Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions.
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.
Division of Molecular Biology of the Cell I, German Cancer Research Center, D-69120 Heidelberg, Germany.
Stephanie
S
Ridder
Sabine
S
Chourbaji
Rainer
R
Hellweg
Alexandre
A
Urani
Christiane
C
Zacher
Wolfgang
W
Schmid
Mathias
M
Zink
Heide
H
Hörtnagl
Herta
H
Flor
Fritz A
FA
Henn
Günther
G
Schütz
Peter
P
Gass
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003214:Conditioning, Classical; D003345:Corticosterone / Q000097:blood; D003866:Depressive Disorder / Q000235:genetics*; D003907:Dexamethasone; D004597:Electroshock; D005239:Fear; D006380:Helplessness, Learned; D006624:Hippocampus / Q000502:physiology* / Q000503:physiopathology; D006799:Housing, Animal; D051379:Mice; D008817:Mice, Mutant Strains; D008959:Models, Neurological; D009414:Nerve Growth Factors / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000502:physiology; D013315:Stress, Psychological / Q000235:genetics*
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D003345:Corticosterone