Elsevier

The Lancet

Volume 362, Issue 9386, 6 September 2003, Pages 798-805
The Lancet

Mechanisms of Disease
Oligodendrocyte dysfunction in schizophrenia and bipolar disorder

https://doi.org/10.1016/S0140-6736(03)14289-4Get rights and content

Summary

Background

Results of array studies have suggested abnormalities in expression of lipid and myelin-related genes in schizophrenia. Here, we investigated oligodendrocyte-specific and myelination-associated gene expression in schizophrenia and bipolar affective disorder.

Methods

We used samples from the Stanley brain collection, consisting of 15 schizophrenia, 15 bipolar affective disorder, and 15 control brains. Indexing-based differential display PCR was done to screen for differences in gene expression in schizophrenia patients versus controls. Results were cross-validated with quantitative PCR, which was also used to investigate expression profiles of 16 other oligodendrocyte and myelin genes in schizophrenia and bipolar disorder. These genes were further investigated with an ongoing microarray analysis.

Findings

Results of differential display and quantitative PCR analysis showed a reduction of key oligodendrocyte-related and myelin-related genes in schizophrenia and bipolar patients; expression changes for both disorders showed a high degree of overlap. Microarray results of the same genes investigated by quantitative PCR correlated well overall.

Interpretation

Schizophrenia and bipolar brains showed downregulation of key oligodendrocyte and myelination genes, including transcription factors that regulate these genes, compared with control brains. These results lend support to and extend observations from other microarray investigations. Our study also showed similar expression changes to the schizophrenia group in bipolar brains, which thus lends support to the notion that the disorders share common causative and pathophysiological pathways.

Introduction

Schizophrenia and bipolar affective disorder are two major psychotic illnesses, affecting about 2% of the population. Increasing evidence suggests that both disorders might be more closely related than previously thought, and a dimensional view is increasingly supported. Greater knowledge of the shared and disease-specific genetic and environmental risk factors is important to advance causative and diagnostic understanding of psychotic disorders and to improve therapeutic and clinical management.

Molecular profiling techniques including high-density array screens and differential display technologies have begun to have an effect on the understanding of complex neuropsychiatric disorders, with the major psychoses arguably representing the greatest challenge. The hope is that global expression profiling techniques will identify individual genes, functionally related genes, or both that are associated causally with a specific disorder and suggest overlapping gene expression profiles for associated syndromes. Results of a microarray study showed reduced expression of myelin-related and oligodendrocyte-related genes in schizophrenia.1 In other expression profiling studies, one from our own laboratory, abnormalities in expression of lipid-related and myelination-related genes in the prefrontal cortex of patients with schizophrenia have been reported.2, 3 Results of other studies have noted general alterations in phospholipid, fatty acid, and cholesteryl ester content within schizophrenia-derived tissues,4 and evidence from neuroimaging studies suggests white-matter pathological findings in both schizophrenia and bipolar affective disorder.5, 6, 7

In this study, we aimed to investigate a large number of myelin-related and oligodendrocyte-related genes and to provide independent evidence pointing towards oligodendrocyte dysfunction in both schizophrenia and bipolar disorder.

Section snippets

Tissue collection

We obtained fresh-frozen prefrontal cortex tissue (Brodmann region 9) from the neuropathology consortium of the Stanley brain collection (Stanley Medical Research Institute, Bethesda, USA). We used blocks with equal amounts of white and grey matter for total RNA extraction. The demographic and clinical characteristics of the population, as well as methods of tissue harvest, preparation, and storage, have been described in detail.8 In brief, we obtained brains from medical examiners with family

Results

We obtained 15 schizophrenia, 15 bipolar, and 15 control brains from the Stanley brain collection. Indexing-based differential display pcr was done with RNA extracted from the prefrontal cortex of three patients with schizophrenia and three matched controls, selected for excellent RNA quality. We identified one band just below the 298 bp marker position, which was very much diminished in schizophrenia samples compared with controls (figure 1). Results of sequence analysis showed that the

Discussion

We believe that our results provide strong evidence for oligodendrocyte and myelin dysfunction in schizophrenia and bipolar affective disorder. Expression profiles of most known oligodendrocyte-related and myelin-related genes were greatly reduced, and several transcription factors known to coordinate myelin gene expression showed corresponding alterations. The high degree of correlation between the expression changes in schizophrenia and bipolar disorder provide compelling evidence for common

GLOSSARY

cell lineage
A pedigree of cells related through mitotic division.
differential display pcr
PCR-based method in which two populations of RNA are compared—eg, RNA from normal and pathological tissue. The technique allows high throughput screening for differential gene expression.
gene expression profile
A population of specific mRNAs detected in a sample.
genome
The complete set of sequences in the genetic material of an organism. It includes the sequence of every chromosome plus any DNA in organelles.

References (36)

  • A Bertolino et al.

    Regionally specific neuronal pathology in untreated patients with schizophrenia: a proton magnetic resonance spectroscopic imaging study

    Biol Psychiatry

    (1998)
  • A Bertolino et al.

    The effect of treatment with antipsychotic drugs on brain N-acetylaspartate measures in patients with schizophrenia

    Biol Psychiatry

    (2001)
  • R Hata et al.

    Up-regulation of calcineurin Abeta mRNA in the Alzheimer's disease brain: assessment by cDNA microarray

    Biochem Biophys Res Commun

    (2001)
  • L Ho et al.

    Altered expression of a-type but not b-type synapsin isoform in the brain of patients at high risk for Alzheimer's disease assessed by DNA microarray technique

    Neurosci Lett

    (2001)
  • C Colantuoni et al.

    Gene expression profiling in postmortem Rett Syndrome brain: differential gene expression and patient classification

    Neurobiol Dis

    (2001)
  • Y Hakak et al.

    Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia

    Proc Natl Acad Sci USA

    (2001)
  • J Pongrac et al.

    Gene expression profiling with DNA microarrays: advancing our understanding of psychiatric disorders

    Neurochem Res

    (2002)
  • ML Mimmack et al.

    Gene expression analysis in schizophrenia: reproducible up-regulation of several members of the apolipoprotein L family located in a high-susceptibility locus for schizophrenia on chromosome 22

    Proc Natl Acad Sci USA

    (2002)
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