Gene-Environment Interactions for Cortical Development and Schizophrenia

成人大脑的功能和行为在发育过程中受到神经元网络形成的影响。因此，大脑发育障碍可能是成人精神障碍的病理基础，如精神分裂症(SZ)和情绪障碍。与这一概念一致，最近被发现的这些疾病的遗传易感因素，包括精神分裂症-1中断(DISC1)和PCM1，在神经发育过程中发挥作用，并可能相互合作，形成分子“路径”。同时，流行病学研究表明，许多环境因素在神经发育过程中对精神分裂症起作用。因此，约翰霍普金斯大学的P50精神分裂症研究中心致力于解决一个关键问题，即遗传和环境风险因素的组合导致的皮质发育缺陷如何导致与成年期额叶皮质相关的分子、组织和行为缺陷，这与SZ有关。根据我们的初步研究，我们假设DISC1及其相互作用因子是本研究有用的遗传探针。因此，整个中心的四个主要目标如下：1)阐明DISC1和几种不同的相互作用因子(如Karlin-7、PCM1、RPGRIP1L、CRMP2、nNOS和NDEL1)在神经发育过程中调节不同过程的机制，这些过程反过来影响出生后大脑成熟，导致与SZ相关的额叶皮质缺陷和行为异常；2)确定与SZ相关的环境因素(产前免疫激活、补体级联激活和出生后弓形虫感染)如何影响与DISCI相关的遗传脆弱性，最终导致与SZ相关的额叶皮质缺陷和行为异常；3)通过比较临床前模型和人体组织中表达谱的变化，确定SZ和SZ相关内表型可能的生物标志物的分子靶点；4)通过从生物学研究中寻找新的基因测序候选对象，识别与SZ相关的罕见遗传变异和/或与SZ相关的某些内表型。在这个中心，6个项目和2个核心将合作实现这些科学目标。

Adult brain function and behavior are influenced by neuronal network formation during development. Consequently, disturbances of brain development may underlie the pathology of adult mental disorders, such as schizophrenia (SZ) and mood disorders. Consistent with this notion, genetic susceptibility factors for these disorders that have been recently indentified, including Disrupted-in-Schizophrenia-1 (DISC1) and PCM1, have roles during neurodevelopment and are likely to cooperate, forming molecular "pathways." Meanwhile, epidemiological studies have indicated that many environmental factors contribute to schizophrenia during neurodevelopment. P50 Schizophrenia Research Center at Johns Hopkins, therefore, is to address the key question of how defects of cortical development elicited by combinations of genetic and environmental risk factors lead to molecular, histological, and behavioral deficits associated with the frontal cortex in adulthood, which are relevant to SZ. Based on our preliminary studies, we hypothesize that DISC1 and its interactors are useful genetic probes for this study. Accordingly, the four major aims of this entire center are as follows: 1) to clarify the mechanisms whereby several different combinations of DISC1 and interactors (e.g., Karilin-7, PCM1, RPGRIP1L, CRMP2, nNOS, and NDEL1) mediate distinct processes during neurodevelopment, which in turn affect postnatal brain maturation and result in deficits of the frontal cortex and behavioral abnormalities relevant to SZ; 2) to determine how environmental factors relevant to SZ (prenatal immune activation, postnatal activation of complement cascade, and postnatal infection of Toxoplasma Gondii) influence genetic vulnerability associated with DISCI, which eventually contribute to the deficits of the frontal cortex and behavioral abnormalities relevant to SZ; 3) to identify molecular targets for possible biomarkers of SZ and SZ-associated endophenotypes by comparing altered expression profiles in preclinical models and human tissues; 4) to identify rare genetic variants associated with SZ and/or some endophenotypes associated with SZ by pinpointing novel candidates for genetic sequencing from biological studies. In this center, 6 projects and 2 cores will collaborate to achieve these scientific goals.