Ultrastructural alterations of oligodendrocytes in prefrontal white matter in schizophrenia: A post-mortem morphometric study

Abstract

Objective

Neuroimaging studies showed abnormalities in frontal white matter (WM) in schizophrenia that were associated with clinical symptoms. Previously, we reported ultrastructural alterations of myelinated fibers and reduction in the numerical density of oligodendrocytes in BA 10 WM in patients with schizophrenia. We aimed to perform a qualitative and morphometric study of the ultrastructure of oligodendrocytes in BA 10 WM in schizophrenia and in normal controls.

Methods

The study was performed using electron microscopy and morphometry. Size, volume density (Vv) and the number (N) of organelles of oligodendrocytes were estimated in 21 patients with schizophrenia and 20 normal controls. The data were examined using the Kolmogorov–Smirnov test for normality. Pearson correlation analysis was performed to assess possible correlations between the parameters measured and age, post-mortem interval, neuroleptic treatment and duration of the disease. Comparisons between the schizophrenia patients and controls were performed using ANCOVA tests.

Results

We found oligodendrocyte swelling, vacuolation, paucity of ribosomes and mitochondria and accumulation of lipofuscin granules in schizophrenia as compared to controls. Morphometry detected a significant reduction in Vv and N of mitochondria and the increase in Vv and N of lipofuscin granules and vacuoles in oligodendrocytes in the schizophrenic group as compared to controls.

Conclusion

Alterations of oligodendrocytes in schizophrenia provide evidence for the disturbance of their energy, lipid and protein metabolism in prefrontal WM. Oligodendrocyte abnormalities might disturb axonal integrity and circuitry and contribute to the pathophysiology of schizophrenia.

Introduction

Multiple lines of evidence from brain imaging, post-mortem and genetic studies have implicated oligodendrocyte and myelin dysfunction and impaired myelination in schizophrenia (Davis et al., 2003, Takahashi et al., 2011, Voineskos et al., 2013). Neuroimaging studies have provided evidence for the widespread disruption of WM integrity in patients with schizophrenia associated with neurocognitive dysfunction and negative and positive symptoms (Dwork et al., 2007, Skelly et al., 2008; Roalf et al., 2015). Combined genetics and neuroimaging data have shown that variants from the MAG, OLIG2 and CNP genes influence WM tract integrity and cognitive performance in patients with schizophrenia (Voineskos et al., 2013). To identify a structural basis for the WM imaging changes, oligodendrocytes and myelin have a become focus of interest.

Postmortem studies have demonstrated reductions in the expression of myelin- and oligodendrocyte-related genes (see Takahashi et al., 2011 for review) and reductions in the number of oligodendrocytes in schizophrenia. Morphometric studies of Nissl-stained sections revealed a deficit of oligodendrocytes in WM in different brain regions in schizophrenia. Hof et al. (2002) detected lower oligodendrocyte density in the superior frontal gyrus in schizophrenia cases compared to controls in both the grey matter (− 22%) and the WM (− 20%) that underlies the DLPFC (BA9). Later, Hof et al. (2003) found a 28% decrease in total numbers (or densities) of cortical layer III oligodendrocytes and a 27% decrease in the WM in schizophrenia compared with controls based on CNP-ase immunostaining. The spatial distribution of oligodendrocytes in WM of the DLPFC exhibited a less clustered arrangement in schizophrenia cases. Vostrikov et al. (2004) have reported a 12% reduction in the numerical density of oligodendrocytes in the WM underlying the prefrontal cortex (BA10), and Farkas et al. (2010) have found a deficit of ADAM12 immunoreactivity in oligodendrocytes in the WM of the anterior cingulate cortex of schizophrenia patients. However, others have shown no significant changes in oligodendrocyte density and distribution in the cingulum bundle (Segal et al., 2009) or in the WM underlying BA9 of the DLPFC (Uranova et al., 2004) in schizophrenia samples as compared to normal controls. In the WM underlying BA9 of the DLPFC, Hercher et al. (2014) have reported no differences in Nissl-stained sections in oligodendrocyte nuclear area and diameter and oligodendrocyte density between the schizophrenia and the control groups. In contrast to these studies, Bernstein et al. (2012) have reported a significant increase in the numerical density of prohibitin-expressing oligodendrocytes in the right dorsolateral WM area and DISC1-immunoreactive oligodendrocytes in fronto-parietal WM of patients with paranoid schizophrenia (Bernstein et al., 2015). Mauney et al. (2015) have recently reported decreased density of OLIG2-immunoreactive cells in subjects with schizophrenia, which is consistent with the notion that oiligodendrocyte progenitor cell differentiation impairment may contribute to oligodendrocyte disturbances. Martins-de-Souza et al. (2009) performed proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and reported the involvement of the cytoskeleton, oligodendrocytes and energy metabolism in schizophrenia.

Ultrastructural dystrophic and degenerative changes of oligodendrocytes and myelinated fibers have been reported in grey matter in the prefrontal cortex, caudate nucleus and hippocampus in schizophrenia as compared to normal controls (Uranova et al., 2001, Uranova et al., 2007, Uranova et al., 2011; Kolomeets and Uranova, 2008). Due to these observed changes, we aimed to study the ultrastructure of oligodendrocytes in the prefrontal BA 10 WM in schizophrenia and normal controls.