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Analysis of the molecular bases on the stress sensitivity and abnormal emotional function in the developmental process of Fyn-deficient mice.

Fyn缺陷小鼠发育过程中应激敏感性和情绪功能异常的分子基础分析

基本信息

批准号：
17591130
负责人：
YUASA Shigeki
金额：
$ 2.24万
依托单位：
National Center of Neurology and Psychiatry
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

The molecular mechanisms of defective emotional functions and neural development as found in the Fyn-tyrosine-kinase-deficient mice were investigated as a model for developmental disorders based on the distinct molecular defect. The defective neocorticogenesis, abnormal response to anti-psychotics and the defective function of amygdala were mainly analysed as well as the developmental mechanisms of amygdala.1. Functional analysis of Fyn in the neocorticogenesis: the formation of the layers II-III was demonstrated to be defective in the Fyn deficiency, and the expression of Fyn was made clear to well correspond to the stage of generation and migration of the layer II-III neurons. The transfer of fyn gene into the neuroepithelium of the neocortical primordium of Fyn deficiency by in utero electroporation at the stage of neurogenesis of the layers II-III partially rescued the defective migration and stratification of the cortical neurons. The involvement of focal adhesion kinase in the Fy … More n-signal transduction pathway was also demonstrated in the process of neocorticogenesis.2. Functional analysis of Fyn in the striatum: Fyn deficiency displays abnormal response to the administration of anti-psychotics such as haloperidol, a dopamine D2 receptor antagonist. In vivo and in vitro analysis revealed that haloperidol activates Fyn, and activated Fyn stimulates the tyrosine-phosphorylation of NMDA receptor NR2B subunit, subsequently enhancing the channel activity of NMDA receptor and the excitability of the striatal neurons.3. Functional analysis of Fyn in the amygdala: since abnormal response to NMDA administration is found in the amygdala of Fyn deficiency, comprehensive analysis on the difference of gene expression in the amygdala between the control and Fyn deficiency was carried out following NMDA administration. Based on the laser capture micro-dissection and cDNA array analysis revealed that Swim6 gene was significantly down regulated in the amygdalar central nucleus of Fyn deficiency. I t was suggested that Swim6 is functionally coupled to MAPK signal transduction pathway. Less

研究了Fyn酪氨酸激酶缺陷小鼠中发现的情感功能和神经发育缺陷的分子机制，作为基于不同分子缺陷的发育障碍模型。主要分析了新皮质发育缺陷、抗精神病药物反应异常和杏仁核功能缺陷等，并对杏仁核的发育机制进行了探讨. Fyn在新皮质发生中的功能分析：Fyn缺乏时II-III层的形成是有缺陷的，Fyn的表达清楚地对应于II-III层神经元的产生和迁移阶段。通过子宫内电穿孔将Fyn基因转移到Fyn缺陷的新皮层原基的神经上皮中，在神经发生的第II-III层的阶段，部分挽救了皮层神经元的缺陷性迁移和分层。粘着斑激酶参与Fy ...更多信息 N-信号转导通路也参与了皮质激素的生成过程.纹状体中Fyn的功能分析：Fyn缺乏显示对抗精神病药物如氟哌啶醇（一种多巴胺D2受体拮抗剂）的异常反应。体内外实验结果表明，氟哌啶醇激活Fyn，激活的Fyn刺激NMDA受体NR 2B亚基酪氨酸磷酸化，从而增强NMDA受体通道活性和纹状体神经元兴奋性. Fyn在杏仁核中的功能分析：由于在Fyn缺乏的杏仁核中发现了对NMDA给药的异常反应，因此对NMDA给药后对照和Fyn缺乏的杏仁核中基因表达的差异进行了综合分析。基于激光捕获显微切割和cDNA微阵列分析，发现Fyn缺乏症大鼠杏仁中央核中Swim 6基因表达显著下调。提示Swim 6在功能上与MAPK信号转导通路偶联。少