Mechanisms underlying astroglial influence on neuronal function in schizophrenia

摘要/项目摘要 全世界约有2100万人患有精神分裂症，美国约有350万人患有精神分裂症，这意味着沉重的社会经济负担。尽管如此，目前还没有有效的治疗精神分裂症的方法，这主要归因于其发病机制不明和病理异质性。越来越多的证据表明，神经胶质基因与精神分裂症的易感性很高。由于星形胶质细胞主要参与神经网络的发育组织、支持和神经传递，星形胶质细胞的病理被认为是精神分裂症中广泛记录的神经元异常特征的原因，如神经元发育和连接中断，突触传递异常。在最近的研究中，戈德曼和他的同事利用来自精神分裂症患者的神经胶质祖细胞设计了人脑胶质嵌合体小鼠。这些嵌合小鼠表现出伴随疾病的星形胶质细胞和精神分裂症的行为表型，而抑制易感基因显著改善了疾病表型。这些观察进一步支持了精神分裂症的发生和病理的星形胶质基础。然而，功能障碍的星形胶质细胞对精神分裂症患者异常神经元发育和功能障碍的确切影响仍不确定。因此，在这里，我们将利用精神分裂症(SCZ)-胶质细胞嵌合体来研究精神分裂症(SCZ)来源的星形胶质细胞对神经元网络发育和功能的影响。为此，我将使用系列电子显微镜来描述星形胶质细胞-神经元突触相互作用和合胞网络超微结构的变化。我还将利用质谱分析将先前确定的SCZ来源星形胶质细胞的基因表达模式与其蛋白质组特征相关联。然后，我将利用电生理记录以及SCZ-星形胶质细胞嵌合脑中的钙和谷氨酸成像，建立SCZ-星形胶质细胞对细胞内在病理和神经元网络功能障碍的机制影响。本项目的研究结果将有助于更好地理解星形胶质细胞病理学对精神分裂症的发生和病理的影响。我的长期研究兴趣集中在了解调节干细胞和祖细胞的机制，以开发针对神经精神健康差异的疾病建模和再生方法。因此，本培训计划概述了赞助商的角色和促进专业发展的活动，并最终促进了我成为一名独立神经科学研究人员的长期职业目标。

Abstract/Project Summary Schizophrenia afflicts approximately 21 million people worldwide and 3.5 million in the United States, which translates to an exorbitant socioeconomic burden. Despite this, currently, there is no effective treatment for schizophrenia mainly attributed to its elusive pathogenesis and heterogeneous pathology. Converging evidence highlights an association of glial genes and a high susceptibility to develop schizophrenia. Since astroglia are chiefly involved in the developmental organization, support and neurotransmission of neuronal networks, astrocyte pathology is thought to contribute to the aberrant neuronal traits widely documented in schizophrenia, such as disrupted neuronal development and connectivity, and dysregulated synaptic transmission. In recent studies, Goldman and colleagues engineered humanized glial chimeric mice using glial progenitor cells-derived from schizophrenia patients. These chimeric mice exhibited concomitant disease astroglial and schizophrenia behavioral phenotypes, while suppressing susceptibility genes significantly ameliorated the disease phenotype. These observations further support an astroglial basis on the genesis and pathology of schizophrenia. However, the precise influence of dysfunctional astroglia on the aberrant neuronal development and dysfunction in schizophrenia remains undetermined. Therefore, here, we will investigate the impact of schizophrenia (SCZ)- derived astroglia on neuronal network development and function using SCZ-glial mouse chimeras. To this end, I will employ serial electron microscopy to characterize changes in the ultrastructure of astroglia-neuron synaptic interactions and syncytial networks. I will also correlate previously identified gene expression patterns of SCZderived astroglia to their proteomic profile using mass spectrometry analysis. I will then establish the mechanistic influence of SCZ-astroglia on cell-intrinsic pathology and neuronal network dysfunction using electrophysiological recordings and calcium and glutamate imaging in the SCZ-astroglia chimeric brain. Results from this project will provide a better understanding on the influence of astrocyte pathology to the genesis and pathology of schizophrenia. My long-term research interest focuses on understanding the mechanisms regulating stem and progenitor cells to develop disease modeling and regenerative approaches for neuropsychiatric health disparities. Therefore, this training plan outlines the role of the sponsor and activities to promote the professional development, and ultimately facilitate my long-term professional goal of becoming an independent neuroscience investigator.