Inducible expression of mutant DISC1: transgenic mouse model

描述（由申请人提供）：DISC1基因是研究精神分裂症发病机制的一个强有力的候选基因。在一个患有精神分裂症和其他主要精神疾病的苏格兰血统中，一个平衡的易位分离导致DISC1基因缺失，导致影响神经发育的蛋白质产物被截断。遗传小鼠模型将促进我们对突变的人类DISC1 （hDISC1）在精神分裂症发病机制中的作用的理解。在这个探索性的应用中，我们提出表征我们的新的转基因小鼠模型，诱导前脑限制突变和全长hDISC1蛋白的表达。我们将验证突变体而非全长hDISC1的表达影响小鼠大脑和行为发育的假设。特异性目的1将评估突变体和全长hDISC1在发育和成年转基因小鼠和对照小鼠中的行为影响。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hDISC1转基因小鼠的关键行为异常。特异性目的2将使用基于高尔基染色的定量分析评估突变体和全长DISC1对幼龄和成年小鼠皮质和海马锥体神经元树突和海马颗粒细胞的影响。本实验将确定突变体hDISC1对转基因小鼠树突成熟的影响。意义：该提案将表征突变体hDISC1的发育神经行为影响，并将促进未来突变体DISC1基因对神经发育影响的机制研究，与精神分裂症及相关精神障碍的发病机制相关。该资助申请提议对携带突变人类基因“精神分裂症紊乱基因1”（DISC1）的转基因小鼠的大脑和行为发育进行表征，该基因与精神分裂症和其他主要精神疾病有关。该研究将促进我们对与严重精神疾病发病机制相关的突变基因对脑成熟和行为异常的影响的理解，并将促进将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.