Identifying molecular substrates in a mouse model of the serotonin transporter x environment risk factor for anxiety and depression
Identifying molecular substrates in a mouse model of the serotonin transporter x environment risk factor for anxiety and depression
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DOI：
10.1016/j.biopsych.2007.08.013
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发表时间：
2008-05-01
影响因子：
10.6
通讯作者：
Gross, Cornelius
中科院分区：
文献类型：
--
作者：
Carola, Valeria;Frazzetto, Giovanni;Gross, Cornelius
背景资料：5-羟色胺转运体（5-HTT）基因多态性调节不良早期经历与成年期重度抑郁症风险之间的关联虽然人类成像研究已经开始阐明参与5-HTT x环境风险因素的神经回路，但缺乏对这种现象的分子理解。这样的理解可能有助于确定诊断和治疗情绪障碍的新靶点。为了解决这一问题，我们开发了一个基因环境筛选paradigm in the mouse.Methods：我们建立了一个小鼠模型，在该模型中，5-HTT中的杂合无效突变缓和了母亲护理不良对成人焦虑和抑郁相关行为的影响。从这些动物的大脑进行了生化分析，以确定分子基板的基因，环境，和基因x环境的影响。结果：小鼠经历低孕产妇护理表现出缺陷γ-氨基丁酸-A受体结合在杏仁核和5-HTT杂合子无效小鼠表现出降低5-羟色胺营业额在海马和纹状体。引人注目的是，海马中脑源性神经营养因子（BDNF）信使RNA的水平仅在5-HTT杂合缺失小鼠经历不良的母亲护理时升高，这表明海马回路的发育编程可能是5-HTT x环境风险因素的基础。这些发现表明，血清素在改变长-在不同的哺乳动物物种饲养环境的长期行为影响，并确定BDNF作为这种危险因素的分子底物。
Background: A polymorphism in the serotonin transporter (5-HTT) gene modulates the association between adverse early experiences and risk for major depression in adulthood. Although human imaging studies have begun to elucidate the neural circuits involved in the 5-HTT x environment risk factor, a molecular understanding of this phenomenon is lacking. Such an understanding might help to identify novel targets for the diagnosis and therapy of mood disorders. To address this need, we developed a gene-environment screening paradigm in the mouse.Methods: We established a mouse model in which a heterozygous null mutation in 5-HTT moderates the effects of poor maternal care on adult anxiety and depression-related behavior. Biochemical analysis of brains from these animals was performed to identify molecular substrates of the gene, environment, and gene x environment effects.Results: Mice experiencing low maternal care showed deficient gamma-aminobutyric acid-A receptor binding in the amygdala and 5-HTT heterozygous null mice showed decreased serotonin turnover in hippocampus and striatum. Strikingly, levels of brain-derived neurotrophic factor (BDNF) messenger RNA in hippocampus were elevated exclusively in 5-HTT heterozygous null mice experiencing poor maternal care, suggesting that developmental programming of hippocampal circuits might underlie the 5-HTT x environment risk factor.Conclusions: These findings demonstrate that serotonin plays a similar role in modifying the long-term behavioral effects of rearing environment in diverse mammalian species and identifies BDNF as a molecular substrate of this risk factor.