Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits.
Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits.
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DOI：
10.1016/j.neuron.2010.01.019
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发表时间：
2010-02-25
期刊：
影响因子：
16.2
通讯作者：
Nabeshima T
中科院分区：
文献类型：
--
作者：
Niwa M;Kamiya A;Murai R;Kubo K;Gruber AJ;Tomita K;Lu L;Tomisato S;Jaaro-Peled H;Seshadri S;Hiyama H;Huang B;Kohda K;Noda Y;O'Donnell P;Nakajima K;Sawa A;Nabeshima T
成年人的大脑功能和行为受到发育过程中神经元网络形成的影响。成人精神疾病的遗传易感性因素，如神经调节蛋白-1和精神分裂症中断-1（DISC 1），影响成人高级大脑功能，包括认知和信息处理。这些因素在神经发育过程中发挥作用，并可能合作，形成“通路”或“信号体”。在这里，我们报告了通过子宫内基因转移产生动物模型的潜力，以解决一个重要的问题，即早期发育中的非致死性缺陷如何影响出生后的脑成熟和成年后的高脑功能，这些功能在各种精神疾病中受损，如精神分裂症。我们发现，在产前和围产期阶段，特别是在一个谱系的锥体神经元主要在前额叶皮层，短暂敲低DISC 1，导致选择性异常，出生后中皮层多巴胺能成熟和行为异常与青春期后的皮质神经回路紊乱。
Adult brain function and behavior are influenced by neuronal network formation during development. Genetic susceptibility factors for adult psychiatric illnesses, such as Neuregulin-1 and Disrupted-in-Schizophrenia-1 (DISC1), influence adult high brain functions, including cognition and information processing. These factors have roles during neurodevelopment and are likely to cooperate, forming “pathways” or “signalosomes.” Here we report the potential to generate an animal model via in utero gene transfer in order to address an important question of how nonlethal deficits in early development may affect postnatal brain maturation and high brain functions in adulthood, which are impaired in various psychiatric illnesses, such as schizophrenia. We show that transient knockdown of DISC1 in the pre- and peri-natal stages, specifically in a lineage of pyramidal neurons mainly in the prefrontal cortex, leads to selective abnormalities in postnatal mesocortical dopaminergic maturation and behavioral abnormalities associated with disturbed cortical neurocircuitry after puberty.
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