Elucidating the Effect of Disc 1 on Neurodevelopment and Synaptic Transmission

阐明 Disc 1 对神经发育和突触传递的影响

• 批准号: 8289152
• 负责人: JOSEPH A GOGOS
• 金额: $ 39.79万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289152
• 关键词: Acute; Adult; Alleles; Area; Balanced Chromosomal Translocation; Behavior; Behavioral; Biochemical; Biological; Biological Markers; Biology; Brain; Characteristics; Chemicals; Cognitive; Communication; Complex; Cyclic AMP; Data; Defect; Development; Disease; Functional disorder; Generations; Genes; Genetic; Genetic Transcription; Goals; Grant; Growth; Hippocampus (Brain); Human; Impaired cognition; Knock-in Mouse; Knowledge; Lead; Left; Lesion; Link; Mediating; Medical; Mental disorders; Modeling; Mood Disorders; Mus; Mutagenesis; Mutant Strains Mice; Mutation; Nature; Neonatal; Neurobiology; Neurons; Pathogenesis; Pathway interactions; Patients; Pattern; Penetrance; Predisposition; Prefrontal Cortex; Public Health; RNA Interference; Rare Diseases; Research; Risk; Schizophrenia; Science; Short-Term Memory; Structure; Susceptibility Gene; Synaptic Transmission; Synaptic plasticity; System; Temporal Lobe; Testing; Work; adult neurogenesis; analytical tool; axonal pathfinding; cognitive function; dentate gyrus; design; disability; genetic pedigree; improved; mortality; mossy fiber; mouse model; neural circuit; neurobiological mechanism; neurodevelopment; neurophysiology; novel; novel strategies; overexpression; relating to nervous system; research study

DESCRIPTION (provided by applicant): The identification of rare mutations that result in predisposition to SCZ with relatively high penetrance has led to the development of mouse models of proven etiologic relevance. DISC1 is a susceptibility gene identified through a rare genetic lesion, a balanced chromosomal translocation segregating with SCZ and mood disorders in a large pedigree. We used a disease-focused knock-in approach to introduce a truncating lesion in the murine Disc1 orthologue designed to model the effects of this translocation. During the first round of this grant we showed that Disc1 mutant mice display specific and robust deficiencies in spatial working memory tests. We also uncovered widespread cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal pathfinding and are accompanied by changes in neural activity and short-term plasticity. We also showed that dysregulation of cAMP levels contributes to the structural connectivity deficits. Finally we provided evidence that mutant mice have altered functional connectivity of prefrontal areas with temporal lobe structures. Building on these findings, here we propose to complete our analysis on the effect of the Disc1 mutation on hippocampus, extend our structural and functional analysis to prefrontal cortex and finally analyze the effect of the modeled mutation on the communication between these two areas. In addition to our previous results from Disc1 mutant mice our proposed research is dictated by parallel analysis of other models of rare mutations, which affords the opportunity to compare results, identify key common pathways and enable development of a comprehensive and integrative model of schizophrenia pathogenesis and pathophysiology. This knowledge will facilitate discovery of novel treatments and biomarkers. PUBLIC HEALTH RELEVANCE: Schizophrenia is a common and complex psychiatric disorder with a strong genetic component. This proposal is inherently translational in nature, aimed at identifying specific patterns of abnormal brain structure and function caused by schizophrenia predisposing genes. Identifying such patterns would facilitate novel approaches to therapies aimed at reversing the underlying pathophysiology and restoring normal function.

描述(由申请人提供)：对导致SCZ易感性的罕见突变的鉴定导致了具有已证实的病因学相关性的小鼠模型的开发。DISC1是一种易感基因，通过一种罕见的遗传损伤、平衡的染色体易位与SCZ和心境障碍分离出来，在一个大的家系中被发现。我们使用了一种专注于疾病的敲入方法，在小鼠DISC1同源基因中引入了截断病变，旨在模拟这种易位的影响。在这项资助的第一轮中，我们发现DISC1突变小鼠在空间工作记忆测试中表现出特殊而强大的缺陷。我们还发现，在新生和成年神经发生过程中，齿状回中广泛存在细胞结构变化，包括轴突寻路错误，并伴随着神经活动和短期可塑性的变化。我们还表明，cAMP水平的失调导致了结构性连接缺陷。最后，我们提供了突变小鼠改变前额叶区域与颞叶结构的功能连通性的证据。在基础上建设 在这里，我们建议完成对DISC1突变对海马区影响的分析，并将我们的结构和功能分析扩展到前额叶皮质，最后分析模型突变对这两个区域之间通讯的影响。除了我们之前对DISC1突变小鼠的结果外，我们建议的研究还取决于对其他罕见突变模型的平行分析，这提供了比较结果、确定关键共同途径并能够开发精神分裂症发病机制和病理生理学的全面和综合模型的机会。这些知识将有助于发现新的治疗方法和生物标记物。 公共卫生相关性：精神分裂症是一种常见而复杂的精神疾病，具有很强的遗传成分。这一建议本质上是翻译的，旨在确定精神分裂症易感基因导致的大脑结构和功能异常的特定模式。识别这种模式将促进旨在逆转潜在病理生理学和恢复正常功能的治疗的新方法。