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. 2005 Jun 29;25(26):6243-50.
doi: 10.1523/JNEUROSCI.0736-05.2005.

Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions

Stephanie Ridder  1 , Sabine Chourbaji, Rainer Hellweg, Alexandre Urani, Christiane Zacher, Wolfgang Schmid, Mathias Zink, Heide Hörtnagl, Herta Flor, Fritz A Henn, Günther Schütz, Peter Gass
Affiliations

Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions

Stephanie Ridder et al. J Neurosci. .

Abstract

Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR+/-) with a 50% GR gene dose reduction, and (2) mice overexpressing GR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR+/- mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR+/- mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/- mice, which is in agreement with the so-called neurotrophin hypothesis of depression.

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Figures

Figure 1.
Figure 1.
Expression levels of GR protein in GR+/- and YGR mice in the hippocampus. Western blot analyses show a marked downregulation of GR in GR+/- mice compared with wild-type littermates (top gel; each lane represents a hippocampal protein extract from a different animal). Conversely, YGR mice exhibit a distinct GR upregulation compared with their control littermates (bottom gel). wt, Wild type.
Figure 2.
Figure 2.
Corticosterone levels in GR+/- mice under basal and stressful conditions. a, Plasma corticosterone levels are unchanged in GR+/- mice compared with wild-type mice, both during the animals' active (dark) and inactive (light) phase. b, After stress exposure, however, corticosterone levels are higher in GR+/- mice at 40 and 60 min (*p < 0.05) after immobilization.
Figure 3.
Figure 3.
GR+/- mice display increased helplessness in a shuttle box test after exposure to inescapable footshocks on the 2 d preceding the test. a, GR+/- mice exhibit significantly increased escape latencies compared with their wild-type littermates (*p < 0.05). b, GR+/- mice also show a higher number of escape failures (*p < 0.05). c, Latencies and numbers of failures are highly correlated when plotted for individual mutant and wild-type mice, demonstrating that the subjects with the worst coping (in the top right area of the graph) are all GR+/- mice.
Figure 4.
Figure 4.
GR+/- mice are nonsuppressors in the Dex/CRH test. a, After administration of dexamethasone, wild-type mice show decreased corticosterone levels, whereas GR+/- mice exhibit nonsuppression (**p < 0.01). b, In the combined Dex/CRH test, corticosterone levels are significantly elevated in GR+/- mice compared with the levels of wild-type mice (***p < 0.001).
Figure 5.
Figure 5.
YGR mice have a stress-resistant HPA system and are oversuppressors in the Dex test. a, After stress exposure, corticosterone levels are significantly lower in YGR mice at 40 min after immobilization than in wild-type controls (**p < 0.05). b, After administration of dexamethasone, YGR mice show a significant oversuppression of corticosterone levels compared with wild-type mice (**p < 0.01). c, In the combined Dex/CRH test, corticosterone levels are lower in YGR mice compared with the levels of wild-type mice (p = 0.07).
Figure 6.
Figure 6.
YGR mice are more resistant in the learned-helplessness paradigm. a, YGR mice exhibit significantly decreased escape failures compared with their wild-type littermates (*p < 0.05). b, YGR mice also show a reduced number of escape latencies (*p<0.05). c, Latencies and numbers of failures are highly correlated when plotted for individual mutant and wild-type mice, demonstrating worse coping (in the top right area of the graph) in wild-type mice, whereas YGR mice cluster in the bottom left area of the graph.
Figure 7.
Figure 7.
BDNF protein levels in the hippocampus are significantly diminished in GR+/- mice (p < 0.05) and significantly increased in YGR mice (*p < 0.05). In contrast, the expression levels of NGF are unaltered in both mutant strains.
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