Microglia-Oligodendrocyte Interactions in White Matter of the Prefrontal Cortex in Attack-Like Schizophrenia
https://doi.org/10.30629/2618-6667-2022-20-4-84-95
Abstract
Background: the authors previously reported the ultrastructural pathology of oligodendrocytes in contacts with microglia in white matter of the prefrontal cortex in attack-like schizophrenia supposedly associated with microglial activation. Aim of the study: to perform morphometry of the ultrastructural parameters of microglia in contact with oligodendrocytes and to analyze correlations between the parameters of microglia and oligodendrocytes previously studied in the schizophrenia group as compared to the control group. Material and methods: a postmortem ultrastructural morphometric study of microglia in contact with oligodendrocytes in white matter of the prefrontal cortex was performed in 8 cases of attack-like schizophrenia and 20 healthy controls. Group comparisons were performed using ANCOVA and Pearson correlation analyses. Results: we found reduced volume fraction (Vv) and the number of mitochondria and increased Vv, area and number of vacuoles of endoplasmic reticulum and area of heterochromatin in microglia in the schizophrenia group as compared to the control group. Area of microglial cytoplasm correlated positively with area and number of vacuoles in microglia, and Vv and the number of mitochondria in microglia correlated positively with Vv and the number of vacuoles in microglia in the schizophrenia but not in the control group. Positive correlations were found between area of lipofuscin granules in oligodendrocytes and areas of microglial cell, nucleus and cytoplasm and the number of mitochondria in microglia only in the schizophrenia group. Also, area of vacuoles in oligodendrocytes correlated positively with the number of mitochondria in microglia in the schizophrenia group. In contrast, in the control group but not in the schizophrenia group the parameters of mitochondria and lipofuscin granules correlated positively with the same parameters in oligodendrocytes. Conclusion: these data suggest that normal relationships between energy and lipid metabolism of microglia and oligodendrocytes are disturbed in schizophrenia. Dystrophic changes of oligodendrocytes in attack-like schizophrenia might be associated with the effects of microglial activation on lipid and protein metabolism.
About the Authors
O. V. VikhrevaRussian Federation
Olga V. Vikhreva - Candidate of Biological Sciences, Laboratory of Clinical Neuropathology, Mental Health Research Centre.
Moscow
V. I. Rakhmanova
Russian Federation
Valentina I. Rakhmanova - Laboratory of Clinical Neuropathology, Mental Health Research Centre.
Moscow
N. A. Uranova
Russian Federation
Natalya A. Uranova - Dr. of Sci. (Med.), Head of Clinical Neuropathology Laboratory, Mental Health Research Centre.
Moscow
References
1. Najjar S, Pearlman DM.Neuroinfammation and white matter pathology in schizophrenia: systematic review. Schizophr Res. 2015;161:102-112. doi: 10.1016/j.schres.2014.04.041
2. Uranova N. The Neuropathology of White Matter in Schizophrenia. In: Williams M. (eds). The Neuropathology of Schizophrenia. Springer, Cham, 2021. doi: 10.1007/978-3-030-68308-5_11
3. Mansouri FA, Koechlin E, Rosa MGP, Buckley MJ. Managing competing goals — a key role for the fronto-polar cortex. Nat Rev Neurosci. 2017;18(11):645-657. doi: 10.1038/nrn.2017.111
4. 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):102-129. doi: 10.1159/000346157 Epub 2013 Feb 27. PMID: 23446060; PMCID: PMC4531048
5. Maas DA, Valles A, Martens GJM. Oxidative stress, prefrontal cortex hypomyelination and cognitive symptoms in schizophrenia. Transl Psychiatry. 2017;7(7):e1171. doi: 10.1038/tp.2017.138
6. Olabi B, Ellison-Wright I, McIntosh AM, Wood SJ, Bullmore E, Lawrie SM. Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiatry. 2011;70(1):88-96. doi: 10.1016/j.bio-psych.2011.01.032
7. Fields RD. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 2008;31(7):361-370. doi: 10.1016/j.tins.2008.04.001
8. Flynn SW, Lang DJ, Mackay AL, Goghari V, Vavasour IM, Whittall KP, Smith GN, Arango V, Mann JJ, Dwork AJ, Falkai P, Honer WG. Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. Mol Psychiatry. 2003;8(9):811-820. doi: 10.1038/sj.mp.4001337
9. 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):102-129. doi: 10.1159/000346157
10. Du Y, Dreyfus CF. Oligodendrocytes as providers of growth factors. J Neurosci Res. 2002;68(6):647-654. doi: 10.1002/jnr.10245
11. 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. doi: 10.1016/j.schres.2016.04.023
12. Uranova NA, Vikhreva OV, Rakhmanova VI, Orlovskaya DD. Ultrastructural pathology of oligodendrocytes in the white matter in continuous paranoid schizophrenia: a role for microglia. Zhurnal Nevrologii i Psihiatrii imeni S.S. Korsakova. 2017;117(9):76-81. (In Russ.). doi: 10.17116/jnevro20171179176-81
13. Vikhreva OV, Rakhmanova VI, Orlovskaya DD, Uranova NA. Ultrastructural pathology of oligodendrocytes in white matter in continuous attack-like schizophrenia and a role for microglia. Zhurnal Nevrologii i Psihiatrii imeni S.S. Korsakova. 2018;118(5):69-74. (In Russ.). doi: 10.17116/jnevro20181185169
14. Uranova NA, Vikhreva OV, Rakhmanova VI, Orlovskaya DD. Ultrastructural pathology of oligodendrocytes adjacent to microglia in prefrontal white matter in schizophrenia. NPJ Schizophr. 2018;13;4(1):26. doi: 10.1038/s41537-018-0068-2
15. Uranova NA, Vikhreva OV, Rachmanova VI, Orlovskaya DD. Ultrastructural alterations of myelinated fibers and oligodendrocytes in the prefrontal cortex in schizophrenia: a postmortem morphometric study. Schizophr Res Treatment. 2011;2011:325789. doi: 10.1155/2011/325789
16. Uranova NA, Kolomeets NS, Vikhreva OV, Zimina IS, Rakhmanova VI, Orlovskaya DD. Ultrastructural changes of myelinated fibers in the brain in continuous and attack-like paranoid schizophrenia. Zhurnal Nevrologii i Psihiatrii imeni S.S. Korsakova. 2017;117(2):104-109. (In Russ.). doi: 10.17116/jnevro201711721104-109
17. Vostrikov VM, Uranova NA, Rakhmanova VI, Orlovskaia DD. Lowered oligodendroglial cell density in the prefrontal cortex in schizophrenia. Zhurnal Nevrologii i Psihiatrii imeni S.S. Korsakova. 2004;104(1):47-51. (In Russ.).
18. Hof PR, Haroutunian V, Friedrich VL, Byne W, Buitron C, Perl DP, Davis KL. Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry. 2003;53:1075-1085. doi: 10.1016/S0006-3223(03)00237-3
19. 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):376-385. doi: 10.1503/jpn.130277
20. Bernstein HG, Jauch E, Dobrowolny H, Mawrin C, Steiner J, Bogerts B. Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2016;266(6):495-504. doi: 10.1007/s00406-015-0640-y
21. Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009;63(3):257-265. doi: 10.1111/j.1440-1819.2009.01945.x
22. De Picker LJ, Morrens M, Chance SA, Boche D. Microglia and Brain Plasticity in Acute Psychosis and Schizophrenia Illness Course: A Meta-Review. Front Psychiatry. 2017;16(8):238. doi: 10.3389/fpsyt.2017.00238
23. Müller N. Inflammation in Schizophrenia: Pathogenetic aspects and therapeutic considerations. Schizophr Bull. 2018;44(5):973-982. doi: 10.1093/schbul/sby024
24. De Picker LJ, Victoriano GM, Richards R, Gorvett AJ, Lyons S, Buckland GR, Tofani T, Norman JL, Chatelet DS, Nicoll JAR, Boche D. Immune environment of the brain in schizophrenia and during the psychotic episode: A human post-mortem study. Brain Behav Immun. 2021;97:319-327. doi: 10.1016/j.bbi.2021.07.017
25. Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC. Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med. 2009;50(11):1801-1807. doi: 10.2967/jnumed.109.066647
26. Takano A, Arakawa R, Ito H, Tateno A, Takahashi H, Matsumoto R, Okubo Y, Suhara T. Peripheral benzodiazepine receptors in patients with chronic schizophrenia: a PET study with [11C] DAA1106. Int J Neuropsychopharmacol. 2010;13(7):943-950. doi: 10.1017/S1461145710000313
27. Laskaris LE, Di Biase MA, Everall I, Chana G, Christopoulos A, Skafidas E, Cropley VL, Pantelis C. Microglial activation and progressive brain changes in schizophrenia. Br J Pharmacol. 2016;173(4):666-680. doi: 10.1111/bph.13364
28. Kenk M, Selvanathan T, Rao N, Suridjan I, Rusjan P, Remington G, Meyer JH, Wilson AA, Houle S, Mizrahi R. Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA. Schizophr Bull. 2015;41(1):85-93. doi: 10.1093/schbul/sbu157
29. 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):206-214. doi: 10.1038/mp.2012.110
30. Gober R, Ardalan M, Shiadeh SMJ, Duque L, Garamszegi SP, Ascona M, Barreda A, Sun X, Mallard C, Vontell RT. Microglia activation in postmortem brains with schizophrenia demonstrates distinct morphological changes between brain regions. Brain Pathol. 2022;32(1):e13003. doi: 10.1111/bpa.13003
31. Uranova NA, Vikhreva OV, Rakhmanova VI. Abnormal microglial reactivity in gray matter of the prefrontal cortex in schizophrenia. Asian J Psychiatr. 2021;63:102752. doi: 10.1016/j.ajp.2021.102752
32. Vikhreva OV, Uranova NA. Microglial reactivity in the prefrontal cortex in different types of schizophrenia. S.S. Korsakov Journal of Neurology and Psychiatry/ Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2021;121(12):77-83. (In Russ.). doi: 10.17116/jnevro202112112177
33. Chan ST, McCarthy MJ, Vawter MP. Psychiatric drugs impact mitochondrial function in brain and other tissues. Schizophr. Res. 2020;217:136-147. doi: 10.1016/j.schres.2019.09.007
34. Roberts RC. Mitochondrial dysfunction in schizophrenia: with a focus on postmortem studies. Mitochondrion. 2021;56:91-101. doi: 10.1016/j.mito.2020.11.009
35. Bortolasci CC, Spolding B, Kidnapillai S, Richardson MF, Vasilijevic N, Martin SD, Gray LJ, McGee SL, Berk M, Walder K. Effects of psychoactive drugs on cellular bioenergetic pathways. World J Biol Psychiatry. 2021;22(2):79-93. doi: 10.1080/15622975.2020. 1755450
36. Kato TA, Monji A, Mizoguchi Y, Hashioka S, Horikawa H, Seki Y, Kasai M, Utsumi H, Kanba S. Anti-Inflammatory properties of antipsychotics via microglia modulations: are antipsychotics a ‘fire extinguisher' in the brain of schizophrenia? Mini Rev Med Chem. 2011;11(7):565-574. doi: 10.2174/138955711795906941
37. Kliushnik TP, Zozulia SA, Androsova LV, Sarmanova ZV, Otman IN, Dupin AM, Panteleeva GP, Oleichik IV, Abramova LI, Stoliarov SA, Shipilova ES, Borisova OA. Immunological monitoring of endogenous attack-like psychoses. Zhurnal nevrologii i psihiatrii imeni S.S. Korsakova. 2014;114(2):37-41. (In Russ.).
38. De Picker L, Fransen E, Coppens V, Timmers M, de Boer P, Oberacher H, Fuchs D, Verkerk R, Sabbe B, Morrens M. Immune and Neuroendocrine Trait and State Markers in Psychotic Illness: Decreased Kynurenines Marking Psychotic Exacerbations. Front Immunol. 2020;17;10:2971. doi: 10.3389/fimmu.2019.02971
39. Uranova NA, Bonartsev PD, Androsova LV, Rakhmanova VI, Kaleda VG. Impaired monocyte activation in schizophrenia: ultrastructural abnormalities and increased IL-ip production. Eur Arch Psychiatry Clin Neurosci. 2017;267(5):417-426. doi: 10.1007/s00406-017-0782-1
40. Janova H, Arinrad S, Balmuth E, Mitjans M, Hertel J, Habes M, Bittner RA, Pan H, Goebbels S, Begemann M, Gerwig UC, Langner S, Werner HB, Kittel-Schneider S, Homuth G, Davatzikos C, Volzke H, West BL, Reif A, Grabe HJ, Boretius S, Ehrenreich H, Nave KA. Microglia ablation alleviates myelin-associated catatonic signs in mice. J Clin Invest. 2018;128(2):734-745. doi: 10.1172/JCI97032
41. Comer AL, Carrier M, Tremblay M-E, Cruz-Martfn A. The inflamed brain in schizophrenia: the convergence of genetic and environmental risk factors that lead to uncontrolled neuroinflammation. Front Cell Neurosci. 2020;14:274. doi: 10.3389/fncel.2020.00274
42. Bergink V, Gibney SM, Drexhage HA. Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol. Psychiatry 2014;75:324-331. doi: 10.1016/j.biopsych.2013.09.037
43. Peferoen L, Kipp M, van der Valk P, van Noort JM, Amor S. Oligodendrocyte microglia cross-talk in the central nervous system. Immunology 2014;141(3):302-313. doi: 10.1111/imm.12163
44. Bitanihirwe BK, Woo TU. Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev. 2011;35(3):878-893. doi: 10.1016/j.neubiorev.2010.10.008
45. Hagemeyer N, Hanft KM, Akriditou MA, Unger N, Park ES, Stanley ER, Staszewski O, Dimou L, Prinz M. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol. 2017;134(3):441-458. doi: 10.1007/s00401-017-1747-1
46. Kolomeets NS, Vostrikov VM, Uranova NA. Abnormalities of oligodendrocyte clusters in supra- and infragranular layers of the prefrontal cortex in schizophrenia. S.S. Korsakov Journal of Neurology and Psychiatry/Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2019;119(12):62-68. (In Russ.). doi: 10.17116/jnevro201911912162
47. Taylor DL, Pirianov G, Holland S, McGinnity CJ, Norman AL, Reali C, Diemel LT, Gveric D, Yeung D, Mehmet H. Attenuation of proliferation in oligodendrocyte precursor cells by activated microglia. J Neurosci Res. 2010;88(8):1632-1644. doi: 10.1002/jnr.22335
48. Vostrikov V, Uranova N. Age-related increase in the number of oligodendrocytes is dysregulated in schizophrenia and mood disorders. Schizophr Res Treatment. 2011;2011:174689. doi: 10.1155/2011/174689
49. Kochunov P, Glahn DC, Rowland LM, Olvera RL, Winkler A, Yang YH, Sampath H, Carpenter WT, Duggirala R, Curran J, Blangero J, Hong LE. Testing the hypothesis of accelerated cerebral white matter aging in schizophrenia and major depression. Biol Psychiatry. 2013;73(5):482-491. doi: 10.1016/j.bio-psych.2012.10.002
50. Kirkpatrick B, Kennedy BK. Accelerated aging in schizophrenia and related disorders: future research. Schizophr Res. 2018;196:4-8. doi: 10.1016/j.schres.2017.06.034
Review
For citations:
Vikhreva O.V., Rakhmanova V.I., Uranova N.A. Microglia-Oligodendrocyte Interactions in White Matter of the Prefrontal Cortex in Attack-Like Schizophrenia. Psychiatry (Moscow) (Psikhiatriya). 2022;20(4):84-95. (In Russ.) https://doi.org/10.30629/2618-6667-2022-20-4-84-95