Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia

Abstract

Background

Brain imaging, molecular genetic, and ultrastructural evidence indicate the existence of pathologic alterations in the cortical and subcortical white matter of schizophrenic patients.

Methods

We performed a stereologic analysis of numbers, densities, and spatial distribution of oligodendrocytes in layer III and in the gyral white matter of Brodmann’s area 9 in the superior frontal gyrus to assess whether these cells are affected in schizophrenia. Counts were obtained on Nissl-stained materials and on sections immunolabeled for the oligodendrocyte marker 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) in seven schizophrenic and seven age-matched control cases.

Results

A 28% decrease in total numbers (or densities) of cortical layer III oligodendrocytes and a 27% decrease in the white matter were detected in schizophrenic compared with control cases based on CNPase immunostaining. Nissl and CNPase immunohistochemistry yielded comparable results. The spatial distribution of oligodendrocytes in area 9 white matter exhibited a less clustered arrangement in schizophrenic cases.

Conclusions

These results suggest a severe pathology of oligodendrocytes in schizophrenia and provide a quantitative cellular correlate of the white matter changes observed by brain imaging in vivo, showing reduced fractional anisotropy in schizophrenia. The data support recent evidence that several genes encoding myelin-related proteins consistently exhibit reduced expression in schizophrenia.

Introduction

Demyelinating diseases have long been known to be associated with behavioral disturbances, and alterations in brain connectivity have long been suspected to play a key role in the development of schizophrenia Davis et al, Hyde et al 1992. Recent evidence revealed that the expression levels of several myelin-related genes are consistently and substantially lower in schizophrenic patients than in control subjects (Hakak et al 2001). In addition, differences in white matter organization have been reported by diffusion tensor imaging (DTI) and magnetic transfer imaging (MTI) in schizophrenia Buchsbaum et al 1998, Foong et al 2000, Foong et al 2001, Lim et al 1999. A parsimonious explanation for the decreased expression of myelin-related genes in schizophrenia and for the fact that these genes differentiate control from schizophrenic cases is that oligodendroglial cells are dysfunctional or reduced in number Davis et al, Hof et al 2002.

Schizophrenia is a multigenic disorder involving the conjugated effects of a constellation of deficits that lead to a common set of functional abnormalities Lewis 2000, Lewis and Lieberman 2000, Mirnics et al 2001. Genetic, pharmacologic, and imaging evidence point to a severe dysfunction of excitatory neurotransmission in schizophrenia Akbarian et al 1996, Dracheva et al 2001, Gao et al 2000, Ibrahim et al 2000, Mirnics et al 2000, Olney and Farber 1995, Théberge et al 2002 that may lead to excitotoxic damage of oligodendrocytes Matute et al 1997, McDonald et al 1998 and influence neuronal plasticity and synaptic connectivity. To estimate the severity of possible alterations in the prefrontal cortex white matter, we conducted an analysis of oligodendrocyte numbers and distribution in the superior frontal cortex in schizophrenic and age-matched control cases using rigorous stereologic sampling methods.