Glucocorticoid and mineralocorticoid receptor alterations in the human hippocampus in mood disorders.
A. Medina; V. Sharma; S. Burke; W. Bunney; R.M. Myers; A. Schatzberg; J.D. Barchas; E.J. Jones; H. Akil; S.J. Watson
Society for Neuroscience. 2010.
The involvement of the hypothalamic-pituitary-adrenal (HPA) axis in stress and mood disorders has been widely documented. The physiological adrenal steroids, aldosterone and cortisol bind respectively to the nuclear mineralocorticoid (MR) and glucocorticoid (GR) receptors. These receptors are known to act as transcription factors in the central nervous system. In this study we evaluate the mRNA expression and the correlation between these two receptors in post mortem hippocampal samples of controls and mood disorder subjects. Materials and Methods: Human brain samples from major depression disorder (MDD), bipolar disorder (BPD) and control subjects were obtained from the Brain Donor Program at the University of California, Irvine. Blocks containing the hippocampus were cut using a cryostat in to 10 µm sections and radioactive in situ hybridization (ISH) was performed in adjacent sections 500 µm apart using 35S labeled probes against the MR and GR. The sections were afterwards stained using Kluver's protocol. To perform an adequate anatomical alignment Digitized images of ISH autoradiograms and histological slides were overlaid using AdobeÂ® PhotoshopÂ® CS 8.0, and subjects containing homologous regions of the dentate gyrus (DG) were selected for the study (control n=11, MDD n= 21, BPD n=10). The optical density levels of MR and GR mRNA in the DG were quantified using Image J. The resulting data was analyzed using t test to compare total values for MR and GR on each disease group against controls and linear regression and correlation analysis to examine the relationship between MR and GR for each group. Results: The linear regression analysis showed a positive correlation between MR and GR in control subjects. The level of correlation was different in the MDD group. When separating the MDD group in to suicides and non-suicides, the differential effect seemed to be driven by the non-suicide subgroup. It also appears to be a gender effect, where the difference from controls was higher in the females than in males. As for BPD no differences were found compared to controls, or when separating suicides and non suicides. However, there was a difference in the female subgroup compared to controls. Although the MR/GR ratio for both the disorders did not show any significant difference in comparison with controls, the MR/GR ratio did show significant difference in the suicidal subgroup of both MDD and BPD compared to controls and there was a significant correlation observed to the control group in the suicidal subgroup of both MDD and BPD. In conclusion, MR and GR seem to have a coordinated biological activity that is altered in mood disorders.