Functions of the Mineralocorticoid Receptor in the Hippocampus.

[摘要] In the central nervous system, glucocorticoids influence neuroendocrine function, cognition, neurogenesis, neurodegeneration, and cell survival.Glucocorticoid hormones signal through the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), closely related members of the steroid hormone receptor superfamily.Their expression profiles and modes of action suggest both overlapping and distinct functions in mediating glucocorticoid effects.As GR function has been widely examined, research in this thesis focuses on the roles of MR action in the central nervous system using both in vivo and in vitro approaches.First, we generated a transgenic mouse model that overexpresses MR in the forebrain (MRov).Relative to wild-type littermate controls, MRov mice display reduced anxiety-like behaviors and exhibit suppressed HPA axis activity in response to stress.These data demonstrate that functions of forebrain MR can both overlap (regulation of neuroendocrine function) and oppose (modulation of anxiety-like behavior)GR-mediated actions.Second, we utilized the mouse hippocampal cell line, HT-22, to address corticosteroid receptor-mediated effects on both cell survival and regulation of transcription in an in vitro system.HT-22 cells express GR but not MR, and have been shown to be sensitive to glutamate toxicity in a manner that is exacerbated by activation of GR.To address the role of MR in this ;;glucocorticoid endangerment”, we generated stable clones of HT-22 cells that express MR in addition to GR.Using these cell lines, we confirmed that while GR activation enhanced glutamate toxicity, the co-activation of MR and GR in the HT-22/MR clone attenuated the glucocorticoid endangerment of the cells.Finally, MR- and GR-mediated regulation of glucocorticoid responsive genes was monitored at the transcriptome level in HT-22/Parent and HT-22/MR cells.This research demonstrated that co-activation of MR and GR resulted in the regulation of a substantially larger set of genes relative to GR activation alone, including classes of genes known to regulate cell survival and proliferation, suggesting that changes in the balance of receptor levels may result in functionally significant alterations in global transcriptome regulation.Together, these data reveal important overlapping and distinct roles for hippocampal MR and GR.

[发布机构] University of Michigan

[效力级别] Glucocorticoid Receptor

[关键词] Mineralocorticoid Receptor;Glucocorticoid Receptor;Science (General);Science;Cellular & Molecular Biology