PT  - JOURNAL ARTICLE
AU  - Ridder, Stephanie
AU  - Chourbaji, Sabine
AU  - Hellweg, Rainer
AU  - Urani, Alexandre
AU  - Zacher, Christiane
AU  - Schmid, Wolfgang
AU  - Zink, Mathias
AU  - Hörtnagl, Heide
AU  - Flor, Herta
AU  - Henn, Fritz A.
AU  - Schütz, Günther
AU  - Gass, Peter
TI  - Mice with Genetically Altered Glucocorticoid Receptor Expression Show Altered Sensitivity for Stress-Induced Depressive Reactions
AID  - 10.1523/JNEUROSCI.0736-05.2005
DP  - 2005 Jun 29
TA  - The Journal of Neuroscience
PG  - 6243--6250
VI  - 25
IP  - 26
4099  - http://www.jneurosci.org/content/25/26/6243.short
4100  - http://www.jneurosci.org/content/25/26/6243.full
SO  - J. Neurosci.2005 Jun 29; 25
AB  - 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.