, Daly MJ, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530(7589):177–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Benros ME, Eaton WW, Mortensen PB. The epidemiologic evidence linking autoimmune diseases and psychosis. Biol Psychiatry. 2014;75(4):300–6.

    Article  PubMed  Google Scholar 

  133. Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T, Cairns M, Weickert CS. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. 2013;18(2):206–14.

    Article  CAS  PubMed  Google Scholar 

  134. Chan MK, Cooper JD, Heilmann-Heimbach S, Frank J, Witt SH, Nöthen MM, Steiner J, Rietschel M, Bahn S. Associations between SNPs and immune-related circulating proteins in schizophrenia. Sci Rep. 2017;7(1):12586.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Sun S, Wang F, Wei J, Cao LY, Qi LY, Xiu MH, Chen S, Li XH, Kosten TA, Kosten TR, Zhang XY. Association between interleukin-6 receptor polymorphism and patients with schizophrenia. Schizophr Res. 2008;102:346–7.

    Article  PubMed  Google Scholar 

  136. Hattori K, Tanaka H, Wakabayashi C, Yamamoto N, Uchiyama H, Teraishi T, Hori H, Arima K, Kunugi H. Expression of Ca2+-dependent activator protein for secretion 2 is increased in the brains of schizophrenic patients. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35(7):1738–43.

    Article  CAS  Google Scholar 

  137. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.

    Article  Google Scholar 

  138. D’Amico MA, Ghinassi B, Izzicupo P, Manzoli L, Di Baldassarre A. Biological function and clinical relevance of chromogranin A and derived peptides. Endocr Connect. 2014;3(2):R45–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Iwazaki T, Shibata I, Niwa S, Matsumoto I. Selective reduction of chromogranin A-like immunoreactivities in the prefrontal cortex of schizophrenic subjects: a postmortem study. Neurosci Lett. 2004;367(3):293–7.

    Article  CAS  PubMed  Google Scholar 

  140. Shibata H, Naito J. Organization of anterior cingulate and frontal cortical projections to the anterior and laterodorsal thalamic nuclei in the rat. Brain Res. 2005;1059(1):93–103.

    Article  CAS  PubMed  Google Scholar 

  141. Takahashi N, Ishihara R, Saito S, Maemo N, Aoyama N, Ji X, Miura H, Ikeda M, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y, Ozaki N, Inada T. Association between chromogranin A gene polymorphism and schizophrenia in the Japanese population. Schizophr Res. 2006;83(2–3):179–83.

    Article  PubMed  Google Scholar 

  142. van Kammen DP, Peters J, Yao J, Neylan T, Beuger M, Pontius E, O'Connor DT. CSF chromogranin A-like immunoreactivity in schizophrenia. Assessment of clinical and biochemical relationships. Schizophr Res. 1991;6(1):31–9.

    Article  PubMed  Google Scholar 

  143. Gavish M, Laor N, Bidder M, Fisher D, Fonia O, Muller U, Reiss A, Wolmer L, Karp L, Weizman R. Altered platelet peripheral-type benzodiazepine receptor in posttraumatic stress disorder. Neuropsychopharmacology. 1996;14(3):181–6.

    Article  CAS  PubMed  Google Scholar 

  144. Gavish M, Weizman A, Karp L, Tyano S, Tanne Z. Decreased peripheral benzodiazepine binding sites in platelets of neuroleptic-treated schizophrenics. Eur J Pharmacol. 1986;121(2):275–9.

    Article  CAS  PubMed  Google Scholar 

  145. Ritsner M, Modai I, Gibel A, Leschiner S, Silver H, Tsinovoy G, Weizman A, Gavish M. Decreased platelet peripheral-type benzodiazepine receptors in persistently violent schizophrenia patients. J Psychiatr Res. 2003;37(6):549–56.

    Article  PubMed  Google Scholar 

  146. Weizman R, Tanne Z, Karp L, Tyano S, Gavish M. Peripheral-type benzodiazepine-binding sites in platelets of schizophrenics with and without tardive dyskinesia. Life Sci. 1986;39(6):549–55.

    Article  CAS  PubMed  Google Scholar 

  147. Chen MK, Baidoo K, Verina T, Guilarte TR. Peripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization. Brain. 2004;127(Pt 6):1379–92.

    Article  PubMed  Google Scholar 

  148. Guilarte TR. TSPO in diverse CNS pathologies and psychiatric disease: a critical review and a way forward. Pharmacol Ther. 2019;194:44–58.

    Article  CAS  PubMed  Google Scholar 

  149. Venneti S, Lopresti BJ, Wiley CA. The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging. Prog Neurobiol. 2006;80(6):308–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Venneti S, Wagner AK, Wang G, Slagel SL, Chen X, Lopresti BJ, Mathis CA, Wiley CA. The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds specifically to microglia in a rat model of traumatic brain injury: implications for PET imaging. Exp Neurol. 2007;207(1):118–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Prof. Steven Hirsch for advice on the manuscript. This commentary was written with support from the Grupo de Investigacion Junta de Andalucia CTS113, Consejería de Salud of the Junta de Andalucia (PI-0036-2014).

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  1. Francis Fraser Clinic, Hammersmith Hospital, London, UK

    Matthew Williams

  2. Guys Hospital, London, UK

    Claire Macdonald

  3. Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Cádiz, Andalusia, Spain

    Mario Cordero

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    Matthew Williams

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Williams, M., Macdonald, C., Cordero, M. (2021). Glial Cells. In: Williams, M. (eds) The Neuropathology of Schizophrenia. Springer, Cham. https://doi.org/10.1007/978-3-030-68308-5_12

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