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. 2019 Dec 23;14(12):e0226753.
doi: 10.1371/journal.pone.0226753. eCollection 2019.

Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization

Kelly Van Looveren  1   2 , Michiel Van Boxelaere  3 , Zsuzsanna Callaerts-Vegh  3   4   5 , Claude Libert  1   2
Affiliations

Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization

Kelly Van Looveren et al. PLoS One. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Order of tests.
Open field (OP), elevated plus maze (EPM), 23h cage activity (CA), anhedonia (AnH), social preference and social novelty (SPSN), Y-maze spontaneous alternations (Ym), conditioned place preference (CPP), passive avoidance (PA).
Fig 2
Fig 2. Overnight cage activity in GRwt/wt and GRdim/dim mice at baseline (BSL) and under chronic corticosterone (CORT) treatment.
(A) In GRwt/wt animals cage activity showed a typical activity pattern over 20h recording at baseline (black symbols, n = 12) or under chronic corticosterone (white symbols, n = 7). (B) GRdim/dim animals show a similar activity pattern under baseline condition (black symbols, n = 11). Chronic corticosterone treatment (white symbols, n = 10) increased activity during the night period, but the contrast was not significant. Data are presented as means ±SEMs. (C) Total activity counts show the extreme increase in cage activity in 2 GRwt/wt animals. Each data point reflects one animal, and bars indicate level of median. Baseline: n = 12 GRwt/wt and n = 11 GRdim/dim mice; CORT: n = 7 GRwt/wt and n = 10 GRdim/dim mice.
Fig 3
Fig 3. Explorative behaviour in the open field in GRwt/wt and GRdim/dim mice at baseline (BSL) and under chronic corticosterone (CORT) treatment.
When placed in an open field, overall exploration was similar in both genotypes expressed as path length (A), as time spent in the centre (B), and number of centre visits (C), and as time spent in the 4 corners (D). Data are expressed as means ± SEMs. Baseline: n = 12 GRwt/wt and n = 11 GRdim/dim mice; CORT: n = 9 GRwt/wt and n = 10 GRdim/dim mice.
Fig 4
Fig 4. Sociability (SP) and preference for social novelty (SN) in GRwt/wt (black bars) and GRdim/dim mice (white bars) under baseline and under chronic corticosterone treatment.
Under baseline conditions, no difference in path length (m/min) was observed between the genotypes.CORT treatment increased path length (m/min) in both genotype similarly in comparison to baseline (A). When presented with a stranger mouse (S1), under baseline and CORT conditions, both genotypes showed more approach behaviour towards S1 than to an empty (E) cage (B). When presented with a second stranger (S2), under baseline conditions GRdim/dim mice show a preference towards S2, while under CORT treatment, GRdim/dim mice do not display preference towards S2 anymore (C). Calculation of individual preference scores indicate that under baseline conditions, both genotypes show normal social preference (SP: S1-E), however, only GRdim/dim mice show preference for social novelty (SN: S1-S2). Under CORT, GRwt/wt show preference during SN and SP, while GRdim/dim mice show no preference in SP and SN (D). Data are shown as means ± SEMs. (B-D) * p < 0.05, **p < 0.01 ** p < 0.01, ***p < 0.001, (one sample t-test to chance level at 50%). Baseline: n = 12 GRwt/wt and n = 11 GRdim/dim mice; CORT: n = 9 GRwt/wt and n = 10 GRdim/dim mice.
Fig 5
Fig 5. Spontaneous alternation Y-maze.
CORT reduced the number of arm visits compared to baseline in both genotype (A). In contrast, spontaneous alternations were higher in GRwt/wt mice (B). Data are shown as mean ± SEM. *p < 0.05. Baseline: n = 12 GRwt/wt and n = 11 GRdim/dim mice; CORT: n = 9 GRwt/wt and n = 10 GRdim/dim mice.
Fig 6
Fig 6. Passive avoidance.
During training (TR), the animal received a mild foot shock upon entering the dark compartment. 24h later during testing (TE), entry to the dark compartment is avoided when contextual memory is intact. No differences were observed at baseline conditions (BSL). After CORT treatment, the latency in GRdim/dim mice was significantly lower when compared to BSL, as well as to GRwt/wt mice. Data are presented as mean +/- SEM. ** p < 0.01 (2-way ANOVA, post hoc with Sidak correction). Baseline: n = 12 GRwt/wt and n = 11 GRdim/dim mice; CORT: n = 9 GRwt/wt and n = 10 GRdim/dim mice.
Fig 7
Fig 7. Conditioned place preference in GRwt/wt (black symbols) and GRdim/dim mice (white symbols).
Animals were conditioned to locate a food reward in a specific context for 3 days (6 trials). Latency to find the reward (A, C) reduced over trials, and number of correct trials (B, D) increased over training trials. During training, no effect of genotype was found under baseline conditions (A, B) and not under CORT treatment (C, D). During testing, both genotype show clear preference for the correct context under baseline conditions (E), while under CORT treatment, GRdim/dim did not display a context preference (F). Data are shown as mean ± SEM. * p < 0.05. *** p < 0.001, **** P < 0.0001. Baseline: n = 9 GRwt/wt and n = 7 GRdim/dim mice; CORT: n = 9 GRwt/wt and n = 10 GRdim/dim mice.
Fig 8
Fig 8. Gene expression level changes in the dorsal hippocampus of genes associated with increases of corticosterone (BDNF, TRKB, Fkbp5, and Fmr1) and stress and cognition (Drd1, Drd5).
Tissue was extracted from animals after behavioral testing (n = 6) and compared to experimental naïve animals as baseline controls (n = 6). Data are presented as mean +/- SEM as relative expression, normalized to housekeeping genes and scaled to the average across all unknown samples per target, * p < 0.05; ** p < 0.01; *** p < 0.0001 (2-way ANOVA and post-hoc comparison with Sidak’s correction for multiple testing).
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Publication types

Grants and funding

This work was supported by Flanders Institute for Biotechnology, Ghent University, Katholic University Leuven and FWO-Flanders. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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