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

摘要 听觉处理异常是神经发育障碍的常见和突出特征， 自闭症谱系障碍（ASD）。自闭症研究的一个中心挑战是确定共同的机制 导致感觉处理异常包括听觉功能障碍一个普遍的假设是， ASD中的行为表型由脑中改变的功能连接引起。神经影像学研究 人类ASD中的转录谱表明，髓鞘形成和白色物质完整性的改变可能是 一种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的中断。我们的长期目标是研究改变髓鞘形成和脑损伤的机制。 连接性损害神经发育障碍中的听觉处理。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，并阻碍神经元的回路水平功能。 听觉脑干我们最近的研究开创了少突胶质细胞（OL）兴奋性的新概念， 髓鞘形成神经胶质细胞有助于神经元和OL之间的通讯。我们描述了一个 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，并响应神经元活动。值得注意的是，Scn 2a编码Nav1.2的α亚基， 通道，与ASD具有稳健的关联。这些研究表明，少突胶质细胞Scn 2a对于 OL的电兴奋性，用于OL和神经元之间的通信，以及用于建立功能性 听觉脑干的连接拟议研究的主要目标是将 少突胶质细胞Scn 2a对听觉系统髓鞘形成和神经连接的改变， 了解在Scn 2a介导的疾病和ASD中听觉处理是如何改变的。我们创造了一个 新的Scn 2a条件性敲除小鼠（cKO），以特异性地删除OL中的Scn 2a。这些老鼠表现出 髓鞘形成、神经传递改变以及听觉功能的显着变化。我们假设 在发育中的OL中Scn 2a表达是协调神经元-OL相互作用所必需的， 髓鞘形成和听觉神经系统中神经回路的适当发育。采用多种方法 包括体内和体外电生理学，我们将确定Scn 2a在OL发育中的作用， 髓鞘形成（目的1），研究表达Scn 2a的OL的缺失如何改变突触传递和可塑性 在听觉脑干的局部突触上（Aim 2），并将少突胶质细胞Scn 2a的丢失与 神经连接和听觉处理异常（目标3）。总之，这项研究将揭示如何损失 Nav1.2介导的OL兴奋性改变了髓鞘形成，功能连接和听觉处理。 听觉脑干了解髓鞘形成的改变如何导致神经回路功能障碍， 在新的模型中与听觉处理异常相关的研究将为ASD提供更好的治疗策略。

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.