Generation and Characterization of GAD67-ErbB4 Transgenic Mice

GAD67-ErbB4 转基因小鼠的产生和表征

• 批准号: 8051047
• 负责人: Lin Mei
• 金额: $ 22.05万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051047
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Aminobutyric Acids; Area; Attentional deficit; Autopsy; Bacterial Artificial Chromosomes; Behavioral; Biological; Brain; Brain region; Cerebrospinal Fluid; Chemicals; Clinic; Complex; Defect; Delusions; Development; Disease; EGF gene; Epidermal Growth Factor; ErbB4 gene; Generations; Genetic Recombination; Genotype; Glutamate Decarboxylase; Hallucinations; Hearing; Human; Image Analysis; Internal Ribosome Entry Site; Interneurons; Investigation; Long-Term Potentiation; Memory impairment; Mental Depression; Mental disorders; Modeling; Molecular; Mus; Mutation; Neck; Neuraxis; Neuregulin 1; Neurons; Output; Pathway interactions; Patients; Phase; Phenotype; Phosphatidylinositols; Phosphotransferases; Physiologic pulse; Physiological; Prefrontal Cortex; Protein Isoforms; Reagent; Regulation; Reporting; Rodent; Rodent Model; Schizophrenia; Short-Term Memory; Shuttle Vectors; Signal Transduction; Single Nucleotide Polymorphism; Smell Perception; Susceptibility Gene; Symptoms; TNF-alpha converting enzyme; Testing; Transgenes; Transgenic Mice; Transgenic Model; Vision; gain of function; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vivo; insight; neurotransmission; novel therapeutic intervention; overexpression; postsynaptic; prepulse inhibition; receptor; research study; success; transgene expression; transmission process; vector; vesicular GABA transporter

DESCRIPTION (provided by applicant): Schizophrenia is a complex psychiatric disorder that is extremely difficult to model in rodents because of structural difference between human and mouse brains, lack of clear pathological hallmarks of the disorder, and inability of mice to demonstrate human psychiatric phenotypes such as delusion, hallucination, or depression. This argues for models to create a piecemeal of different components in schizophrenia with discrete endpoints in behavioral, physiological, and molecular analyses. Such an approach has proved useful in generating and analyzing schizophrenic rodent models. Both neuregulin-1 (NRG1) and its receptor ErbB4 are susceptibility genes of schizophrenia. Recent evidence suggests a gain-of-function of NRG1 signaling in the prefrontal cortex (PFC) in schizophrenic patients. Increased expression of type I NRG1 and CYT-1/JMa ErbB4 have been reported in the PFC of patients with schizophrenia. Moreover, NRG1 signaling was found to be enhanced in the same area of postmortem brains from schizophrenic patients. Despite of the clinic evidence for NRG1/ErbB4 gain-of-function in schizophrenia, there has not been such a rodent model. This appears to be a bottle neck for further in vivo studies of cellular, molecular as well as behavioral deficits and pathological mechanisms of NRG1 and ErbB4 mutations. In preliminary studies, we demonstrated that NRG1, via ErbB4, regulates activity-dependent GABA release in the PFC. Therefore, we propose to generate and characterize GAD67-ErbB4 transgenic mice overexpressing human CYT-1/JMa ErbB4. The R21 Phase has three Specific Aims: 1) Generation of GAD67-ErbB4 transgenic mice; 2) Determine whether NRG1 signaling and induced activity-dependent GABA release are increased in GAD67-ErbB4 transgenic mice; and 3) Determine whether NRG1 regulation of GABA transmission is increased in GAD67-ErbB4 transgenic mice. The R33 Phase has two Specific Aims: 1) Determine whether NRG1 suppression of pyramidal neuron activity is up-regulated in GAD67-ErbB4 mice and 2) Determine whether GAD67-ErbB4 transgenic mice can model working memory deficits, positive and negative symptoms and attentional deficits in schizophrenia. It is our hope that the gain-of- function model of ErbB4 signaling will provide critical insight into pathogenic mechanisms and pathways of NRG1 and ErbB4, two important susceptibility genes. The transgenic mice might be useful for testing chemicals and biological reagents that could facilitate the development of novel therapeutic interventions of schizophrenia. Moreover, successful generation and characterization of GAD67-ErbB4 transgenic mice will offer a proof of principle for other NRG1 gain-of-function models in different regions of the brain. This is a proposal to generate GAD67-ErbB4 transgenic mice over-expressing human CYT-1/JMa ErbB4 to model neurotransmission and behavioral deficits in schizophrenia. The gain-of-function model of ErbB4 signaling will provide critical insight into pathogenic mechanisms and pathways of NRG1 and ErbB4, two important susceptibility genes of schizophrenia.

描述（由申请人提供）：精神分裂症是一种复杂的精神疾病，由于人类和小鼠大脑的结构差异，缺乏明确的病理特征，并且小鼠无法证明人类精神表型，如妄想，幻觉或抑郁，因此极难在啮齿动物中建立模型。这表明，在行为、生理和分子分析中，应该建立一些模型，将精神分裂症的不同组成部分与离散的端点结合起来。这种方法在产生和分析精神分裂症啮齿动物模型中被证明是有用的。神经调节蛋白-1 （NRG1）及其受体ErbB4都是精神分裂症的易感基因。最近的证据表明，在精神分裂症患者的前额皮质（PFC） NRG1信号的功能获得。据报道，在精神分裂症患者的PFC中，I型NRG1和CYT-1/JMa ErbB4表达增加。此外，NRG1信号在精神分裂症患者死后大脑的同一区域被发现增强。尽管NRG1/ErbB4在精神分裂症中有功能获得的临床证据，但还没有这样的啮齿动物模型。这似乎是NRG1和ErbB4突变的细胞、分子、行为缺陷和病理机制的进一步体内研究的瓶颈。在前期研究中，我们证实NRG1通过ErbB4调控pfc中活性依赖性GABA的释放，因此，我们提出构建并表征过表达人CYT-1/JMa ErbB4的GAD67-ErbB4转基因小鼠。R21期有三个特定目的：1)产生GAD67-ErbB4转基因小鼠；2) GAD67-ErbB4转基因小鼠NRG1信号和诱导活性依赖性GABA释放是否增加；3)确定在GAD67-ErbB4转基因小鼠中，NRG1对GABA传递的调控是否增加。R33期有两个特定目的：1)确定GAD67-ErbB4小鼠中NRG1对锥体神经元活性的抑制是否上调；2)确定GAD67-ErbB4转基因小鼠是否可以模拟精神分裂症的工作记忆缺陷、阳性和阴性症状以及注意缺陷。我们希望ErbB4信号的功能增益模型将为NRG1和ErbB4这两个重要的易感基因的致病机制和途径提供重要的见解。这些转基因小鼠可能有助于测试化学物质和生物试剂，从而促进精神分裂症新治疗干预措施的发展。此外，GAD67-ErbB4转基因小鼠的成功产生和表征将为其他NRG1在大脑不同区域的功能获得模型提供原理证明。这是一个建立GAD67-ErbB4转基因小鼠过表达人CYT-1/JMa ErbB4来模拟精神分裂症的神经传递和行为缺陷的建议。ErbB4信号的功能获得模型将为了解NRG1和ErbB4这两个重要的精神分裂症易感基因的致病机制和途径提供重要的见解。