Oligodendrocytes as A New Therapeutic Target in Schizophrenia: From Histopathological Findings to Neuron-Oligodendrocyte Interaction

Raabe, Florian; Slapakova, Lenka; Rossner, Moritz J.; Cantuti-Castelvetri, Ludovico; Simons, Mikael; Falkai, Peter; Schmitt, Aurore

doi:10.3390/cells8121496

Cited by 58 publications

(43 citation statements)

References 112 publications

(155 reference statements)

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“…In the present study we found dystrophic changes but no degeneration of oligodendrocytes in layer 5 of the PFC in schizophrenia. Thus, a prominent deficit of oligodendrocytes in layer 5 of the PFC cannot be explained by current oligodendrocyte degeneration, it may be the result of disrupted maturation and proliferation of oligodendrocyte progenitors in schizophrenia (75)(76)(77)(78).…”

Section: Discussionmentioning

confidence: 99%

Dystrophy of Oligodendrocytes and Adjacent Microglia in Prefrontal Gray Matter in Schizophrenia

et al. 2020

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Background: Some evidence support the notion that microglia activation in acute state of schizophrenia might contribute to damage of oligodendrocytes and myelinated fibers. Previously we found dystrophic changes of oligodendrocytes in prefrontal white matter in schizophrenia subjects displaying predominantly positive symptoms as compared to controls. The aim of the study was to verify whether microglial activation might contribute to dystrophic changes of oligodendrocytes in prefrontal gray matter in this clinical subgroup. Methods: Transmission electron microscopy and morphometry of microglia and adjacent oligodendrocytes were performed in layer 5 of the prefrontal cortex (BA10) in the schizophrenia subjects displaying predominantly positive symptoms (SPPS, n = 12), predominantly negative symptoms (SPNS, n = 9) and healthy controls (n = 20). Results: Qualitative study showed microglial activation and dystrophic alterations of microglia and oligodendrocytes adjacent to each other in both subgroups as compared to controls. A significant reduction in volume density (Vv) and the number (N) of mitochondria and an increase in N of lipofuscin granules were found in oligodendrocytes and adjacent microglia in both subgroups. Vv of lipofuscin granules, Vv and N of vacuoles of endoplasmic reticulum in microglia were increased significantly in the SPPS subgroup as compared to controls. In the SPPS subgroup Vv and N of mitochondria in microglia were correlated with N of vacuoles in microglia (r =-0.61, p < 0.05) and with Vv (r = 0.79, p < 0.01) and N (r = 0.59, p < 0.05) of mitochondria in oligodendrocytes. Vv of mitochondria in microglia was also correlated with Vv and N of vacuoles in oligodendrocytes in the SPPS subgroup (r = 0.76, p < 0.01). Area of nucleus of microglial cells was correlated negatively with age (r =-0.76, p < 0.01) and age at illness onset (r =-0.65, p < 0.05) in the SPPS subgroup. In the SPNS subgroup N of mitochondria in microglia was correlated with Vv of lipofuscin granules in oligodendrocytes (r =-0.9, p < 0.01). There were no significant correlations between these parameters in the control group. Discussion: Microglial dystrophy might contribute to oligodendrocyte dystrophy in the schizophrenia subjects with predominantly positive symptoms during relapse. Mitochondria in microglia and oligodendrocytes may be a target for treatment strategy of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Dystrophy of Oligodendrocytes and Adjacent Microglia in Prefrontal Gray Matter in Schizophrenia

et al. 2020

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“…A widely accepted hypothesis for the origin of schizophrenia is that variations in several risk genes interact with environmental stimuli, affecting brain development and function, leading to abnormal information processing by the brain 1,2,14 . Studies have associated the development and establishment of schizophrenia with dysfunctions in neurotransmitter systems and oligodendrocytes 15,16 . Oligodendrocytes are cells that wrap around axons in specialized layers of cell membrane to form the myelin sheath.…”

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confidence: 99%

“…Neuropathological and neuroimaging studies have also found abnormalities and degeneration related to OLs, especially in the frontal and temporal lobes and in the corpus callosum of schizophrenia patients 21 . Moreover, studies have suggested that oligodendrocytes may be a target of antipsychotics 16,21,22 . Thus, studying the effects of these drugs on oligodendrocytes may contribute to the improvement of current treatments and to the development of new therapeutic approaches.…”

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confidence: 99%

Ubiquitin–proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia

Seabra

Almeida

Reis‐de‐Oliveira

et al. 2020

Sci Rep

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Schizophrenia is a chronic, severe and disabling psychiatric disorder, whose treatment is based on psychosocial interventions and the use of antipsychotic drugs. While the effects of these drugs are well elucidated in neuronal cells, they are still not so clear in oligodendrocytes, which play a vital role in schizophrenia. Thus, we aimed to characterize biochemical profiles by proteomic analyses of human oligodendrocytes (MO3.13) which were matured using a protocol we developed and treated with either haloperidol (a typical antipsychotic), clozapine (an atypical antipsychotic) or a clozapine + d-serine co-treatment, which has emerged lately as an alternative type of treatment. this was accomplished by employing shotgun proteomics, using nanoeSi-Lc-MS/MS labelfree quantitation. Proteomic analysis revealed biochemical pathways commonly affected by all tested antipsychotics were mainly associated to ubiquitination, proteasome degradation, lipid metabolism and DNA damage repair. Clozapine and haloperidol treatments also affected proteins involved with the actin cytoskeleton and with EIF2 signaling. In turn, metabolic processes, especially the metabolism of nitrogenous compounds, were a predominant target of modulation of clozapine + d-serine treatment. in this context, we seek to contribute to the understanding of the biochemical and molecular mechanisms involved in the action of antipsychotics on oligodendrocytes, along with their possible implications in schizophrenia. Abbreviations ACC Anterior cingulate cortex ACN Acetonitrile ACTB Beta-actin CNPase 2′,3′-Cyclic-nucleotide-3-phosphodiesterase COPS8 COP9 signalosome complex subunit 8 DIA Data-independent acquisition DLPFC Dorsolateral prefrontal cortex DMEM Dulbecco's modified eagle medium DTT Dithiothreitol eIF2 Eukaryotic initiation factor-2

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“…Moreover, an oligodendrocyte deficit can cause impaired myelination with a subsequent lack of nerve impulse transmission and cognitive impairment related to SCZ. It has also been hypothesized that inflammation in the brain along with microglia overactivity is involved in oligodendrocyte dysfunction (Raabe et al 2018(Raabe et al , 2019.…”

Section: Recent Issuesmentioning

confidence: 99%

“…(1) cells from tissues other than the brain may sometimes be contaminated, (2) due to different embryonal origins, microglia cannot be included in almost all of the iPSC cellderived brain models and (3) conditions arising from longlasting processes such as aging and maturation are difficult to reproduce when using brain organoids (Quadrato et al 2016;Raabe et al 2018Raabe et al , 2019.…”

Section: Recent Issuesmentioning

confidence: 99%

Genetic and environmental factors of schizophrenia and autism spectrum disorder: insights from twin studies

et al. 2020

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Twin studies of psychiatric disorders such as schizophrenia and autism spectrum disorder have employed epidemiological approaches that determine heritability by comparing the concordance rate between monozygotic twins (MZs) and dizygotic twins. The basis for these studies is that MZs share 100% of their genetic information. Recently, biological studies based on molecular methods are now being increasingly applied to examine the differences between MZs discordance for psychiatric disorders to unravel their possible causes. Although recent advances in next-generation sequencing have increased the accuracy of this line of research, there has been greater emphasis placed on epigenetic changes versus DNA sequence changes as the probable cause of discordant psychiatric disorders in MZs. Since the epigenetic status differs in each tissue type, in addition to the DNA from the peripheral blood, studies using DNA from nerve cells induced from postmortem brains or induced pluripotent stem cells are being carried out. Although it was originally thought that epigenetic changes occurred as a result of environmental factors, and thus were not transmittable, it is now known that such changes might possibly be transmitted between generations. Therefore, the potential possible effects of intestinal flora inside the body are currently being investigated as a cause of discordance in MZs. As a result, twin studies of psychiatric disorders are greatly contributing to the elucidation of genetic and environmental factors in the etiology of psychiatric conditions.

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Oligodendrocytes as A New Therapeutic Target in Schizophrenia: From Histopathological Findings to Neuron-Oligodendrocyte Interaction

Cited by 58 publications

References 112 publications

Dystrophy of Oligodendrocytes and Adjacent Microglia in Prefrontal Gray Matter in Schizophrenia

Dystrophy of Oligodendrocytes and Adjacent Microglia in Prefrontal Gray Matter in Schizophrenia

Ubiquitin–proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia

Genetic and environmental factors of schizophrenia and autism spectrum disorder: insights from twin studies

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