Inducible expression of mutant DISC1: transgenic mouse model

描述（申请人提供）：Disrupted-In-Schizophrenia-1（DISC 1）基因是研究精神分裂症发病机制的强候选基因的一个例子。在一个患有精神分裂症和其他主要精神疾病的大型苏格兰家系中分离的平衡易位导致DISC 1基因缺失，导致影响神经发育的截短蛋白质产物。遗传小鼠模型将推进我们的理解突变的人DISC 1（hDISC 1）在精神分裂症的发病机制中的作用。在这个探索性的应用中，我们建议我们的新的转基因小鼠模型的诱导前脑限制性表达的突变体和全长hDISC 1蛋白的特点。我们将检验突变体而非全长hDISC 1的表达影响小鼠大脑和行为发育的假设。具体目标1将评估突变体和全长hDISC 1在发育和成年转基因小鼠和对照小鼠中的行为效应。我们将使用一组标准的发育测试来评估小鼠的一般发育，并使用各种行为范式来评估小鼠的感觉-运动门控、情绪反应、学习和记忆以及社会行为。拟议的研究将确定突变hDISC 1转基因小鼠的关键行为异常。具体目标2将使用基于高尔基体染色的定量分析来评估突变体和全长DISC 1对年轻和成年小鼠中的皮质和海马锥体神经元以及海马颗粒细胞的树突乔木的影响。所提出的实验将鉴定突变hDISC 1对转基因小鼠树突成熟的影响。重要性：该提案将表征突变hDISC 1的发育神经行为效应，并将促进未来的机制研究突变DISC 1基因对神经发育的影响与精神分裂症和相关精神障碍的发病机制。该拨款申请提出了对携带突变人类基因Disrupted-In-Schizophrenia 1（DISC 1）的转基因小鼠的大脑和行为发育进行表征，DISC 1与精神分裂症和其他主要精神疾病有关。这项研究将促进我们对突变基因对大脑成熟和与严重精神疾病发病机制相关的行为异常的影响的理解，并将促进这种新的小鼠模型用于临床前治疗试验。

DESCRIPTION (provided by applicant): The Disrupted-In-Schizophrenia-1 (DISC1) gene is an example of a strong candidate gene for studying the pathogenesis of schizophrenia. A balanced translocation that segregates in a large Scottish pedigree with schizophrenia and other major mental illnesses causes a deletion of the DISC1 gene, resulting in a truncated protein product that affects neurodevelopment. Genetic mouse models will advance our understanding of a role of mutant human DISC1 (hDISC1) in the pathogenesis of schizophrenia. In this exploratory application, we propose to characterize our new transgenic mouse model of inducible forebrain-restricted expression of mutant and full-length hDISC1 proteins. We will test the hypothesis that expression of mutant but not full-length hDISC1 affects mouse brain and behavior development. Specific Aim 1 will assess behavioral effects of mutant and full-length hDISC1 in developing and adult transgenic and control mice. We will use a standard battery of developmental tests to assess general mouse development, and various behavioral paradigms to evaluate sensory-motor gating, emotional responses, learning and memory and social behavior in mice. The proposed studies will identify key behavioral abnormalities in mutant hDISC1 transgenic mice. Specific Aim 2 will evaluate effects of mutant and full-length DISC1 on dendrite arbors of cortical and hippocampal pyramidal neurons and hippocampal granule cells in young and adult mice using the Golgi staining-based quantitative analysis. The proposed experiments will identify effects of mutant hDISC1 on the dendritic maturation in transgenic mice. Significance: The proposal will characterize developmental neurobehavioral effects of mutant hDISC1 and will facilitate future mechanistic studies of effects of the mutant DISC1 gene on neurodevelopment with relevance to the pathogenesis of schizophrenia and related mental disorders. The grant application proposes to characterize brain and behavior development in transgenic mice that bear a mutant human gene, Disrupted-In-Schizophrenia 1 (DISC1), which has been associated with schizophrenia and other major psychiatric disorders. The study will advance our understanding of effects of the mutant gene on brain maturation and behavioral abnormalities relevant to the pathogenesis of serious psychiatric diseases and will facilitate use of this new mouse model for pre-clinical therapeutic trials.