Prospective Studies of the Pathogenesis of Schizophrenia

描述(由申请人提供)：建议的北卡罗来纳大学-CCNMD是一个由来自北卡罗来纳大学、杜克大学、哈佛大学和华盛顿大学的科学家组成的多学科组织，由杰弗里·利伯曼博士指导，他是一名研究精神病学家，其职业生涯专注于精神分裂症的自然历史和神经生物学。拟建中心由3个项目和2个核心组成。UNC-CCNMD的总体目标是确定精神分裂症发病的预测因素，以及调节疾病脆弱性和表达的神经发育机制中的潜在病理。尽管精神分裂症被认为是一种基因介导的神经发育障碍，但很少有临床研究表明早期大脑结构和功能异常，也没有确定风险基因的明确数据。此外，研究既没有确定致病的神经生物学机制，也没有将它们与疾病的自然病史和临床发病联系起来。精神分裂症的症状主要出现在15至25岁之间。因此，青春期的神经发育事件可能是导致疾病脆弱性和表达的致病过程的靶点。我们假设，精神分裂症的易感性和表达来自丘脑-边缘-皮质回路(TLC)的连接障碍的后果，这是由于皮质GABA神经元及其调节局部皮质回路的细胞元件的分化中断所致。GABA中间神经元的这些发育异常提供了脆弱性，当在青春期受到个体发育和环境事件的作用时，会引发TLC回路的功能障碍和疾病表达。2个临床项目和2个临床前项目将解决这一假设。临床项目是对两个独特的高危人群进行的前瞻性纵向研究，这些人群丰富了精神分裂症的发展：具有前驱症状的青少年和年轻人(项目1)和患有精神分裂症的父母的胎儿和新生儿(项目2)。临床前项目包括研究皮质GABA神经元树突和轴突发育的细胞生物学机制，以及可疑易损性基因突变对这一过程的影响(项目3)。因此，UNC-CCNMD的不同之处在于它专注于导致疾病发生的行为和神经生物学机制，而不是一旦诊断出来就出现的临床或病理关联。我们的结果将有助于在精神分裂症的临床恶化之前确定诊断方法和新的干预目标。通过这种方式，该中心不仅将推动精神分裂症的神经科学，而且将对精神分裂症患者和有精神分裂症风险的人的临床护理和治疗产生直接影响。

DESCRIPTION (provided by applicant): The proposed UNC-CCNMD is a multidisciplinary organization comprised of scientists from the University of North Carolina, Duke, Harvard and the University of Washington directed by Dr. Jeffrey Lieberman, a research psychiatrist whose career has focused on the natural history and neurobiology of schizophrenia. The proposed center consists of 3 projects and 2 cores. The general aim of the UNC-CCNMD is to identify predictors of onset of schizophrenia and the underlying pathology in neurodevelopmental mechanisms that mediate disease vulnerability and expression. Although schizophrenia is believed to be a genetically mediated neurodevelopmental disorder, there is little clinical research demonstrating early abnormalities in brain structure and function and no definitive data identifying risk genes. Moreover, studies have neither identified causal neurobiologic mechanisms nor linked them to the natural history and clinical onset of the disease. Symptoms of schizophrenia emerge predominantly between the ages of 15 and 25 years. Thus, neurodevelopmental events in adolescence may be targets of pathogenic processes that contribute to disease vulnerability and expression. We hypothesize that schizophrenia vulnerability and expression arises from the consequences of dysconnectivity in thalamo-limbic-cortical circuits (TLC) due to disrupted differentiation of cortical GABA neurons and the cellular elements with which they modulate local cortical circuitry. These developmental anomalies in GABA interneurons confer vulnerability that when acted on by ontogenetic and environmental events during adolescence trigger dysfunction in TLC circuits and disease expression. 2 clinical and 2 preclinical projects will address this hypothesis. The clinical projects are prospective longitudinal studies of 2 unique high-risk populations enriched for the development of schizophrenia: adolescents and young adults with prodromal signs (Project 1) and fetuses and neonates of parents with schizophrenia (Project 2). The preclinical project involves a study of cell biological mechanisms of dendritic and axonal development in cortical GABA neurons as well as consequences of mutations in suspected vulnerability genes on this process (Project 3). Thus, the UNC-CCNMD is distinguished by its focus on behavioral and neurobiologic mechanisms that lead to the onset of the disease rather than clinical or pathologic correlates that emerge once it has been diagnosed. Our results will contribute to the identification of diagnostic methods and novel targets for intervention prior to the clinical deterioration that characterizes schizophrenia. In this way the Center will not only advance the neuroscience of schizophrenia but will have an immediate impact on the clinical care and treatment of persons who have and are at risk for schizophrenia.