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

被引:322
作者
Ridder, S
Chourbaji, S
Hellweg, R
Urani, A
Zacher, C
Schmid, W
Zink, M
Hörtnagl, H
Flor, H
Henn, FA
Schütz, G
Gass, P
机构
[1] Univ Heidelberg, Cent Inst Mental Hlth, D-68159 Mannheim, Germany
[2] German Canc Res Ctr, Div Mol Biol Cell 1, D-69120 Heidelberg, Germany
[3] Charite Univ Med, Dept Psychiat, D-14050 Berlin, Germany
[4] Charite Univ Med, Inst Pharmacol & Toxicol, D-14050 Berlin, Germany
关键词
depression; stress; glucocorticoid receptor; helplessness; transgenic mice; behavior;
D O I
10.1523/JNEUROSCI.0736-05.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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% GRgene dose reduction, and (2) mice overexpressingGR 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.
引用
收藏
页码:6243 / 6250
页数:8
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