Journal
SCHIZOPHRENIA RESEARCH
Volume 120, Issue 1-3, Pages 150-158Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.schres.2010.04.012
Keywords
Schizophrenia; Oligodendrocyte; Myelin; Internal capsule; Cell cycle; Notch signaling; Glia; Astrocyte; Density
Categories
Funding
- VA Merit Program
- Stanley Medical Research Institute [09R-2134]
- Office of Research and Development
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Deficits in the expression of oligodendrocyte (01) and myelin genes have been described in numerous brain regions in schizophrenia (SZ) in association with abnormalities of cell cycle markers. We have previously reported a SZ-associated decrease in the expression of genes expressed after, but not prior to, the terminal differentiation of Ols in the posterior limb of the internal capsule (ICp). This pattern of deficits could reflect a failure of 01 precursors to exit the cell cycle and differentiate to meet the demands imposed by the high rate of apoptosis among myelinating Ols. Here we explore this hypothesis using quantitative real time PCR to examine the mRNA expression of additional genes in the ICp of the previously examined sample of 14 subjects with SZ and 15 normal controls (NCs). The genes examined in the present study were chosen because they are associated with particular phases of the cell cycle (CCND1, CCND2, p21(Cip1), p27(Kip1) and p57(Kip2)), with DNA replication and repair (PCNA), apoptosis (CASP3), or the Notch signaling pathway (JAG1, HES1, HES5, and DTX1). The Notch pathway influences whether 01 precursors continue to proliferate or exit the cell cycle. We also determined the densities of Ols in the ICp. Genes associated with maintenance of the cell cycle tended to exhibit increased expression levels in SZ relative to NCs and to be negatively correlated with the expression levels of the previously assessed mature 01 genes. In contrast, genes associated with cell cycle arrest tended to show the opposite pattern (decreased expression in SZ and positive correlations with mature 01 genes). CASP3 and PCNA expression levels were significantly decreased in SZ and positively correlated with mature 01 genes, suggesting that myelinating Ols may turnover more rapidly in normal controls than in subjects with SZ. JAG1 expression was significantly increased in SZ and exhibited positive correlations with mediators of the canonical Notch pathway but negative correlations with mature 01 genes. 01 densities were significantly decreased in SZ. These data are consistent with the hypothesis that 01 and myelin deficits in SZ involve a failure of 01 precursors to appropriately exit the cell cycle in order to differentiate and mature into myelinating Ols. Published by Elsevier B.V.
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