Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders.
Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders.
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DOI：
10.1038/mp.2009.144
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发表时间：
2011-03
影响因子：
11
通讯作者：
中科院分区：
文献类型：
--
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强有力的遗传学证据表明，DISC1基因的突变和多态性是精神分裂症和心境障碍的危险因素。最近的研究表明，DISC1在脑发育和成人脑功能中具有重要功能。我们先前已经描述了一个转基因小鼠模型的诱导表达的突变型人类DISC1（hDISC1），在显性负性的方式来诱导显着的神经行为异常。为了深入了解DISC1在神经发育各个阶段的作用，我们检测了突变hDISC1在（1）仅产前期，（2）仅产后期，或（3）两个时期表达的影响。所有时期的表达同样导致皮质多巴胺（DA）水平下降，皮质中的小清蛋白阳性神经元减少。出生前和出生后的表达相结合，产生了增加的侵略性和增强的反应，精神兴奋剂在雄性小鼠沿着与增加的线性密度的树突棘的海马齿状回的神经元，内源性DISC1和LIS1的水平较低。产前表达只导致较小的脑体积，而选择性的产后表达引起雄性小鼠的社会行为减少和雌性小鼠的抑郁样反应，以及雌性小鼠的侧脑室扩大和海马中DA含量降低，内源性DISC1水平降低。我们的数据表明，突变hDISC1神经行为表型发挥不同的影响，这取决于蛋白质表达的发展阶段。在突变型DISC1小鼠中检测到的多种多样的异常让人想起主要精神疾病的发现。
Strong genetic evidence implicates mutations and polymorphisms in the gene Disrupted-In-Schizophrenia-1 (DISC1) as risk factors for both schizophrenia and mood disorders. Recent studies have shown that DISC1 has important functions in both brain development and adult brain function. We have described earlier a transgenic mouse model of inducible expression of mutant human DISC1 (hDISC1) that acts in a dominant-negative manner to induce the marked neurobehavioral abnormalities. To gain insight into the roles of DISC1 at various stages of neurodevelopment, we examined the effects of mutant hDISC1 expressed during (1) only prenatal period, (2) only postnatal period, or (3) both periods. All periods of expression similarly led to decreased levels of cortical dopamine (DA) and fewer parvalbumin-positive neurons in the cortex. Combined prenatal and postnatal expression produced increased aggression and enhanced response to psychostimulants in male mice along with increased linear density of dendritic spines on neurons of the dentate gyrus of the hippocampus, and lower levels of endogenous DISC1 and LIS1. Prenatal expression only resulted in smaller brain volume, whereas selective postnatal expression gave rise to decreased social behavior in male mice and depression-like responses in female mice as well as enlarged lateral ventricles and decreased DA content in the hippocampus of female mice, and decreased level of endogenous DISC1. Our data show that mutant hDISC1 exerts differential effects on neurobehavioral phenotypes, depending on the stage of development at which the protein is expressed. The multiple and diverse abnormalities detected in mutant DISC1 mice are reminiscent of findings in major mental diseases.
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影响因子：
11
作者：
Camargo, L. M.;Collura, V.;Brandon, N. J.
通讯作者：
Brandon, N. J.
影响因子：
2.7
作者：
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通讯作者：
Pletnikov, Mikhail V.
影响因子：
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作者：
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通讯作者：
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影响因子：
3.1
作者：
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通讯作者：
Furey, Maura L.
影响因子：
64.5
作者：
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通讯作者：
Song, Hongjun