Male-specific effects of lipopolysaccharide on glucocorticoid receptor nuclear translocation in the prefrontal cortex of depressive rats.

RATIONALE: Inflammation plays a key role in the pathogenesis of major depressive disorder (MDD) for a subset of depressed individuals. One of the possible routes by which cytokines can induce depressive symptoms is by promoting the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis via altering glucocorticoid receptor (GR) function.

OBJECTIVES: We investigated the mechanisms that finely tune the GR functioning upon lipopolysaccharide (LPS), i.e., subcellular localization of the GR, the levels of its co-chaperones FK506 binding protein 52 (FKBP4) and FK506 binding protein 51 (FKBP5), the receptor phosphorylation status along with its upstream kinases, as well as mRNA levels of GR-regulated genes in the prefrontal cortex (PFC) of male and female Wistar rats.

RESULTS: We found that upon LPS treatment, animals of both sexes exhibited depressive-like behavior and elevated serum corticosterone. However, the nuclear translocation of the GR and both FKBPs was found only in males, together with elevated phosphorylation of the GR at serine 232 and 246 and the activation and nuclear translocation of all analyzed kinases. This activation of the GR in males was paralleled with altered expression of GR-related genes, particularly PTGS2 and BDNF.

CONCLUSION: Our data suggest that LPS treatment produced alterations in the mechanisms that control the GR nuclear translocation in the PFC of males, and that these mechanisms may contribute to the sex-specific dysfunction of GR-related neurotrophic and neuroinflammatory processes in inflammation-associated depression.