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，如 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 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 ASD的行为表型源于大脑功能连接的改变。神经影像研究 人类ASD的转录图谱表明，髓鞘形成和白质完整性的改变可能是 一种损害功能连通性的常见病理生理学。听觉处理要求准确和及时 轴突传导和突触活动的控制，使听觉系统容易受到发育的影响 房间隔缺乏症的破坏。我们的长期目标是研究髓鞘形成和大脑改变的机制 在神经发育障碍中，连接性损害听觉处理。我们之前的研究表明， 髓鞘的改变扰乱了轴突传导，改变了突触功能，并阻碍了脑内电路水平的功能 听觉脑干。我们最近的研究开创了一个新的概念，即少突胶质细胞(OL)的兴奋性如何， 有髓鞘的神经胶质细胞负责神经元和神经元之间的通讯。我们描述了一个 表达电压门控钠通道1.2(Nav1.2)的可兴奋OL的亚群，显示Nav1.2- 介导尖峰放电，并对神经元活动做出反应。值得注意的是，SCN2A编码Nav1.2的阿尔法亚单位 渠道，与ASD有着密切的联系。这些研究表明，少突胶质细胞SCN2A在 OL的电兴奋性，OL和神经元之间的交流，以及建立功能性 听觉脑干的连通性。拟议研究的主要目标是将 少突胶质细胞SCN2A对听觉系统髓鞘形成和神经连接的影响 了解在SCN2A介导的疾病和ASD中听觉处理是如何改变的。我们已经生成了一个 一种新型的SCN2A条件性基因敲除小鼠(CKO)，可以特异性地删除OLS中的SCN2A。这些小鼠表现出缺陷 在髓鞘形成中，神经传递改变，听觉功能显著改变。我们假设 发育中的OL中SCN2A的表达是协调神经元-OL相互作用所必需的，这种相互作用对 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发育和 髓鞘形成(目标1)，研究表达SCN2A的OL的缺失如何改变突触传递和可塑性 在听性脑干的局部突触(目标2)，并将少突胶质细胞SCN2A的丢失与改变联系起来 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是如何 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。了解髓鞘改变如何导致神经回路功能障碍 与听觉加工相关的新模型中的异常将为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.