Deficit Of Oligodendrocytes Research Articles

Oligodendrocyte differentiation alters tRNA modifications and codon optimality-mediated mRNA decay

Oligodendrocytes are specialized cells that confer neuronal myelination in the central nervous system. Leukodystrophies associated with oligodendrocyte deficits and hypomyelination are known to result when a number of tRNA metabolism genes are mutated. Thus, for unknown reasons, oligodendrocytes may be hypersensitive to perturbations in tRNA biology. In this study, we survey the tRNA transcriptome in the murine oligodendrocyte cell lineage and find that specific tRNAs are hypomodified in oligodendrocytes within or near the anticodon compared to oligodendrocyte progenitor cells (OPCs). This hypomodified state may be the result of differential expression of key modification enzymes during oligodendrocyte differentiation. Moreover, we observe a concomitant relationship between tRNA hypomodification and tRNA decoding potential; observing oligodendrocyte specific alterations in codon optimality-mediated mRNA decay and ribosome transit. Our results reveal that oligodendrocytes naturally maintain a delicate, hypersensitized tRNA/mRNA axis. We suggest this axis is a potential mediator of pathology in leukodystrophies and white matter disease when further insult to tRNA metabolism is introduced.

Reduced number of satellite oligodendrocytes of pyramidal neurons in layer 5 of the prefrontal cortex in schizophrenia.

Neuroimaging, genetic and molecular biological studies have shown impaired intra-cortical myelination in patients with schizophrenia, particularly in the prefrontal cortex. Previously we reported a significant deficit of oligodendrocytes and oligodendrocyte clusters in layers 3 and 5 of the prefrontal cortex, Brodmann area 10 (BA10) in schizophrenia. In this current study, we investigate the number of oligodendrocyte satellites (Sat-Ol) per pyramidal neuron in layer 5 of BA10 in schizophrenia (n = 17) as compared to healthy controls (n = 20) in the same section collection as previously used to study the numerical density (Nv) of oligodendrocytes and oligodendrocyte clusters. We find a significant reduction (-39%, p < 0.001) in the number of Sat-Ol per neuron in schizophrenia as compared to the control group. The number of Sat-Ol per neuron did not correlate with the Nv of oligodendrocytes or with the Nv of oligodendrocyte clusters. Our previous studies of the inferior parietal lobule (BA39 and BA40), demonstrated significant decrease of the number of Sat-Ol only in patient subgroups with poor and fair insight. Additionally, correlation pattern between number of Sat-Ol and Nv of oligodendrocytes and oligodendrocyte clusters was similar between the two functionally interconnected cortical areas, BA10 and BA40, whereas in BA39, strong significant correlations were revealed between the number of Sat-Ol and Nv of oligodendrocyte clusters (0.9 ≤ R ≥ 0.66; p < 0.001). These data suggest that that specific features of Sat-Ol alterations patterns may be associated with specific activity-driven plasticity of corresponding networks in the brain of people with schizophrenia.

Zebrafish spinal cord oligodendrocyte formation requires boc function.

The axis of the vertebrate neural tube is patterned, in part, by a ventral to dorsal gradient of Shh signaling. In the ventral spinal cord, Shh induces concentration-dependent expression of transcription factors, subdividing neural progenitors into distinct domains that subsequently produce distinct neuronal and glial subtypes. In particular, progenitors of the pMN domain express the bHLH transcription factor Olig2 and produce motor neurons followed by oligodendrocytes, the myelinating glial cell type of the central nervous system. In addition to its role in patterning ventral progenitors, Shh signaling must be maintained through development to specify pMN progenitors for oligodendrocyte fate. Using a forward genetic screen in zebrafish for mutations that disrupt the development of oligodendrocytes, we identified a new mutant allele of boc, which encodes a type I transmembrane protein that functions as a coreceptor for Shh. Embryos homozygous for the bocco25 allele, which creates a missense mutation in a Fibronectin type III domain that binds Shh, have normally patterned spinal cords but fail to maintain pMN progenitors, resulting in a deficit of oligodendrocytes. Using a sensitive fluorescent detection method for in situ RNA hybridization, we found that spinal cord cells express boc in a graded fashion that is inverse to the gradient of Shh signaling activity and that boc function is necessary to maintain pMN progenitors by shaping the Shh signaling gradient.

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

Imaging and postmortem studies have revealed disturbed oligodendroglia-related processes in patients with schizophrenia and provided much evidence for disturbed myelination, irregular gene expression, and altered numbers of oligodendrocytes in the brains of schizophrenia patients. Oligodendrocyte deficits in schizophrenia might be a result of failed maturation and disturbed regeneration and may underlie the cognitive deficits of the disease, which are strongly associated with impaired long-term outcome. Cognition depends on the coordinated activity of neurons and interneurons and intact connectivity. Oligodendrocyte precursors form a synaptic network with parvalbuminergic interneurons, and disturbed crosstalk between these cells may be a cellular basis of pathology in schizophrenia. However, very little is known about the exact axon-glial cellular and molecular processes that may be disturbed in schizophrenia. Until now, investigations were restricted to peripheral tissues, such as blood, correlative imaging studies, genetics, and molecular and histological analyses of postmortem brain samples. The advent of human-induced pluripotent stem cells (hiPSCs) will enable functional analysis in patient-derived living cells and holds great potential for understanding the molecular mechanisms of disturbed oligodendroglial function in schizophrenia. Targeting such mechanisms may contribute to new treatment strategies for previously treatment-resistant cognitive symptoms.

Deficit of oligodendrocytes in the frontal cortex in schizophrenia

Oligodendrocyte abnormalities are thought to be one of the key cellular pathologies involved in disturbances of neuronal connectivity in schizophrenia. The density of oligodendrocytes in layer III of the prefrontal cortex, BA10, in schizophrenia (n=20) was compared to controls (n=20) using optical dissector method. MANCOVA was applied for group comparisons. The density of oligodendrocytes was significantly lower in each sublayers of layer III (≤20% p≤0.05) in the schizophrenia group as compared to the control group. The deficit of oligodendrocytes in the prefrontal cortex in schizophrenia may be of developmental origin or the result of alterations in the neural tissue of the brain during disease course.

Ultrastructural pathology of oligodendrocytes in the white matter in continuous paranoid schizophrenia: a role for microglia

Previously the authors have reported the ultrastructural pathology and deficit of oligodendrocytes in gray and white matter of the prefrontal cortex in schizophrenia. The aim of the study was to determine of the effects of microglia on the ultrastructure of oligodendrocytes in the white matter underlying the prefrontal cortex in continuous schizophrenia. Postmortem morphometric electron microscopic study of oligodendrocytes in close apposition to microglia was performed in white matter underlying the prefrontal cortex (BA10). Eleven cases of chronic continuous schizophrenia and 11 normal controls were studied. Areas of oligodendrocytes, of their nuclei and cytoplasm, volume density (Vv) and the number of mitochondria, vacuoles of endoplasmic reticulum and lipofuscin granules were estimated. Group comparison was performed using ANCOVA. The schizophrenia group differed from the control group by paucity of ribosomes in the cytoplasm of oligodendrocytes, a significant decrease in Vv and the number of mitochondria and increase in the number of lipofuscin granules. Significant correlations between the parameters of lipofuscin granules, mitochondria and vacuoles were found only in the schizophrenia group. The number of lipofuscin granules were correlated positively with the illness duration. Dystrophic alterations of oligodendrocytes attached to microglial cells were found in the white matter of the prefrontal cortex in chronic paranoid schizophrenia as compared to controls. The data obtained suggest that microglia might contribute to abnormalities of energy, lipid and protein metabolism of oligodendrocytes in schizophrenia.

ST8SIA2 promotes oligodendrocyte differentiation and the integrity of myelin and axons.

ST8SIA2 is a polysialyltransferase that attaches polysialic acid to the glycoproteins NCAM1 and CADM1. Polysialylation is involved in brain development and plasticity. ST8SIA2 is a schizophrenia candidate gene, and St8sia2 −/− mice exhibit schizophrenia‐like behavior. We sought to identify new pathological consequences of ST8SIA2 deficiency. Our proteomic analysis suggested myelin impairment in St8sia2 −/− mice. Histological and immune staining together with Western blot revealed that the onset of myelination was not delayed in St8sia2 −/− mice, but the content of myelin was lower. Ultrastructure analysis of the corpus callosum showed thinner myelin sheaths, smaller and irregularly shaped axons, and white matter lesions in adult St8sia2 −/− mice. Then we evaluated oligodendrocyte differentiation in vivo and in vitro. Fewer OLIG2+ cells in the cortex and corpus callosum, together with the higher percentage of undifferentiated oligodenroglia in St8sia2 −/− mice suggested an impairment in oligodendrocyte generation. Experiment on primary cultures of oligodendrocyte precursor cells (OPCs) confirmed a cell‐autonomous effect of ST8SIA2 in oligodendroglia, and demonstrated that OPC to oligodendrocyte transition is inhibited in St8sia2 −/− mice. Concluding, ST8SIA2‐mediated polysialylation influences on oligodendrocyte differentiation, and oligodendrocyte deficits in St8sia2 mice are a possible cause of the demyelination and degeneration of axons, resembling nerve fiber alterations in schizophrenia. GLIA 2016;65:34–49

CNS myelination requires cytoplasmic dynein function.

Cytoplasmic dynein provides the main motor force for minus-end-directed transport of cargo on microtubules. Within the vertebrate central nervous system (CNS), proliferation, neuronal migration, and retrograde axon transport are among the cellular functions known to require dynein. Accordingly, mutations of DYNC1H1, which encodes the heavy chain subunit of cytoplasmic dynein, have been linked to developmental brain malformations and axonal pathologies. Oligodendrocytes, the myelinating glial cell type of the CNS, migrate from their origins to their target axons and subsequently extend multiple long processes that ensheath axons with specialized insulating membrane. These processes are filled with microtubules, which facilitate molecular transport of myelin components. However, whether oligodendrocytes require cytoplasmic dynein to ensheath axons with myelin is not known. We identified a mutation of zebrafish dync1h1 in a forward genetic screen that caused a deficit of oligodendrocytes. Using in vivo imaging and gene expression analyses, we additionally found evidence that dync1h1 promotes axon ensheathment and myelin gene expression. In addition to its well known roles in axon transport and neuronal migration, cytoplasmic dynein contributes to neural development by promoting myelination.

Desvenlafaxine prevents white matter injury and improves the decreased phosphorylation of the rate-limiting enzyme of cholesterol synthesis in a chronic mouse model of depression.

Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2-3weeks for the mood-enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10mg/kg/day 1week before they went through a 7-week stress procedure and lasted for over 8weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte-related proteins were significantly reduced in UCMS mice. DVS prevented the stress-induced injury to white matter and the decrease of phosphorylated 5'-AMP-activated protein kinase and 3-hydroxy-3-methyl-glutaryl-CoA reductase protein expression. DVS increased open arm entries in an elevated plus-maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression-like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression-like phenotypes in these mice. We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.

Abnormalities in oligodendrocyte clusters in the inferior parietal cortex in schizophrenia are associated with insight

Background and Objectives: Deficits in oligodendrocytes have been consistently reported in the brains of patients with schizophrenia and include alterations in the clustering pattern of oligodendrocytes. Recently it has been shown that oligodendrocyte progenitors proliferate in the adult mammalian brain to form oligodendrocyte clusters (OlC). We previously found a deficit of oligodendrocytes in layer 3 of the inferior parietal lobule (IPL) in subjects with schizophrenia with poor insight into disorder. We hypothesized that the number of OlC might be reduced in schizophrenia subjects with poor insight. Methods: Nissl-stained sections from the Stanley �Parietal Collection� from male schizophrenia subjects (n = 24) that have poor, fair, or good insight into their disorder and normal matched controls (n = 24) were studied. The numerical density (Nv) of OlC was estimated in layer 3 of BA 39 and BA 40 by optical disector method. Results: The Nv of OlC was 23% lower in BA 39 and 30% lower in BA40 in the schizophrenia group compared to the control group (p<0.01). Normal hemispheric differences in the Nv of OlC in BA 39 were absent in the schizophrenia group. The Nv of OlC was significantly decreased in BA39 in the subgroup with poor insight and in BA40 in the subgroups with fair and good insight as compared to controls. In BA40 lower Nv of OlC (-40%, p<0.01) was found in the subgroup with adolescent onset of disease as compared to controls. Conclusions: The deficit of OlC may be associated with altered proliferation and/or maturation of oligodendrocyte progenitors in schizophrenia.

Increased nuclear Olig1-expression in the pregenual anterior cingulate white matter of patients with major depression: A regenerative attempt to compensate oligodendrocyte loss?

BackgroundStructural and functional oligodendrocyte deficits as well as impaired myelin integrity have been described in affective disorders and schizophrenia, and may disturb the connectivity between disease-relevant brain regions. Olig1, an oligodendroglial transcription factor, might be important in this context, but has not been systematically studied so far. MethodsNissl- and Olig1-stained oligodendrocytes were quantified in the pregenual anterior cingulate (pACC)/dorsolateral prefrontal cortex (DLPFC), and adjacent white matter of patients with major depressive disorder (MDD, n = 9), bipolar disorder (BD, n = 8), schizophrenia (SZ, n = 13), and matched controls (n = 16). Potential downstream effects of increased Olig1-expression were analyzed. Antidepressant drug effects on Olig1-expression were further explored in OLN-93 oligodendrocyte cultures. ResultsNissl-stainings of both white matter regions showed a 19–27% reduction of total oligodendrocyte densities in MDD and BD, but not in SZ. In contrast, nuclear Olig1-immunoreactivity was elevated in MDD in the pACC-adjacent white matter (left: p = 0.008; right: p = 0.018); this effect tended to increase with antidepressant dosage (r = 0.631, p = 0.069). This reactive increase of Olig1 was confirmed by partly dose-dependent effects of imipramine and amitriptyline in oligodendrocyte cultures. Correspondingly, MBP expression in the pACC-adjacent white matter tended to increase with antidepressant dosage (r = 0.637, p = 0.065). Other tested brain regions showed no diagnosis-dependent differences regarding Olig1-immunoreactivity. ConclusionsSince nuclear Olig1-expression marks oligodendrocyte precursor cells, its increased expression along with reduced total oligodendrocyte densities (Nissl-stained) in the pACC-adjacent white matter of MDD patients might indicate a (putatively medication-boosted) regenerative attempt to compensate oligodendrocyte loss.

Gene expression abnormalities and oligodendrocyte deficits in the internal capsule in schizophrenia

Deficits in the expression of oligodendrocyte (Ol) and myelin genes have been described in numerous brain regions in schizophrenia (SZ) in association with abnormalities of cell cycle markers. We have previously reported a SZ-associated decrease in the expression of genes expressed after, but not prior to, the terminal differentiation of Ols in the posterior limb of the internal capsule (ICp). This pattern of deficits could reflect a failure of Ol precursors to exit the cell cycle and differentiate to meet the demands imposed by the high rate of apoptosis among myelinating Ols. Here we explore this hypothesis using quantitative real time PCR to examine the mRNA expression of additional genes in the ICp of the previously examined sample of 14 subjects with SZ and 15 normal controls (NCs). The genes examined in the present study were chosen because they are associated with particular phases of the cell cycle (CCND1, CCND2, p21Cip1, p27Kip1, and p57Kip2), with DNA replication and repair (PCNA), apoptosis (CASP3), or the Notch signaling pathway (JAG1, HES1, HES5, andDTX1). The Notch pathway influences whether Ol precursors continue to proliferate or exit the cell cycle. We also determined the densities of Ols in the ICp. Genes associated with maintenance of the cell cycle tended to exhibit increased expression levels in SZ relative to NCs and to be negatively correlated with the expression levels of the previously assessed mature Ol genes. In contrast, genes associated with cell cycle arrest tended to show the opposite pattern (decreased expression in SZ and positive correlations with mature Ol genes). CASP3 and PCNA expression levels were significantly decreased in SZ and positively correlated with mature Ol genes, suggesting that myelinating Ols may turnover more rapidly in normal controls than in subjects with SZ. JAG1 expression was significantly increased in SZ and exhibited positive correlations with mediators of the canonical Notch pathway but negative correlations with mature Ol genes. Ol densities were significantly decreased in SZ. These data are consistent with the hypothesis that Ol and myelin deficits in SZ involve a failure of Ol precursors to appropriately exit the cell cycle in order to differentiate and mature into myelinating Ols.

Deficit of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenia

Objective: Our previous studies have shown a significant decrease of numerical density of oligodendrocytes in the prefrontal cortex in postmortem schizophrenic brains. Deficit of oligodendrocytes was associated with loss of oligodendroglial satellites of pyramidal neurons. In this study we tested the hypothesis that there might be a deficit and loss of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenia. Method: Autopsy samples from the prefrontal cortex (BA 10) were obtained from 12 normal controls and 12 chronic schizophrenic cases. Capillaries and oligodendrocytes were viewed in paraffin sections stained with a Luxol-fast blue and cresyl violet. Electron microscopy was applied to study the ultrastructure of oligodendrocytes. For morphometric analysis, an average of 100 rectilinear capillary segments from layer V was sampled for each individual. The number of oligodendrocytes visible along rectilinear segments was expressed as the number of oligodendrocytes per 0.01 mm of capillary length. Results: Subjects with schizophrenia had a significantly lower (−23%; P<0.005) number of pericapillary oligodendrocytes compared to controls. Prominent ultrastructural dystrophic and degenerative alterations of pericapillary oligodendrocytes have been revealed in schizophrenic brains. Conclusion: The present study provides evidence that there is a prominent reduction, damage and loss of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenia. These changes may contribute to the pathophysiological basis for altered blood–brain barrier and lowered metabolic rates in subjects with schizophrenia.

Deficit of perineuronal oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders

ObjectiveA deficit of oligodendrocytes has been reported in the prefrontal cortex (PFC) in schizophrenia (SCH), bipolar disorder (BPD) and major depression (MDD). Also, a decreased size of pyramidal neurons has been detected in layer III in SCH and in mood disorders. Since oligodendrocytes have a trophic influence on neurons, reduced neuronal size reported in these disorders might be associated with the deficit in subpopulation of perineuronal oligodendrocytes. We hypothesized that deficit of perineuronal oligodendrocytes might occur in SCH and mood disorders. MethodWe estimated the number of oligodendroglial satellites of pyramidal neurons and the size of pyramidal neurons in layer III (Brodmann's area 9) in Nissl stained sections in SCH, BPD, MDD and normal controls. The Stanley Foundation Neuropathology Consortium brain collection consisted of 15 cases in each of four groups was used. ResultsWe detected a prominent and significant reduction in the number of perineuronal oligodendrocytes in the sublayers IIIa, IIIb and IIIc in SCH, BPD and MDD as compared to controls. The BPD group differed significantly from SCH group and from MDD group. There were no significant differences in somal sizes of pyramidal neurons in the sublayers IIIa, IIIb, IIIc between each of the psychiatric groups and the control group. Only BPD group showed significantly smaller neuronal size in sublayer IIIc as compared to controls. ConclusionsOur data provide evidence for a deficit of perineuronal oligodendrocytes in severe mental disorders that may play a key role in the pathophysiology of SCH, BPD and MDD.

The role of oligodendrocyte pathology in schizophrenia

Neuroimaging and microarray studies provide evidence for myelin and oligodendrocyte abnormalities in schizophrenia (SZ). Electron microscopy demonstrated dystrophy, necrosis and apoptosis of oligodendrocytes, the most severely affected cells in SZ. The proportion of myelinated fibres with atrophy of axon and swelling of periaxonal oligodendrocyte processes increased significantly in the prefrontal cortex (PFC), caudate nucleus and hippocampus in SZ compared to controls. Morphometry showed a deficit of oligodendrocytes in the PFC and in adjacent white matter, lower number of oligodendroglial satellites of pyramidal neurons and a loss of pericapillar oligodendrocytes in the PFC in SZ compared to normal controls. A lowered number of oligodendrocytes in the PFC was also found in mood disorders. These data provide evidence for altered oligodendrocyte-axon, oligodendrocyte-neuron and oligodendrocyte-capillar interactions in SZ brains suggesting a key role of damage and loss of oligodendrocytes in altered neuronal connectivity and in atrophy of neurons in SZ.

Tennet XIII Abstracts

Structural and functional oligodendrocyte deficits as well as impaired myelin integrity have been described in affective disorders and schizophrenia, and may disturb the connectivity between disease-relevant brain regions. Olig1, an oligodendroglial transcription factor, might be important in this context, but has not been systematically studied so far.Nissl- and Olig1-stained oligodendrocytes were quantified in the pregenual anterior cingulate (pACC)/dorsolateral prefrontal cortex (DLPFC), and adjacent white matter of patients with major depressive disorder (MDD, n = 9), bipolar disorder (BD, n = 8), schizophrenia (SZ, n = 13), and matched controls (n = 16). Potential downstream effects of increased Olig1-expression were analyzed. Antidepressant drug effects on Olig1-expression were further explored in OLN-93 oligodendrocyte cultures.Nissl-stainings of both white matter regions showed a 19–27% reduction of total oligodendrocyte densities in MDD and BD, but not in SZ. In contrast, nuclear Olig1-immunoreactivity was elevated in MDD in the pACC-adjacent white matter (left: p = 0.008; right: p = 0.018); this effect tended to increase with antidepressant dosage (r = 0.631, p = 0.069). This reactive increase of Olig1 was confirmed by partly dose-dependent effects of imipramine and amitriptyline in oligodendrocyte cultures. Correspondingly, MBP expression in the pACC-adjacent white matter tended to increase with antidepressant dosage (r = 0.637, p = 0.065). Other tested brain regions showed no diagnosis-dependent differences regarding Olig1-immunoreactivity.Since nuclear Olig1-expression marks oligodendrocyte precursor cells, its increased expression along with reduced total oligodendrocyte densities (Nissl-stained) in the pACC-adjacent white matter of MDD patients might indicate a (putatively medication-boosted) regenerative attempt to compensate oligodendrocyte loss.