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

• 批准号: 10678826
• 负责人: Jun Hee Kim
• 金额: $ 49.16万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10678826
• 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

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 作为自闭症谱系障碍（ASD）。自闭症研究的核心挑战是确定常见机制 这是感觉处理异常（包括听觉功能障碍）的基础。一个普遍的假设是 ASD中的行为表型来自大脑中功能连接的改变。神经影像学研究 人ASD中的转录曲线表明，髓鞘变化和白质完整性可能是 损害功能连通性的常见病理生理学。听觉处理需要精确，及时 控制轴突传导和突触活动，使听觉系统容易受到发育 ASD的破坏。我们的长期目标是研究改变髓鞘和大脑的机制 连接性损害神经发育障碍中的听觉处理。我们以前的研究表明 髓鞘化的改变破坏轴突传导，改变突触功能并阻碍电路级功能 听觉的脑干。我们最近的研究开创了一个关于少突胶质细胞（OL）如何兴奋性的新概念， 髓神经胶质细胞有助于神经元与OLS之间的通信。我们描述了一个 表达电压门控的Na+通道1.2（NAV1.2）的可激发OL的亚群，显示NAV1.2-- 介导的尖峰并应对神经元活性。值得注意的是，编码nav1.2的alpha亚基的SCN2A 频道，与ASD有牢固的关联。这些研究表明，寡头scn2a对 OL中的电兴奋性，用于OL和神经元之间的通信以及建立功能 听觉脑干中的连通性。拟议研究的主要目的是将 少突齿SCN2A对听觉系统中髓鞘形成和神经连通性的改变以更好 了解SCN2A介导的疾病和ASD中的听觉处理如何改变。我们已经产生了 新型SCN2A条件敲除小鼠（CKO）在OLS中特异性删除SCN2A。这些小鼠表现出缺陷 在髓鞘中，神经传递的改变以及听觉功能的显着变化。我们假设这一点 在开发OL中的SCN2a表达对于协调神经元-OR相互作用是必不可少的 听觉神经系统中神经回路的髓鞘形成和适当的发展。使用多重接触 包括体内和体外电生理学，我们将确定SCN2A在OL发育和 髓鞘化（AIM 1），检查表达SCN2A的损失如何改变突触传播和可塑性 在听觉脑干中的局部突触（AIM 2）中 神经连通性和听觉处理异常（AIM 3）。总而言之，这项研究将揭示如何损失 NAV1.2介导的OL兴奋性改变了髓鞘，功能连接性和听觉处理 听觉脑干。了解髓鞘变化如何导致神经回路功能障碍，从而在功能上 与新型模型中的听觉处理异常相关，将为ASD提供更好的治疗策略。