Mechanisms underlying astroglial influence on neuronal function in schizophrenia

摘要/项目摘要 精神分裂症困扰着全世界大约2100万人，美国有350万人，这意味着过高的社会经济负担。尽管如此，目前，没有有效的治疗精神分裂症主要归因于其难以捉摸的发病机制和异质性病理。越来越多的证据强调了神经胶质基因与精神分裂症易感性的关联。由于星形胶质细胞主要参与神经元网络的发育组织、支持和神经传递，因此星形胶质细胞病理被认为有助于精神分裂症中广泛记录的异常神经元特征，例如神经元发育和连接中断以及突触传递失调。在最近的研究中，Goldman和他的同事利用神经胶质祖细胞（来自精神分裂症患者）设计了人源化神经胶质嵌合小鼠。这些嵌合体小鼠表现出伴随疾病星形胶质细胞和精神分裂症的行为表型，而抑制易感基因显着改善疾病表型。这些观察结果进一步支持了星形胶质细胞的精神分裂症的发生和病理基础。然而，精神分裂症中功能失调的星形胶质细胞对异常神经元发育和功能障碍的确切影响仍未确定。因此，在这里，我们将研究精神分裂症（SCZ）衍生的星形胶质细胞对神经元网络的发展和功能的影响，使用SCZ-胶质细胞嵌合体小鼠。为此，我将采用连续电子显微镜表征星形胶质细胞神经元突触相互作用和合胞体网络的超微结构的变化。我还将关联先前确定的基因表达模式SCZ衍生的星形胶质细胞，以其蛋白质组学谱使用质谱分析。然后，我将建立SCZ-星形胶质细胞对细胞内在病理学和神经元网络功能障碍的机制影响，使用SCZ-星形胶质细胞嵌合脑中的电生理记录和钙和谷氨酸成像。本研究的结果将有助于我们更好地了解星形胶质细胞病理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理解调节干细胞和祖细胞的机制，以开发神经精神健康差异的疾病建模和再生方法。因此，本培训计划概述了申办者的作用和促进专业发展的活动，并最终促进我成为独立神经科学研究者的长期专业目标。

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.