Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization

Abstract

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.

Point mutation I634A in the glucocorticoid receptor causes embryonic lethality by reduced ligand binding

“…GR variants with impaired dimerization have proven to be invaluable tools to study the various receptor mechanisms of action in physiology and disease, to develop synthetic GCs and to understand glucocorticoid resistance ( 42 , 43 , 44 ). A GR with a disruptive mutation in the primary dimerization interface in the DBD, the GR dim version expressing an A465T mutation, has been generated in 1998 ( 32 ).…”

Adrenergic and Glucocorticoid Receptors in the Pulmonary Health Effects of Air Pollution

“…On binding to glucocorticoids, GRs complexed with a number of proteins that are replaced by FK506-binding protein 51 (FKBP51) and p23 chaperone protein, preparing complexes for nuclear translocation and DNA binding [13]. In addition to binding of GR homodimers to palindromic sequences on DNA (glucocorticoid response elements; GREs), GR complexes can also be exported back to the cytoplasm as another regulatory control of its transcriptional activity [55]. GR homodimer binding to GREs directly activates transcription of genes (transactivation) or silencing of transcription (reviewed in [13]).…”

ZBTB32 performs crosstalk with the glucocorticoid receptor and is crucial in glucocorticoid responses to starvation

“…The obese phenotype of the NZO/HlLtJ (New Zealand Obese) mice has been linked to a locus on proximal chromosome 7 (Taylor et al, 2001). In our recently released database of naturally occurring variant protein coding genes (mousepost.be (Timmermans et al, 2017)) across all 36 sequenced mouse inbred lines, we observe that the obese NZO/HlLtJ mice, compared to most other strains, express a mutant version of the Zbtb32 gene, leading to a W226L mutation in the ZBTB32 protein, a mutation that, according to the Protein Variation Effect Analyzer (PROVEAN), has a high chance to impact protein function (Choi et al, 2012). These observations suggest that at least some obese phenotypes, maybe also in humans, are due to mutations in the gene coding for ZBTB32.…”

“…Equally important would be a way to supplement ZBTB32 À/À mice with extra corticosterone to complement for the reduced production in these mice and revert the heavier weight phenotype. Such experiments have been tried with corticosterone, but had to be stopped as this led to unacceptable stress as we published before (van Looveren et al, 2019).…”