Mechanisms of DiseaseOligodendrocyte dysfunction in schizophrenia and bipolar disorder
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.
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