Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium

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Abstract

Our previous electron microscopic study of the prefrontal cortex (PFC) demonstrated ultrastructural signs of apoptosis and necrosis of oligodendroglial cells in schizophrenia (SCH) and bipolar disorder (BPD). Using optical dissector methodology, we have now conducted a morphometric study of numerical density (Nv) of oligodendroglial cells in layer VI and in adjacent white matter of Brodmann area 9 (BA 9) of the Stanley Foundation Neuropathology Consortium (SFNC). The SFNC consists of 15 cases in each of four groups: schizophrenia, bipolar disorder, major depression (MDD) and unaffected controls. A significant reduction in Nv of oligodendroglial cells was found in layer VI of subjects with schizophrenia (−25%), bipolar disorder (−29%) and major depression (−19%) as compared to controls. In adjacent white matter, there were no significant differences between groups. The data suggest that lowered density of oligodendroglial cells that occurs in schizophrenia and mood disorders could contribute to the atrophy of neurones that has been described in the prefrontal cortex of subjects with severe mental illness.

Introduction

Many neuroimaging studies have implicated the prefrontal cortex (PFC) as a site of functional and structural abnormalities in schizophrenia (SCH) and mood disorders DeLisi et al., 1997, McCarley et al., 1999, Soares and Mann, 1997. Recent neuroimaging studies provide evidence for common pathology in SCH and major depression (MDD), particularly in the PFC, e.g., a reduction in grey matter volume, changes in glucose metabolism and blood flow have all been reported in the PFC in SCH and mood disorders Bearden et al., 2001, Buchanan et al., 1998, Buchsbaum and Hazlett, 1998, Drevets et al., 1997.

Neuropathological studies have demonstrated a decrease in neuronal size in the PFC in SCH (Rajkowska et al., 1998), in MDD and bipolar disorder (BPD) Rajkowska et al., 1999, Rajkowska, 2000 and an increase in neuronal density has been reported in the PFC in SCH (Selemon et al., 1995). However, there was no change in neuronal density in PFC in MDD (Rajkowska et al., 1999). Prominent reductions in total glial cell density have also been demonstrated in the PFC in SCH Cotter et al., 2002, Rajkowska-Markov et al., 1999, BPD (Cotter et al., 2002) and MDD Cotter et al., 2002, Rajkowska et al., 1999. While it remains uncertain as to what types of glial cells are reduced in the brain in severe mental illness, a previous electron microscopic study demonstrated severe dystrophic and destructive ultrastructural changes of oligodendroglial cells in the PFC (Uranova et al., 2001). Alteration of myelinated fibers has also observed in layer VI of PFC in SCH and BPD as compared to controls (Uranova et al., 2001). In addition, several myelin-related genes appear to be dysregulated in the PFC of subjects with SCH (Hakak et al., 2001). The data suggest that a lowered density of oligodendrogliocytes might occur in the PFC in severe mental illness.

Oligodendroglia are known to serve as neuronal satellites in grey matter and form myelin sheaths in white matter. We performed a morphometric study of the numerical density of oligodendroglial cells in layer VI of BA9 and in adjacent white matter in SCH, BPD and MDD compared to unaffected control cases to determine if there is a reduction in oligodendroglial density in Brodmann area 9 (BA 9) in severe mental disorders.

Section snippets

Specimens

Human brain specimens in the form of 10-μm-thick paraffin sections from BA 9 were obtained from the Stanley Foundation Neuropathology Consortium (SFNC). The SFNC consists of 60 subjects: 15 SCH, 15 BPD, 15 MDD and 15 unaffected controls. Clinical records were obtained and DSM-IV diagnoses were made by psychiatrists from the SFNC. Routine neuropathological examinations were also conducted on each case by neuropathologists from the SFNC. Demographic data are given in Table 1. For more detailed

Layer VI

One-way ANOVA with four-subject groups demonstrated a significant effect of disease on Nv of oligodendroglial cells [F(3,56)=4.01, p=0.012]. Post hoc test showed a significant decrease in the mean values of the parameter in SCH (−25%, p=0.04), BPD (−29%, p=0.03) and MDD (−19%, p=0.04) as compared to controls. There were no significant differences between SCH, BPD and MDD (Fig. 1A).

ANCOVA was performed for four diagnostic groups with Nv of oligodendrogliocytes as the dependent variable,

Discussion

There is increasing evidence of reduced glial density in the neocortex of subjects with SCH Benes et al., 1986, Cotter et al., 2002, Rajkowska-Markov et al., 1999 and in mood disorders Ongur et al., 1998, Rajkowska et al., 1999, Rajkowska, 2000. The present study provides new evidence that there is a prominent reduction of numerical density of oligodendroglial cells in layer VI of the PFC in SCH (25%), BPD (29%) and MDD (19%) as compared to controls. There were no effects of confounding

Acknowledgments

The authors express their gratitude to the Stanley Medical Research Institute for support this work. Postmortem brains were donated by The Stanley Brain Collection courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster and Robert H. Yolken. We thank Dr. M.J. Webster for editing the manuscript, Dr. A. Ju. Klintsova for consulting help and T.E. Makeeva for technical assistance.

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