Isoform switching of steroid receptor co-activator-1 attenuates glucocorticoid-induced anxiogenic amygdala CRH expression

• Published in: Molecular psychiatry 2016-12, Vol.21 (12), p.1733-1739
• Main Authors: Zalachoras, I, Verhoeve, S L, Toonen, L J, van Weert, L T C M, van Vlodrop, A M, Mol, I M, Meelis, W, de Kloet, E R, Meijer, O C
• Format: Article
• Language: English
• Subjects: 38/23; 38/32; 38/77; 631/337; 631/378; 64/60; Alternative Splicing; Amygdala; Animals; Behavior; Behavioral Sciences; Biological Psychology; Brain research; Corticosterone - metabolism; Corticotropin-releasing hormone; Corticotropin-Releasing Hormone - metabolism; DNA methylation; Endocrinology; Experiments; Exploratory behavior; Fear; Gene expression; Gene Expression Regulation - drug effects; Glucocorticoids; Glucocorticoids - metabolism; Heat shock proteins; Hypothalamus; Hypotheses; Medicine; Medicine & Public Health; Mice; Motivation; Neurosciences; Nuclear Receptor Coactivator 1 - genetics; Nuclear Receptor Coactivator 1 - metabolism; original-article; Pharmacotherapy; Promoter Regions, Genetic - drug effects; Protein Isoforms - genetics; Psychiatry; Psychopathology; Receptors, Glucocorticoid - metabolism; Receptors, Steroid; RNA Isoforms; RNA, Messenger - metabolism; Signal transduction; Steroid receptor coactivator 1; Steroid receptors; Steroids; Stress; Tacrolimus Binding Proteins - metabolism; Transcription
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2016.16

Maladaptive glucocorticoid effects contribute to stress-related psychopathology. The glucocorticoid receptor (GR) that mediates many of these effects uses multiple signaling pathways. We have tested the hypothesis that manipulation of downstream factors (‘coregulators’) can abrogate potentially maladaptive GR-mediated effects on fear-motivated behavior that are linked to corticotropin releasing hormone (CRH). For this purpose the expression ratio of two splice variants of steroid receptor coactivator-1 (SRC-1) was altered via antisense-mediated ‘exon-skipping’ in the central amygdala of the mouse brain. We observed that a change in splicing towards the repressive isoform SRC-1a strongly reduced glucocorticoid-induced responsiveness of Crh mRNA expression and increased methylation of the Crh promoter. The transcriptional GR target gene Fkbp5 remained responsive to glucocorticoids, indicating gene specificity of the effect. The shift of the SRC-1 splice variants altered glucocorticoid-dependent exploratory behavior and attenuated consolidation of contextual fear memory. In conclusion, our findings demonstrate that manipulation of GR signaling pathways related to the Crh gene can selectively diminish potentially maladaptive effects of glucocorticoids.