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摘要
Stress has been implicated in the onset and illness course of schizophrenia and bipolar disorder. The effects of stress in these disorders may be mediated by abnormalities of the hypothalamic-pituitary-adrenal axis, and its corticosteroid receptors. We investigated mRNA expression of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and protein expression of multiple GR alpha isoforms, in the prefrontal cortex of 37 schizophrenia cases and 37 matched controls. Quantitative real-time PCR, western blotting, and luciferase assays were employed. In multiple regression analysis, schizophrenia diagnosis was a significant predictor of total GR mRNA expression (p < 0.05), which was decreased (11.4%) in schizophrenia cases relative to controls. No significant effect of diagnosis on MR mRNA was detected. At the protein level, no significant predictors of total GR alpha protein or the full-length GR alpha isoform were identified. However, schizophrenia diagnosis was a strong predictor (p < 0.0005) of the abundance of a truncated similar to 50 kDa GR alpha protein isoform, putative GR alpha-D1, which was increased in schizophrenia cases (80.4%) relative to controls. This finding was replicated in a second cohort of 35 schizophrenia cases, 34 bipolar disorder cases, and 35 controls, in which both schizophrenia and bipolar disorder diagnoses were significant predictors of putative GR alpha-D1 abundance (p < 0.05 and p = 0.005, respectively). Full-length GR alpha was increased in bipolar disorder relative to schizophrenia cases. Luciferase assays demonstrated that the GR alpha-D1 isoform can activate transcription at glucocorticoid response elements. These findings confirm total GR mRNA reductions in schizophrenia and provide the first evidence of GR protein isoform abnormalities in schizophrenia and bipolar disorder. Neuropsychopharmacology (2011) 36, 2698-2709; doi: 10.1038/npp.2011.160; published online 31 August 2011
- 出版日期2011-12
