Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization

Stress is a major risk factor for depression and anxiety. One of the effects of stress is the (over-) activation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of stress hormones such as glucocorticoids (GCs). Chronically increased stress hormone levels have been shown to have detrimental effects on neuronal networks by inhibiting neurotrophic processes particularly in the hippocampus proper. Centrally, GCs modulate metabolic as well as behavioural processes by activating two classes of corticoid receptors, high-affinity mineralocorticoid receptors (MR) and low-affinity glucocorticoid receptors (GR). Upon activation, GR can modulate gene transcription either as a monomeric protein, or as a dimer interacting directly with DNA. GR can also modulate cellular processes via non-genomic mechanisms, for example via a GPCR-protein interaction. We evaluated the behavioral phenotype in mice with a targeted mutation in the GR in a FVB/NJ background. In GR(dim/dim) mice, GR proteins form poor homodimers, while the GR monomer remains intact. We evaluated the effect of poor GR dimerization on hippocampus-dependent cognition as well as on exploration and emotional behavior under baseline and chronically increased stress hormone levels. We found that GR(dim/dim) mice did not behave differently from GR(wt/wt) littermates under baseline conditions. However, after chronic elevation of stress hormone levels, GR(dim/dim) mice displayed a significant impairment in hippocampus-dependent memory compared to GR(wt/wt) mice, which correlated with differential expression of hippocampal Bdnf/TrkB and Fkbp5.

Jaar van publicatie:2019

Toegankelijkheid:Open