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

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
Externally publishedYes

Keywords

  • Childhood trauma
  • Fear conditioning
  • Glucocorticoid receptor
  • Plasticity

ASJC Scopus subject areas

  • Pharmacology
  • Biological Psychiatry

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