Maladaptive Myelination in Pediatric Epilepsy

项目总结/摘要 缺席癫痫发作发生在儿科全身性癫痫中，涉及大脑的过度同步性 丘脑皮层神经网络一种未被探索的可能性是异常的活动依赖性髓鞘形成 通过促进网络同步而促进失神发作进展。最近的一个发现是， 神经元活性驱动体内髓磷脂可塑性（髓磷脂结构的变化）。反过来，髓鞘形成是一个关键的 神经网络同步性和功能的决定因素。活性调节的新髓鞘形成需要 脑源性神经营养因子（BDNF）通过其受体TrkB在少突胶质细胞前体上的信号传导 细胞（OPC）。病理性癫痫发作活动也可能引起髓鞘结构的变化，这反过来又可能导致 导致网络功能障碍。这项提案调查了失神发作与 活性依赖性髓鞘可塑性。初步数据表明，失神发作与 在两种具有自发失神发作的啮齿动物模型中，髓鞘形成异常增加：Wag/Rij大鼠（a 广泛使用的近交系大鼠品系）和Scn 8a +/mut小鼠。这些小鼠在SCN 8A中具有功能缺失突变， 类似于由于SCN 8A功能丧失而患有全身性癫痫的儿童。两款车型表现出更高的 胼胝体前部的OPCs和髓鞘厚度。乙琥胺预防癫痫发作 阻止了胼胝体髓鞘形成的增加，表明癫痫发作是必需的。我的假设是 癫痫引起的异常髓鞘形成促进过度同步并导致癫痫发作 负担在目标1中，丘脑皮质网络中异常髓鞘形成的性质和程度将被描述为： 使用Scn 8a +/mut小鼠的磁化转移和基于扩散的磁共振成像进行研究。 测量将通过量化髓鞘形成的金标准方法（电子显微镜）进行验证。 目的2将确定活动依赖性髓鞘形成在丘脑皮质超同步性中的作用， 失神发作这将通过从OPCs中有条件地缺失TrkB受体来实现， Scn 8a +/mut小鼠，特别是在癫痫发作开始和进展期间，使用新的小鼠品系 （Scn8a+/mut; trkB fl/fl; PDGFR α：：Cre）。将在急性丘脑切片中测量网络同步性指数 来自具有或不具有正常活性依赖性髓鞘形成的Scn 8a +/mut小鼠。目标3将决定是否 髓鞘可塑性通过基因阻断活动依赖性髓鞘形成而导致癫痫发作，如Aim 2、脑电图定量癫痫发作。因此，拟议的研究将使用创新的方法来阐明 癫痫的一种新的和潜在的范式转移病理机制， 治疗策略

Project Summary / Abstract Absence seizures occur in pediatric generalized epilepsy and involve excessive synchrony of the thalamocortical neural network. An unexplored possibility is that aberrant activity-dependent myelination contributes to absence seizure progression by promoting network synchrony. A recent discovery is that neuronal activity drives myelin plasticity (changes in myelin structure) in vivo. Myelination, in turn, is a critical determinant of neuronal network synchrony and function. Activity-regulated formation of new myelin requires Brain Derived Neurotrophic Factor (BDNF) signaling through its receptor, TrkB, on oligodendrocyte precursor cells (OPCs). Pathological seizure activity may also induce changes in myelin structure, which in turn could contribute to network dysfunction. This proposal investigates the relationship between absence seizures and activity-dependent myelin plasticity. Preliminary data indicate that absence seizures are associated with abnormally increased myelination in two rodent models with spontaneous absence seizures: Wag/Rij rats (a widely used inbred rat strain) and Scn8a+/mut mice. These mice have a loss of function mutation in SCN8A, similar to children with generalized epilepsy due to loss of function in SCN8A. Both models exhibit increased OPCs and myelin sheath thickness in the anterior corpus callosum. Preventing seizures with ethosuximide prevented the increased callosal myelination, indicating that seizures are required. My hypothesis is that seizure-induced aberrant myelination facilitates excessive synchrony and contributes to seizure burden. In Aim 1, the nature and extent of abnormal myelination in the thalamocortical network will be investigated using magnetization transfer and diffusion-based magnetic resonance imaging of Scn8a+/mut mice. Measurements will be validated by the gold standard method of quantifying myelination, electron microscopy. Aim 2 will determine the role of activity-dependent myelination in thalamocortical hyper-synchrony underlying absence seizures. This will be accomplished by conditionally deleting the TrkB receptor from OPCs in Scn8a+/mut mice specifically during the period of seizure initiation and progression, using a novel mouse line (Scn8a+/mut; trkB fl/fl; PDGFR::Cre). Indices of network synchrony will be measured in acute thalamic slices from Scn8a+/mut mice with or without normal activity-dependent myelination. Aim 3 will determine whether myelin plasticity contributes to seizure burden, by genetically blocking activity-dependent myelination as in Aim 2, and quantifying seizures with EEG. Thus, the proposed studies will use innovative methods to elucidate a novel and potentially paradigm-shifting pathological mechanism in epilepsy, with implications for new therapeutic strategies.