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.
Ridder
Stephanie
S
Division of Molecular Biology of the Cell I, German Cancer Research Center, D-69120 Heidelberg, Germany.
Chourbaji
Sabine
S
Hellweg
Rainer
R
Urani
Alexandre
A
Zacher
Christiane
C
Schmid
Wolfgang
W
Zink
Mathias
M
Hörtnagl
Heide
H
Flor
Herta
H
Henn
Fritz A
FA
Schütz
Günther
G
Gass
Peter
P
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