Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions
Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions
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DOI：
10.1523/jneurosci.0736-05.2005
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发表时间：
2005-06-29
影响因子：
5.3
通讯作者：
Gass, P
中科院分区：
文献类型：
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作者：
Ridder, S;Chourbaji, S;Gass, P
糖皮质激素受体（GR）信号传导的改变是重度抑郁症发病机制的假设机制。为了模仿人类因抑郁症而导致 GR 功能改变的情况，我们培育了 GR 表达不足或过度表达的小鼠品系，但维持了控制 GR 基因的调控遗传背景。为了实现这一目标，我们使用了以下方法：(1) GR 杂合突变小鼠 (GR(+/-))，GR 基因剂量减少 50%；(2) 通过酵母人工染色体过度表达 GR 的小鼠，导致基因剂量提高两倍。 GR(+/-) 小鼠表现出正常的基线行为，但在暴露于压力后表现出更多的无助感，这是小鼠抑郁症的行为相关性。与抑郁症患者类似，GR(+/-) 小鼠的下丘脑-垂体-肾上腺 (HPA) 系统不受抑制，并且具有病理性地塞米松/促肾上腺皮质激素释放激素测试。因此，它们代表了具有良好表面效度和结构效度的小鼠抑郁症模型。 GR 在小鼠体内的过度表达会减少应激后的无助感，并增强 HPA 系统的反馈调节。因此，它们可能代表了抗应激菌株的模型。这些小鼠模型现在可用于研究抑郁症发病机制背后的生物学变化。作为此类变化的第一个潜在分子关联，我们发现 GR+/- 小鼠海马中 BDNF 蛋白含量下调，这与所谓的抑郁症神经营养素假说一致。
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.