Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states
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Nešić, Milica J.
Soldatović, Ivan A.
Marić, Nađa P.
Article (Published version)
© 2018 Elsevier Inc
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Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα their interactions and FKBP5 explained 22%–35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. T...he association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα and emphasized its role in fear extinction and neural plasticity. © 2018 Elsevier Inc.
Keywords:Childhood trauma / Glucocorticoid receptor / Fear conditioning / Plasticity
Source:Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2019, 90, 288-299
- Defining a cluster of molecular biomarkers for improved diagnostics and therapy of mood disorders (RS-41029)
- NIH grant (R21MH098793)
ISSN: 0278-5846 (print); 1878-4216 (electronic)