Astrocyte dysfunction in idiopathic autism

项目总结 自闭症谱系障碍(ASD)是一种发育性疾病，涉及范围广泛的条件 以社交、重复行为、沟通以及认知缺陷为特征的挑战。 尽管ASD的确切分子机制尚不清楚，但累积的证据表明 突触发育异常是这种疾病的许多特征。该领域的大部分工作都集中在 ASD的神经元异常而神经胶质病理几十年来一直被忽视。大量的 自闭症相关基因在星形胶质细胞中高度表达并显著丰富，这表明 ASD患者突触异常中的星形胶质细胞功能障碍。 星形胶质细胞参与了综合征ASDS小鼠模型的发病机制。然而，a ASD中星形胶质细胞功能障碍的详细特征尚未完成，因此仍存在 尚不清楚星形胶质细胞功能障碍是否直接导致突触可塑性和行为结局 ASD.大约95%的自闭症是特发性病例，自闭症是主要诊断，而不是 由一种众所周知的基因变异引起的现有疾病的继发性的。人类尸检研究 提示星形胶质细胞增多症是ASD的分子特征之一。然而，目前还不清楚是否 星形胶质细胞病理在ASD中起致病作用，而不是代表代偿机制。 这项应用的目的是了解星形胶质细胞功能障碍在特发性ASD中的作用。我们发现了 小鼠在新生脑部植入神经前体细胞后表现出社会和记忆缺陷 来自ASD患者诱导的多能干细胞。这些祖细胞最终分化为星形胶质细胞 移植的大脑，表明星形胶质细胞解释了在ASD中观察到的行为表型 嵌合体小鼠。同样，植入从患者大脑器官中分离出的星形胶质细胞的小鼠表现出 社交能力下降。根据已发表的文献和我们的初步研究，我们假设 星形胶质细胞功能障碍是ASD的一个潜在机制，并导致特定的行为障碍 这种紊乱。为了验证这一假设，我们建议确定1)星形胶质细胞 促进ASD；2)ASD星形胶质细胞的功能缺陷(例如，通过评估钙活性、蛋白质图谱 和神经递质摄取能力)；以及3)ASD星形胶质细胞对神经元的影响(例如，评估神经元 网络连通性和突触可塑性)。我们将使用一系列技术，包括患者派生的 脑器官，细胞移植，双光子钙成像，电生理学和行为分析。 尽管人们越来越认识到星形胶质细胞在突触功能和连接中的重要性，但星形胶质细胞 功能障碍是ASD发生和发展的一种相对未知的机制。这个 这项研究的成功完成将为星形胶质细胞参与ASD和 这可能会彻底改变我们对ASD发病机制及其治疗的理解。

PROJECT SUMMARY Autism Spectrum Disorder (ASD) is a developmental disease that refers to a broad range of conditions characterized by challenges with sociability, repetitive behaviors, communication as well as cognitive deficits. Although the exact molecular mechanisms of ASD are poorly understood, cumulative evidence suggests that abnormal synapse development underlies many features of this disease. Most work in the field has focused on neuronal abnormalities while glial pathology in ASD has been overlooked for decades. A large number of autism-linked genes are highly expressed and significantly enriched in astrocytes suggesting a role for astrocyte dysfunction in the synaptic abnormalities observed in ASD. Astrocytes have been implicated in the pathogenesis of mouse models of syndromic ASDs. However, a detailed characterization of astrocyte dysfunction in ASD has not been completed, and it therefore remains unclear whether astrocyte dysfunction directly contributes to the synaptic plasticity and behavioral outcomes of ASD. Approximately 95 percent of ASD are idiopathic cases where autism is the primary diagnosis and not secondary to an existing condition caused by a well-known genetic variant. Human postmortem studies suggest that astrogliosis is one of the molecular features of ASD. However, it remains unclear whether astrocyte pathology plays a causative role in ASD, as opposed to representing a compensatory mechanism. The goal of this application is to understand the role of astrocyte dysfunction in idiopathic ASD. We have found that!mice exhibit social and memory deficits following neonatal brain engraftment of neural progenitors derived from ASD patient induced pluripotent stem cells. These progenitors terminally differentiated into astrocytes in transplanted brains, indicating that astrocytes account for the behavioral phenotypes observed in the ASD chimeric mice. Similarly, mice engrafted with astrocytes isolated from patient cerebral organoids exhibited reduced sociability. Based on the published literature and our preliminary studies, we hypothesize that astrocyte dysfunction is an underlying mechanism in ASD and contributes to specific behavioral impairments in this disorder. To test this hypothesis, we propose to determine 1) the behavioral impairments that astrocytes contribute to in ASD; 2) the functional deficits of ASD astrocytes (e.g., by assessing Ca2+ activity, protein profile and neurotransmitter uptake ability); and 3) the effects of ASD astrocytes on neurons (e.g., assessing neuronal network connectivity and synaptic plasticity). We will use a combination of techniques including patient-derived cerebral organoids, cell transplantation, two-photon Ca2+ imaging, electrophysiology and behavioral assays. Despite the growing realization of the importance of astrocytes in synaptic function and connectivity, astrocyte dysfunction represents a relatively unexplored mechanism for the onset and progression of ASD. The successful completion of this research will provide a coherent view of astrocyte involvement in ASD and potentially revolutionize our understanding of ASD pathogenesis and its treatment.