Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder

Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder

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J Psychiatry Neurosci 2014;39(6):376-85

Christa Hercher, MSc; Vikramjit Chopra, PhD; Clare L. Beasley, PhD

Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada

Abstract

Background: Brain imaging studies suggest that volume reductions and compromised white matter integrity occur in schizophrenia and bipolar disorder (BD). However, the cellular correlates have not yet been identified. To address this issue we assessed oligodendrocyte, astrocyte and microglial populations in postmortem white matter from schizophrenia, BD and nonpsychiatric control samples.

Methods: The density, areal fraction and spatial distribution of glial fibrillary acidic protein (GFAP)-expressing astrocytes and ionized calcium-binding adaptor molecule-1 (IBA-1)-expressing microglia as well as the density, nuclear size and spatial distribution of Nissl-stained oligodendrocytes were quantified in postmortem white matter adjacent to the dorsolateral prefrontal cortex (Brodmann area 9) in schizophrenia, BD and control samples (n = 20). In addition, the oligodendrocyte-associated proteins myelin basic protein and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) were quantified in the same samples by enzyme-linked immunosorbent assay and immunoblotting.

Results: Oligodendrocyte density (p = 0.012) and CNPase protein levels (p = 0.038) differed between groups, being increased in BD compared with control samples. The GFAP area fraction (p = 0.05) and astrocyte spatial distribution (p = 0.040) also differed between groups, reflecting decreased area fraction and increased cell clustering in both schizophrenia and BD samples.

Limitations: Oligodendrocytes were identified using morphological criteria.

Conclusion: This study provides evidence for glial pathology in prefrontal white matter in schizophrenia and BD. Changes in oligodendrocyte and astrocyte populations in white matter in the major psychiatric disorders may reflect disruptions in structural or metabolic support of axons.


Submitted Dec. 3, 2013; Revised Jan. 29, Mar. 21, 2014; Accepted Mar. 24, 2014; Early-released June 17, 2014.

Acknowledgements: Postmortem brain tissue was donated by the Stanley Medical Research Institute’s brain collection. We would like to thank Dr. Athena Ypsilanti for performing the ELISA studies and Dr. Charles Duyckaerts for generously donating the Voron software and providing technical assistance. This study was supported by the Mind Foundation of British Columbia, the Stanley Medical Research Institute, the Michael Smith Foundation for Health Research and the Canadian Institutes of Health Research (#81112, #102525).

Competing interests: C.L. Beasley declares grants from the Canadian Institutes of Health Research, Stanley Medical Research Institute and Michael Smith Foundation for Health Research. No other competing interests declared.

Contributors: C.L. Beasley designed the study. C. Hercher and V. Chopra acquired the data, which C. Hercher and C.L. Beasley analyzed. C. Hercher and C.L. Beasley wrote the article, which V. Chopra reviewed. All authors approved the final version for publication.

DOI: 10.1503/jpn.130277

Correspondence to: C.L. Beasley, BC Mental Health and Addictions Research Institute, A3 115-938 West 28th Ave., Vancouver BC V5Z 4H4; cbeasley@mail.ubc.ca