1Eur Arch Psychiatry Clin Neurosci 2011 Oct 261: 477-82
TitleProtective effects of haloperidol and clozapine on energy-deprived OLN-93 oligodendrocytes.
AbstractMagnetic resonance imaging and postmortem studies on schizophrenia provided evidence for compromised myelin integrity and reduced numbers of oligodendrocytes, which may worsen during the disease course. However, it is not clear whether these findings result from disease-inherent oligodendrocyte degeneration or side effects of antipsychotic treatment. Therefore, effects of haloperidol and clozapine on the viability and apoptosis of immature oligodendrocytes (OLN-93 cells, immunopositive for NG2, OLIG1, Olig2) have been evaluated in the present study by labeling with propidium iodide and a caspase 3 assay. Given the indications for impaired cerebral energy supply in schizophrenia, a serum and glucose deprivation (SGD) model was chosen in comparison with the basal condition (BC). SGD led to increased necrotic and apoptotic cell death. Haloperidol and clozapine were partially protective in this model and reduced the percentage of propidium iodide-positive cells, while caspase 3 activity was not altered. No significant drug effects were observed under BC. The observed protective effects of haloperidol and clozapine on energy-deprived OLN-93 oligodendrocytes suggest that previously reported reductions in oligodendrocyte density in schizophrenia are rather disease related than a side effect of medication. A new mechanism of antipsychotic action is suggested, which may help to establish new oligodendrocyte-directed therapies of schizophrenia.
SCZ Keywordsschizophrenia
2Life Sci. 2013 Oct 93: 429-34
TitleAntipsychotics promote the differentiation of oligodendrocyte progenitor cells by regulating oligodendrocyte lineage transcription factors 1 and 2.
AbstractOligodendrocyte/myelin abnormalities may be an important component of the pathogenesis found in schizophrenia. The aim of this current study was to examine the possible effects of the antipsychotic drugs (APDs) haloperidol (HAL), olanzapine (OLA), and quetiapine (QUE) on the development of oligodendroglial lineage cells.
CG4 cells, an oligodendrocyte progenitor cell line, were treated with various concentrations of HAL, OLA, or QUE for specific periods. The proliferation and differentiation of the CG4 cells were measured. The regulation of CG4 cell differentiation by oligodendrocyte lineage transcription factors 1 and 2 (OLIG1 and Olig2) was examined.
The APDs used in this study had no effect on the proliferation of CG4 cells. The APDs elevated the expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a specific marker of oligodendrocytes, and promoted the CG4 cells to differentiate into CNP positive oligodendrocytes. QUE and OLA increased the expression of both OLIG1 and Olig2 whereas HAL only increased the expression of Olig2.
Our findings suggest that oligodendrocyte development is a target of HAL, OLA, and QUE and provide further evidence of the important role of oligodendrocytes in the pathophysiology and treatment of schizophrenia. They also indicate that the expression level of oligodendrocyte/myelin-related genes could be profoundly affected by APDs, which should be considered in future studies aiming to measure the oligodendrocyte/myelin-related gene expressions in schizophrenia patients.
SCZ Keywordsschizophrenia
3J Psychiatr Res 2013 Aug 47: 1069-79
TitleIncreased nuclear Olig1-expression in the pregenual anterior cingulate white matter of patients with major depression: a regenerative attempt to compensate oligodendrocyte loss?
AbstractStructural 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.
SCZ Keywordsschizophrenia
4Front Cell Neurosci 2016 -1 10: 78
TitleOligodendrocyte and Interneuron Density in Hippocampal Subfields in Schizophrenia and Association of Oligodendrocyte Number with Cognitive Deficits.
AbstractIn schizophrenia, previous stereological post-mortem investigations of anterior, posterior, and total hippocampal subfields showed no alterations in total neuron number but did show decreased oligodendrocyte numbers in CA4, an area that corresponds to the polymorph layer of the dentate gyrus (DG). However, these investigations identified oligodendrocytes only on the basis of morphological criteria in Nissl staining and did not assess alterations of interneurons with immunohistochemical markers. Moreover, the association of findings in the posterior hippocampus with cognitive deficits remains unknown. On the basis of the available clinical records, we compared patients with definite and possible cognitive dysfunction; nine patients had evidence in their records of either definite (n = 4) or possible (n = 5) cognitive dysfunction. Additionally, we assessed the density of two oligodendrocyte subpopulations immunostained by the oligodendrocyte transcription factors OLIG1 and Olig2 and of interneurons immunolabeled by parvalbumin. We investigated posterior hippocampal subregions in the post-mortem brains of the same schizophrenia patients (SZ; n = 10) and healthy controls (n = 10) we examined in our previously published stereological studies. Our stereological studies found that patients with definite cognitive deficits had decreased total/Nissl-stained oligodendrocyte numbers in the left (p = 0.014) and right (p = 0.050) CA4, left CA2/3 (p = 0.050), left CA1 (p = 0.027), and left (p = 0.050) and right (p = 0.014) subiculum of the anterior part of the hippocampus compared to patients with possible cognitive deficits. In the present study, we found no significant influence of definite cognitive deficits in the posterior part of the hippocampus, whereas in the entire hippocampus SZ with definite cognitive deficits showed decreased oligodendrocyte numbers in the left (p = 0.050) and right (p = 0.050) DG and left CA2/3 (p = 0.050). We did not find significant differences in OLIG1-, Olig2-, or parvalbumin-positive cell density between SZ and controls in any of the subregions of the posterior hippocampus. Based on the results from our stereological study we hypothesize that a decreased number of oligodendrocytes in the anterior and entire hippocampus may be involved in cognitive deficits by impairing the connectivity of this structure in schizophrenia. In the posterior hippocampus, we could not replicate previously reported findings of decreased interneurons from the entire hippocampus.
SCZ Keywordsschizophrenia