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

Miroslav Adzic*, Emilija Glavonic, Milica J. Nesic, Minja Milosavljevic, Marina Mihaljevic, Zorica Petrovic, Zorana Pavlovic, Zeljka Brkic, Ester Francija, Ivan Soldatovic, Milos Mitic, Jelena Radulovic, Nadja P. Maric

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)288-299
Number of pages12
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume90
DOIs
StatePublished - Mar 2 2019

Keywords

  • Childhood trauma
  • Fear conditioning
  • Glucocorticoid receptor
  • Plasticity

ASJC Scopus subject areas

  • Pharmacology
  • Biological Psychiatry

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