Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization

Autoři: Kelly Van Looveren aff001;  Michiel Van Boxelaere aff003;  Zsuzsanna Callaerts-Vegh aff003;  Claude Libert aff001
Působiště autorů: Center for Inflammation Research, VIB, Ghent, Belgium aff001;  Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium aff002;  Laboratory of Biological Psychology, KULeuven, Leuven Belgium aff003;  Leuven Research Institute for Neuroscience & Disease (LIND), Leuven, Belgium aff004;  mINT Mouse Behavioural Core Facility, KULeuven, Leuven, Belgium aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


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 GRdim/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 GRdim/dim mice did not behave differently from GRwt/wt littermates under baseline conditions. However, after chronic elevation of stress hormone levels, GRdim/dim mice displayed a significant impairment in hippocampus-dependent memory compared to GRwt/wt mice, which correlated with differential expression of hippocampal Bdnf/TrkB and Fkbp5.

Klíčová slova:

Animal behavior – Behavior – Cognitive impairment – Depression – Hippocampus – Memory – Mice – Psychological stress


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