PTSD-like phenotype of mice lacking GIT2

缺乏 GIT2 的小鼠的 PTSD 样表型

• 批准号: 8055248
• 负责人: Richard T Premont
• 金额: $ 22.64万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-28 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055248
• 关键词: PTSD; like; phenotype; mice; lacking

DESCRIPTION (provided by applicant): The GIT1 and GIT2 proteins are GTPase-activating proteins for the Arf small GTP-binding proteins. Together with the alpha-PIX and beta-PIX proteins (themselves guanine nucleotide exchange factors for Rho family small GTP-binding proteins), GIT proteins form an oligomeric signaling scaffolding complex. GIT/PIX complexes have been shown to bind to a variety of protein kinases as well as other signaling proteins, and to localize to several distinct cellular locations through interaction with specific partners. Although GIT and PIX proteins have been implicated in a wide variety of cellular processes, including vesicle trafficking, focal adhesion dynamics and synapse formation, little is known of the physiological functions of these proteins. To address this, we created GIT1-KO and GIT2-KO knockout mouse lines, with inactivated GIT1 or GIT2 genes, and subjected them to unbiased behavioral screens. One striking difference we noted between GIT1-KO and GIT2-KO mice is that GIT1-KO mice are scarcely affected by fearful stimuli, while GIT2-KO mice greatly over- respond to invoked fear. Since we have previously shown that both GIT1 and GIT2 function as Arf GAPs, form similar GIT/PIX complexes, and are widely expressed throughout the brain, the mechanistic reasons for such dissimilar behavioral effects remain unknown. The main hypothesis underlying this study is that GIT2 is an important regulator of learned fear behavior, and lack of GIT2 predisposes mice to a syndrome with high similarity to post-traumatic stress disorder (PTSD). The major aims of this project are to define the effect of SSRI treatment on fear behavior in GIT2-KO mice, to define the hormonal/neurochemical responses to stress in GIT2-KO mice, and to identify cellular signaling mechanisms through which GIT2 affects fear responses in mice. A more complete understanding of altered fear responses in GIT2-KO mice will allow validation of GIT2- KO mice as an animal model for human PTSD. PUBLIC HEALTH RELEVANCE: The genetic and/or neurochemical bases for the inability to overcome trauma-induced fear in PTSD remains mostly unknown, and treatment options are limited. Mice deficient in the GIT2 protein overrespond to conditioned fear in a manner reminiscent of human PTSD. A deeper understanding of how GIT2 functions to regulate anxiety and the extinction of fear may provide insights into human fear and anxiety disorders such as PTSD.

描述（由申请方提供）：GIT 1和GIT 2蛋白是Arf小GTP结合蛋白的GTP酶激活蛋白。GIT蛋白与α-PIX和β-PIX蛋白（本身是Rho家族小GTP结合蛋白的鸟嘌呤核苷酸交换因子）一起形成寡聚信号支架复合物。GIT/PIX复合物已被证明与多种蛋白激酶以及其他信号蛋白结合，并通过与特定伴侣的相互作用定位于几个不同的细胞位置。虽然GIT和PIX蛋白已经涉及到各种各样的细胞过程，包括囊泡运输，粘着斑动力学和突触形成，这些蛋白的生理功能知之甚少。为了解决这个问题，我们创建了GIT 1-KO和GIT 2-KO敲除小鼠品系，具有失活的GIT 1或GIT 2基因，并使它们进行无偏的行为筛选。我们注意到GIT 1-KO和GIT 2-KO小鼠之间的一个显著差异是GIT 1-KO小鼠几乎不受可怕刺激的影响，而GIT 2-KO小鼠对引起的恐惧反应过度。由于我们之前已经表明GIT 1和GIT 2都具有Arf GAP的功能，形成类似的GIT/PIX复合物，并在整个大脑中广泛表达，因此这种不同行为效应的机制原因仍然未知。这项研究的主要假设是，GIT 2是习得性恐惧行为的重要调节因子，缺乏GIT 2使小鼠易患与创伤后应激障碍（PTSD）高度相似的综合征。该项目的主要目的是确定SSRI治疗对GIT 2-KO小鼠恐惧行为的影响，确定GIT 2-KO小鼠对应激的激素/神经化学反应，并确定GIT 2影响小鼠恐惧反应的细胞信号传导机制。对GIT 2-KO小鼠中改变的恐惧反应的更完整的理解将允许验证GIT 2- KO小鼠作为人类PTSD的动物模型。 公共卫生关系：在PTSD中，无法克服创伤引起的恐惧的遗传和/或神经化学基础仍然是未知的，治疗选择也很有限。缺乏GIT 2蛋白的小鼠对条件性恐惧的反应过度，这让人联想到人类的PTSD。更深入地了解GIT 2如何调节焦虑和消除恐惧，可能会为人类恐惧和焦虑症（如PTSD）提供见解。