Astrocyte dysfunction in idiopathic autism

特发性自闭症的星形胶质细胞功能障碍

• 批准号: 10611317
• 负责人: Dilek Colak
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611317
• 关键词: ASD patient; Affect; Animal Model; Animals; Astrocytes; Autopsy; Behavior Disorders; Behavioral; Behavioral Assay; Behavioral Paradigm; Biological Assay; Brain; Cell Transplantation; Cerebral cortex; Cerebrum; Coculture Techniques; Cognition; Cognitive deficits; Communication; Defect; Development; Developmental Disabilities; Diagnosis; Disease; Electrophysiology (science); Engraftment; Etiology; Excision; Exhibits; Extracellular Space; Functional disorder; Genes; Genetic; Genetic Engineering; Genetic Heterogeneity; Genetic Risk; Glutamates; Goals; Hippocampus; Human; Image; Impairment; Individual; Learning; Link; Literature; Maps; Mass Spectrum Analysis; Measures; Mediating; Memory; Memory impairment; Modeling; Molecular; Mus; Neurites; Neurodevelopmental Disorder; Neurons; Organoids; Pathogenesis; Pathology; Patients; Physiological; Play; Property; Proteins; Proteome; Publishing; Research; Research Proposals; Role; Schizophrenia; Signal Transduction; Slice; Social Behavior; Study models; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Time; Transplantation; Ultrasonics; Wild Type Mouse; Work; astrogliosis; autism spectrum disorder; behavioral impairment; behavioral outcome; behavioral phenotyping; cell type; communication behavior; conditioned fear; curative treatments; design; developmental disease; effective therapy; experimental study; genetic risk factor; genetic variant; genome wide association study; habituation; induced pluripotent stem cell; insight; live cell imaging; morris water maze; mouse model; multi-electrode arrays; neonatal brain; neonatal mice; nerve stem cell; neuronal excitability; neuropathology; neuropsychiatric disorder; neurotransmitter uptake; progenitor; repetitive behavior; social cognition; social deficits; social skills; stem cell model; synaptic function; synaptogenesis; two-photon; uptake; vocalization

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.

项目摘要 自闭症谱系障碍（ASD）是一种发育性疾病，涉及广泛的条件 其特征在于社交能力、重复行为、沟通以及认知缺陷的挑战。 虽然ASD的确切分子机制知之甚少，但累积的证据表明， 异常的突触发育是这种疾病的许多特征的基础。该领域的大多数工作都集中在 神经元异常，而ASD中的神经胶质病理学几十年来一直被忽视。大量的 孤独症相关基因在星形胶质细胞中高度表达并显著富集，这表明孤独症相关基因在星形胶质细胞中的作用。 在ASD中观察到的突触异常中的星形胶质细胞功能障碍。 星形胶质细胞与综合征型ASD小鼠模型的发病机制有关。但 ASD中星形胶质细胞功能障碍的详细特征尚未完成，因此仍然存在 目前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果， 自闭症大约95%的ASD是特发性病例，其中自闭症是主要诊断， 继发于由众所周知的遗传变异引起的现有病症。人体死后研究 提示星形胶质细胞增生是ASD分子特征之一。然而，目前尚不清楚是否 星形胶质细胞病理学在ASD中起致病作用，而不是代表补偿机制。 本申请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 那个！小鼠在新生儿脑移植神经祖细胞后表现出社交和记忆缺陷， 从ASD患者的诱导多能干细胞中提取。这些祖细胞终末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 嵌合小鼠类似地，移植有从患者脑类器官分离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的一种潜在机制， 这种混乱。为了验证这一假设，我们建议确定1）星形胶质细胞 有助于ASD; 2）ASD星形胶质细胞的功能缺陷（例如，通过评估Ca 2+活性、蛋白质谱 和神经递质摄取能力）;和3）ASD星形胶质细胞对神经元的影响（例如，评估神经元 网络连接性和突触可塑性）。我们将使用多种技术的组合，包括患者衍生的 脑类器官、细胞移植、双光子Ca 2+成像、电生理学和行为测定。 尽管越来越多的人认识到星形胶质细胞在突触功能和连接中的重要性， 功能障碍代表了ASD发作和进展的相对未探索的机制。的 这项研究的成功完成将为ASD中星形胶质细胞的参与提供一个连贯的观点， 可能会彻底改变我们对ASD发病机制及其治疗的理解。