Role of SCN2A in Myelination and Neural Circuit Development in Autism Spectrum Disorder

SCN2A 在自闭症谱系障碍髓鞘形成和神经回路发育中的作用

基本信息

批准号：
10923210
负责人：
Jun Hee Kim
金额：
$ 6.56万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10923210
关键词：
Age Attention Attentional deficit Auditory Auditory Brainstem Responses Auditory system Autopsy Axon Behavioral Bilateral Brain Brain Diseases Brain Stem Brain region Cell Lineage Cell Nucleus Cells Communication Cre lox recombination system Development Developmental Delay Disorders Disease Electrophysiology (science)Equilibrium Event Exhibits Fiber Functional disorder Gene Expression Profile Genes Goals Hearing problem Human Hypersensitivity Impairment In Vitro Knockout Mice Link Mediating Modeling Molecular Mus Mutation Myelin Nerve Nervous System Neurodevelopmental Disorder Neuroglia Neurons Oligodendroglia Proliferating Research Role Sensory Signal Transduction Speed Synapses Synaptic Transmission Synaptic plasticity System Testing Therapeutic Transmission Electron Microscopy Western Blotting auditory processing autism spectrum disorder autistic children behavior test behavioral phenotyping conditional knockout density functional disability in vivo individuals with autism spectrum disorder loss of function mutation mouse model myelination neural neural circuit neurodevelopment neuroimaging neuromechanism neuronal excitability neurotransmission neurotropic new therapeutic target novel oligodendrocyte lineage postnatal development regional difference social sound synaptic function transmission process voltage white matter

项目摘要

ABSTRACT Auditory processing abnormalities are common and prominent features of neurodevelopmental disorders such as autism spectrum disorder (ASD). A central challenge of autism research is to identify common mechanisms that underlie sensory processing abnormalities including auditory dysfunction. One prevalent hypothesis is that the behavioral phenotypes in ASD arise from altered functional connectivity in the brain. Neuroimaging studies and the transcriptional profile in human ASD indicate that altered myelination and white matter integrity could be a common pathophysiology that impairs functional connectivity. Auditory processing requires precise and timely control of axonal conduction and synaptic activity, making the auditory system vulnerable to the developmental disruptions of ASD. Our long-term goal is to investigate the mechanisms whereby altered myelination and brain connectivity impair auditory processing in neurodevelopmental disorders. Our previous studies have shown that alterations in myelination disrupt axonal conduction, alter synaptic function, and impede circuit-level functions in the auditory brainstem. Our recent studies pioneered a new concept in how excitability in oligodendrocytes (OL), the myelinating glial cell, contributes to communication between neurons and OLs. We characterized a subpopulation of excitable OLs that express the voltage-gated Na+ channel 1.2 (Nav1.2), display Nav1.2- mediated spiking, and respond to neuronal activity. Notably, Scn2a, which encodes the alpha subunit of Nav1.2 channel, has a robust association with ASD. These studies indicate that oligodendroglial Scn2a is important for electrical excitability in OLs, for communication between OL and neurons, and for establishing functional connectivity in the auditory brainstem. The primary objective of the proposed study is to link the loss of oligodendroglial Scn2a to alterations in myelination and neural connectivity in the auditory system to better understand how auditory processing is altered in Scn2a-mediated disorders and ASD. We have generated a novel Scn2a conditional knockout mouse (cKO) to specifically delete Scn2a in OLs. These mice exhibit deficits in myelination, altered neurotransmission, and remarkable changes in auditory function. We hypothesize that Scn2a expression in developing OLs is required for coordinating neuron-OL interactions that are essential for myelination and proper development of neural circuits in the auditory nervous system. Using multiple-approaches including in vivo and in vitro electrophysiology, we will determine the role of Scn2a in OL development and myelination (Aim 1), examine how the loss of Scn2a-expressing OL alters synaptic transmission and plasticity at a local synapse in the auditory brainstem (Aim 2), and link the loss of oligodendroglial Scn2a to alterations neural connectivity and auditory processing abnormalities (Aim 3). In summary, this study will reveal how loss of Nav1.2-mediated OL excitability alters myelination, functional connectivity, and auditory processing in the auditory brainstem. Understand how altered myelination results in neural circuitry dysfunction that functionally related to auditory processing abnormalities in a novel model will provide better therapeutic strategies for ASD.

抽象的听觉处理异常是神经发育障碍的常见和突出特征，例如作为自闭症谱系障碍（ASD）。自闭症研究的一个核心挑战是确定共同机制这是包括听觉功能障碍在内的感觉处理异常的基础。一种流行的假设是自闭症谱系障碍的行为表型源于大脑功能连接的改变。神经影像学研究人类 ASD 的转录谱表明髓鞘形成和白质完整性的改变可能是损害功能连接的常见病理生理学。听觉处理需要精确和及时控制轴突传导和突触活动，使听觉系统容易受到发育障碍的影响 ASD 的干扰。我们的长期目标是研究改变髓鞘形成和大脑的机制连接性会损害神经发育障碍的听觉处理。我们之前的研究表明髓鞘形成的改变会破坏轴突传导，改变突触功能，并阻碍神经回路水平的功能听觉脑干。我们最近的研究开创了一个关于少突胶质细胞 (OL) 兴奋性如何、髓鞘神经胶质细胞有助于神经元和 OL 之间的通讯。我们表征了一个表达电压门控 Na+ 通道 1.2 (Nav1.2) 的可兴奋 OL 亚群，显示 Nav1.2- 介导的尖峰，并对神经元活动做出反应。值得注意的是，Scn2a，编码 Nav1.2 的 alpha 亚基频道，与自闭症谱系障碍 (ASD) 有着密切的联系。这些研究表明少突胶质细胞 Scn2a 对于 OL 的电兴奋性，用于 OL 和神经元之间的通信，以及建立功能听觉脑干的连通性。拟议研究的主要目标是将损失联系起来少突胶质细胞 Scn2a 改变听觉系统中的髓鞘形成和神经连接，以更好地了解 Scn2a 介导的疾病和自闭症谱系障碍 (ASD) 中听觉处理如何改变。我们已经生成了一个新型 Scn2a 条件敲除小鼠 (cKO)，可特异性删除 OL 中的 Scn2a。这些小鼠表现出缺陷髓鞘形成、神经传递改变和听觉功能显着变化。我们假设发育中的 OL 中的 Scn2a 表达对于协调神经元-OL 相互作用是必需的，这对于听觉神经系统中的髓鞘形成和神经回路的正常发育。使用多种方法包括体内和体外电生理学，我们将确定Scn2a在OL发育中的作用和髓鞘形成（目标 1），检查表达 Scn2a 的 OL 的缺失如何改变突触传递和可塑性位于听觉脑干的局部突触（目标 2），并将少突胶质细胞 Scn2a 的缺失与改变联系起来神经连接和听觉处理异常（目标 3）。总之，这项研究将揭示损失如何 Nav1.2介导的OL兴奋性改变髓鞘形成、功能连接和听觉处理听觉脑干。了解髓鞘形成改变如何导致神经回路功能障碍与听觉处理异常相关的新模型将为 ASD 提供更好的治疗策略。