ABSTRACT
Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress-related psychiatric disorders. Bcl-2 associated athanogene (Bag-1) is a target for the actions of mood stabilizers. Bag-1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag-1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag-1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 min and 24 hr. By contrast, after stimulation with CORT for 3 days, localization of the Bag-1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag-1 over-expression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia-like and depression-like behaviors in the sucrose-consumption test and forced swimming test, and these behaviors were rescued by Bag-1 over-expression. These results suggest that Bag-1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag-1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.
Subject(s)
Affect/drug effects , Corticosterone/pharmacology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Mitochondria/metabolism , Receptors, Glucocorticoid/metabolism , Resilience, Psychological/drug effects , Transcription Factors/genetics , Transcription Factors/metabolism , Anhedonia , Animals , Depression/psychology , Dose-Response Relationship, Drug , Female , Male , Neurons/drug effects , Pregnancy , Primary Cell Culture , Protein Transport , Rats , Rats, Sprague-Dawley , Stimulation, Chemical , Swimming/psychologyABSTRACT
Chronic restraint stress in mice affects hippocampal structure and function. Mice were subjected to daily restraint for 3 weeks, and gene expression in hippocampus was compared to controls using large-scale cDNA microarrays. We found that 444 genes were differentially expressed, and further analysis of 6 genes by real-time reverse transcription PCR confirmed that 3 of them were downregulated by stress. These 3 genes, growth factor receptor-bound protein 2 (Grb2), phosphatidylinositol-4-phosphate 5-kinase, type 1 beta (Pip5k1b), and glutathione S-transferase, pi2 (Gstp2), were also analyzed by in situ hybridization. The downregulation of Gstp2 may induce an increase of oxidative damage in the pyramidal cells of the CA1 and CA3 regions and granular layer of the dentate gyrus, leading to structural and functional damage. Those regions are affected by stress, and our results could help understand further the mechanisms involved in the occurrence of stress-related disorders.
