Astrocyte dysfunction in idiopathic autism

特发性自闭症的星形胶质细胞功能障碍

基本信息

批准号：
10390464
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390464
关键词：
ASD patient Address 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 (Brain)Human Image Impairment Individual Learning Link Literature Mass Spectrum Analysis Measures Mediating Memory Memory impairment Modeling Molecular Mus Neurites Neurons Organoids Pathogenesis Pathology Patients Physiological Plant Roots Play Property Proteins Proteome Publishing Research Research Proposals Role Schizophrenia Signal Transduction Slice Study models Synapses Synaptic Transmission Synaptic plasticity Syndrome System Techniques Testing Time Transplantation Ultrasonics Wild Type Mouse Work astrogliosis autism spectrum disorder base 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 communication impairment social deficits social skills stem cell model synaptic function synaptogenesis two-photon uptake vocalization

项目摘要

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）是一种发育疾病，是指广泛的疾病具有社交性，重复行为，沟通以及认知缺陷的挑战的特征。尽管ASD的确切分子机制知之甚少，但累积证据表明突触异常的发展是该疾病的许多特征。该领域的大多数工作都集中在数十年来，神经元异常而ASD的神经病理学被忽略了。大量自闭症相关的基因高度表达，并在星形胶质细胞中显着富集，这表明了作用在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ASD的小鼠模型的发病机理有关。但是， ASD中星形胶质细胞功能障碍的详细表征尚未完成，因此仍然存在尚不清楚星形胶质细胞功能障碍是否直接有助于突触可塑性和行为结果 ASD。大约95％的ASD是自闭症是主要诊断而不是自闭症的特发性病例继发于由众所周知的遗传变异引起的现有条件。人类验尸研究表明星形胶质细胞增生是ASD的分子特征之一。但是，尚不清楚是否星形胶质细胞病理在ASD中起因作用，而不是代表补偿机制。该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。我们找到了那个小鼠在神经祖细胞的新生儿脑植入后表现出社交和记忆缺陷来自ASD患者诱导多能干细胞。这些祖细胞终止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。同样，植入了从患者脑力器官中分离出的星形胶质细胞的小鼠表现出来降低社交性。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的基本机制，并有助于特定的行为障碍这个疾病。为了检验这一假设，我们建议确定1）星形胶质细胞的行为障碍在ASD中做出贡献； 2）ASD星形胶质细胞的功能缺陷（例如，通过评估Ca2+活性，蛋白质谱和神经递质摄取能力）； 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）。我们将结合包括患者衍生的技术大脑器官，细胞移植，两光子Ca2+成像，电生理学和行为测定。尽管星形胶质细胞在突触功能和连通性中的重要性越来越多，但星形胶质细胞功能障碍代表了ASD发作和进展的相对未开发的机制。这这项研究的成功完成将为ASD和ASD的星形胶质细胞参与提供一致的看法潜在地彻底改变了我们对ASD发病机理及其治疗的理解。