Prospective Studies of the Pathogenesis of Schizophrenia

20多年来，精神分裂症一直被认为是一种神经发育障碍，但导致精神分裂症核心皮质病理的具体神经发育机制仍不清楚。精神分裂症的遗传易感性已被认识到近100年；然而，遗传风险与特定神经发育机制之间的关系尚不清楚。北卡罗来纳大学孔特中心的《精神分裂症发病机制的前瞻性研究》将回答三个关键问题，以努力综合神经发育机制、遗传易损性和 精神分裂症的发展：1)在精神分裂症的危险儿童中，在什么发展阶段会出现皮质病理？2)皮质病理如何有助于精神分裂症认知缺陷和临床症状的发育表现？3)一组明显不同的发育机制和风险基因是否会导致精神分裂症中常见的皮质病理？北卡罗来纳大学孔蒂中心这次竞争性续签的中心假设是 精神分裂症的遗传脆弱性可能会损害早期皮质发育的多种机制，其中每一种机制最终都会导致皮质回路异常、神经认知缺陷和精神分裂症的临床症状。北卡罗来纳大学孔特中心的临床项目将使用最先进的多模式成像和图像分析来研究精神分裂症遗传高危儿童在皮质突触发育的两个关键时期：早期突触形成(项目1)和青春期突触重塑和消除(项目2)的皮质结构和功能的发展。同时，临床前项目将评估三组具有良好特征的风险基因的小鼠模型中的皮质前体增殖、神经元迁移和突触形成：NCAM(项目3)、22q11基因(项目4)和NeuRegin/Erb4(项目5)。这些项目将得到3个核心的支持--1)行政，2)神经影像分析，3)生物统计学和数据管理，目前的COTE中心的每个部分。我们的目标是综合临床特征 遗传脆弱儿童的皮质结构和功能异常，详细评估携带特定风险基因突变的小鼠皮质异常神经发育机制。北卡罗来纳大学孔特中心提供了一套集中、定向和集成的临床和基础项目和实验，这些项目和实验将确定皮质发育的基本机制，这些机制是被认为是精神分裂症基础的神经发育发病机制的基础。

Schizophrenia has been considered a neurodevelopmental disorder for over two decades, yet the specific neurodevelopmental mechanisms that contribute to the cortical pathology central to schizophrenia remain unknown. Genetic vulnerability for schizophrenia has been recognized for almost 100 years; nevertheless, the relationship between genetic risk and specific neurodevelopmental mechanisms is unclear. The UNC Conte Center, "Prospective Studies of the Pathogenesis of Schizophrenia," will answer three key questions in an effort to synthesize neurodevelopmental mechanisms, genetic vulnerability, and the development of schizophrenia: 1) At what stage of development does cortical pathology arise in children at risk for schizophrenia? 2) How does cortical pathology contribute to the developmental expression of cognitive deficits and clinical symptoms of schizophrenia? and 3) Can an apparently diverse set of developmental mechanisms and risk genes give rise to a common cortical pathology implicated in schizophrenia? The central hypothesis of this competitive renewal of the UNC Conte Center is that genetic vulnerability for schizophrenia can compromise multiple mechanisms of early cortical development, each of which can ultimately contribute to aberrant cortical circuitry, neurocognitive deficits, and the clinical symptoms of schizophrenia. The clinical projects of the UNC Conte Center will use state-of-the-art multimodal imaging and image analysis to study the development of cortical structure and function in children at genetic high risk for schizophrenia during the two critical periods of cortical synaptic development: synaptic elaboration during early childhood (Project 1), and synaptic remodeling and elimination during adolescence (Project 2). In parallel, the preclinical projects will assess cortical precursor proliferation, neuronal migration and synapse formation in mouse models of three well characterized sets of risk genes: NCAM (Project 3); 22q11 genes (Project 4), and Neuregulin/Erb4 (Project 5). These projects will be supported by 3 cores - 1) Administrative, 2) Neuroimage Analysis 3) Biostatistics and Data Management; each part of the current Conte Center. Our goal is to synthesize clinical characterization of abnormal cortical structure and function in genetically vulnerable children with detailed assessment of abnormal neurodevelopmental mechanisms in the cortex of mice carrying mutations in specific risk genes. UNC Conte Center offers a focused, directed, and integrated set of clinical and basic projects and experiments that will identify fundamental mechanisms of cortical development that are the basis of the neurodevelopmental pathogenesis that is thought to underlie schizophrenia.