Prospective Studies of the Pathogenesis of Schizophrenia

描述（由申请人提供）：拟建的UNC-CCNMD是一个多学科组织，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，由Jeffrey Lieberman博士领导，Jeffrey Lieberman博士是一位研究精神分裂症的自然历史和神经生物学的研究精神病学家。该中心由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介导疾病易感性和表达的神经发育机制中的潜在病理。虽然精神分裂症被认为是一种遗传介导的神经发育障碍，但很少有临床研究证明大脑结构和功能的早期异常，也没有确定风险基因的明确数据。此外，研究既没有确定因果神经生物学机制，也没有将它们与疾病的自然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易感性和表达的致病过程的目标。我们假设精神分裂症的易感性和表达源于丘脑-边缘-皮层回路（TLC）连接障碍的后果，这是由于皮质GABA神经元和它们调节局部皮质回路的细胞元件的分化被破坏。GABA中间神经元的这些发育异常赋予脆弱性，当青春期个体发生和环境事件作用时，会触发TLC回路功能障碍和疾病表达。2个临床和2个临床前项目将解决这一假设。临床项目是前瞻性的纵向研究，研究对象是两个独特的精神分裂症发展高危人群：有前驱症状的青少年和年轻人（项目1）和父母患有精神分裂症的胎儿和新生儿（项目2）。临床前项目包括研究皮层GABA神经元树突和轴突发育的细胞生物学机制，以及该过程中疑似易感基因突变的后果（项目3）。因此，UNC-CCNMD的特点在于其关注导致疾病发病的行为和神经生物学机制，而不是一旦诊断出疾病就出现的临床或病理相关性。我们的研究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，该中心不仅将推进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.