Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants.
Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants.
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变异脑源性神经营养因子 Val66Met 多态性改变压力脆弱性和抗抑郁药反应
DOI：
10.1523/jneurosci.5048-11.2012
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发表时间：
2012-03-21
期刊：
影响因子：
--
通讯作者：
Chen ZY
中科院分区：
文献类型：
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作者：
Yu H;Wang DD;Wang Y;Liu T;Lee FS;Chen ZY
脑源性神经营养因子（BDNF）在细胞存活、神经可塑性、学习和应激调节等方面发挥着重要作用。然而，最近发现的人类BDNF Val66Met （BDNFMet）多态性是否会改变应激易感性仍存在争议。更重要的是，BDNFMet多态性与应激之间相互作用的分子和结构机制尚不清楚。我们发现，与WT小鼠相比，杂合BDNF+/Met小鼠在7 d限制性应激后表现出下丘脑-垂体-肾上腺轴高反应性，抑郁样和焦虑样行为增加，工作记忆受损。此外，应激后BDNF+/Met小鼠前额叶皮层和杏仁核的BDNF水平和顶端树突棘密度变化更为显著，这与工作记忆受损和焦虑样行为升高有关。最后，急性给予地西帕明而非氟西汀可选择性地恢复BDNF+/Met小鼠的抑郁样行为。这些数据表明，应激与人类遗传BDNFMet多态性之间的相互作用导致了选择性行为、分子和结构缺陷。重要的是，地西帕明而非氟西汀对BDNF+/Met小鼠具有抗抑郁作用，这表明特定类别的抗抑郁药可能是治疗BDNF基因变异患者抑郁症状的更有效选择。
Brain-derived neurotrophic factor (BDNF) plays important roles in cell survival, neural plasticity, learning, and stress regulation. However, whether the recently found human BDNF Val66Met (BDNFMet) polymorphism could alter stress vulnerability remains controversial. More importantly, the molecular and structural mechanisms underlying the interaction between the BDNFMet polymorphism and stress are unclear. We found that heterozygous BDNF+/Met mice displayed hypothalamic-pituitary-adrenal axis hyperreactivity, increased depressive-like and anxiety-like behaviors, and impaired working memory compared with WT mice after 7 d restraint stress. Moreover, BDNF+/Met mice exhibited more prominent changes in BDNF levels and apical dendritic spine density in the prefrontal cortex and amygdala after stress, which correlated with the impaired working memory and elevated anxiety-like behaviors. Finally, the depressive-like behaviors in BDNF+/Met mice could be selectively rescued by acute administration of desipramine but not fluoxetine. These data indicate selective behavioral, molecular, and structural deficits resulting from the interaction between stress and the human genetic BDNFMet polymorphism. Importantly, desipramine but not fluoxetine has antidepressant effects on BDNF+/Met mice, suggesting that specific classes of antidepressant may be a more effective treatment option for depressive symptoms in humans with this genetic variant BDNF.