Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 90; pp. 288 - 299
• Main Authors: Adzic, Miroslav, Glavonic, Emilija, Nesic, Milica J., Milosavljevic, Minja, Mihaljevic, Marina, Petrovic, Zorica, Pavlovic, Zorana, Brkic, Zeljka, Francija, Ester, Soldatovic, Ivan, Mitic, Milos, Radulovic, Jelena, Maric, Nadja P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 02.03.2019
• Subjects: Adult; Adult Survivors of Child Adverse Events - psychology; Affect - physiology; Animals; Cell Nucleus - metabolism; Childhood trauma; Cohort Studies; Conditioning, Psychological; Disease Models, Animal; Extinction, Psychological - physiology; Fear - physiology; Fear conditioning; Female; Glucocorticoid receptor; Humans; Male; Mice, Inbred C57BL; Pilot Projects; Plasticity; Protein Biosynthesis; Protein Isoforms; Random Allocation; Receptors, Glucocorticoid - blood; Childhood trauma; Glucocorticoid receptor; Plasticity; Fear conditioning
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2018.12.011

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. The 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. •Childhood trauma had a direct effect on 40-kDa GRα and negative affectivity (NA).•Indirect association of 40-kDa and NA was mediated by nuclear 95-kDa GRα and FKBP5.•Extinction learning associated with nuclear 40-kDa GRα and BDNF exon IV expression.•GRα translational isoforms linked early trauma exposure with adult psychopathology.