Maladaptive Myelination in Pediatric Epilepsy

项目摘要/摘要 失神发作发生在儿童全面性癫痫中，涉及过度同步的 丘脑皮质神经网络。一种未知的可能性是，异常的依赖活动的髓鞘形成 通过促进网络同步，有助于失神发作的进展。最近的一项发现是 在体内，神经元的活动驱动髓鞘的可塑性(髓鞘结构的改变)。反过来，髓鞘形成是一种关键的 神经网络同步性和功能的决定因素。新髓鞘的活性调节形成需要 脑源性神经营养因子通过其受体TrkB在少突胶质前体细胞上的信号转导 细胞(OPC)。病理性癫痫发作活动也可能导致髓鞘结构的改变，这反过来又可能 导致网络功能障碍。这项建议调查了失神发作和癫痫之间的关系 依赖活性的髓鞘可塑性。初步数据表明，失神发作与 两种自发失神发作的啮齿动物模型中髓鞘异常增多：WAG/RiJ大鼠(A 广泛使用的近交系大鼠)和Scn8a+/mut小鼠。这些小鼠有SCN8A功能突变的丧失， 类似于因SCN8A功能丧失而导致的全身性癫痫儿童。两款车型的销量都有所增加 结果显示，OPC和髓鞘厚度均高于正常对照组。乙硫胺预防癫痫发作 阻止了增加的膝盖骨髓鞘形成，表明癫痫发作是必要的。我的假设是 癫痫诱导的异常髓鞘形成促进过度同步化并导致癫痫发作 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是 使用磁化转移和基于扩散的磁共振成像技术对Scn8a+/mut小鼠进行研究。 测量结果将通过量化髓鞘形成的金标准方法--电子显微镜进行验证。 目标2将确定活动依赖的髓鞘形成在丘脑皮质超同步化中的作用 失神痉挛。这将通过有条件地从OPC中删除TrkB受体来实现 Scn8a+/mut小鼠使用一种新的小鼠系，在癫痫的起始和进展期间特异性地 (Scn8a+/MUT；TrkB fl/fl；PDGFR：：CRE)。网络同步性指数将在急性丘脑切片中测量 来自Scn8a+/MUT小鼠，有或没有正常的活性依赖髓鞘形成。目标3将决定是否 与AIM一样，髓鞘的可塑性通过基因阻断依赖活性的髓鞘形成而导致癫痫发作负担。 2、EEG量化癫痫发作。因此，拟议的研究将使用创新的方法来阐明 癫痫的新的和潜在的范式转换的病理机制，以及对新的 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.