Aberrant Neurogenesis in Experimental Temporal Lobe Epilepsy

描述（由申请人提供）：中颞叶癫痫（mTLE）是一种常见的癫痫综合征，典型表现为药物抵抗性癫痫发作。人类和实验mTLE的组织病理学显示海马锥体和齿状门神经元丢失，齿状颗粒细胞（DGC）层分散，DGC轴突重塑称为苔藓纤维发芽（MFS）。最近的研究发现了与实验性mTLE中DGCs有关的其他病理：持续性门门基底树突（HBDs）和门门和分子层异位位置的DGCs。值得注意的是，这些异常是由神经发生紊乱引起的，因为DGC神经发生持续一生。这些发现导致了癫痫性损伤导致新生儿DGCs异常整合的想法。这一观点得到了形态学和电生理学证据的支持，即异常的神经发生导致了神经网络的高兴奋性。相反，其他研究表明，正常整合的成年出生的DGCs通过在癫痫持续状态（SE）诱导的损伤后恢复抑制来补偿癫痫性高兴奋性。通过大鼠匹罗卡品癫痫模型，我们最近发现，在癫痫发生过程中，只有发育中的DGCs而不是成熟的DGCs负责异常的DGC可塑性，包括MFS、HBDs和异位DGCs的存在。我们和其他实验室的数据还表明，癫痫性海马分泌的发育线索rein表达的减少导致了实验mTLE中神经母细胞的异常迁移，以及人类mTLE中DGC层的分散。基于这些数据，我们提出以下假设：1)只有损伤时未完全成熟的DGCs或损伤后生成的DGCs才容易受到se诱导的可塑性的影响，而齿状回reelin表达的缺失是se诱导的可塑性的某种形式的基础；2)大多数易感DGCs或其祖细胞在癫痫发生过程中整合异常，导致海马高兴奋性和癫痫发作；因此，阻断神经发生或异常的DGC整合将改善癫痫状态。我们提出3个具体目标来检验这些假设。目的1是确定在完整或癫痫的齿状回中，改变的reelin信号是否会导致DGC祖细胞的异常迁移或HBD的形成。目的2是表征不同发育阶段（从SE成熟到SE后出生）的DGCs对SE诱导的可塑性的易感性，并研究在癫痫发生过程中正常或异常整合的DGCs的内在特性和网络影响。在Aim 3中，我们提出要确定是否减弱发展中的DGCs的异常整合会抑制癫痫发生。这些目标的进展将提供对成人神经发生调控的见解，将确定异常神经发生在癫痫中的功能作用，并可能导致新的治疗策略来抑制mTLE的癫痫发生或认知障碍。

DESCRIPTION (provided by applicant): Mesial temporal lobe epilepsy (mTLE) is a common epilepsy syndrome that typically manifests with pharmacoresistant seizures. Histopathology in human and experimental mTLE shows hippocampal pyramidal and dentate hilar neuron loss, dentate granule cell (DGC) layer dispersion, and DGC axonal remodeling known as mossy fiber sprouting (MFS). Recent work has uncovered additional pathology involving DGCs in experimental mTLE: persistent hilar basal dendrites (HBDs) and DGCs in ectopic locations in the hilus and molecular layer. Remarkably, these abnormalities arise from disordered neurogenesis, as DGC neurogenesis persists throughout life. These findings have led to the idea that epileptogenic insults result in the aberrant integration of newborn DGCs. This idea is supported by morphological and electrophysiological evidence that aberrant neurogenesis induces network hyperexcitability. Other work, in contrast, suggests that normally integrated adult-born DGCs compensate for epileptogenic hyperexcitability by restoring inhibition after status epilepticus (SE)-induced injury. Using the rat pilocarpine epilepsy model, we recently discovered that only developing, and not mature, DGCs are responsible for abnormal DGC plasticity during epileptogenesis, including MFS and the presence of HBDs and ectopic DGCs. Data from our lab and others also suggest that reduced expression of the secreted developmental cue reelin in epileptic hippocampus contributes to aberrant neuroblast migration in experimental mTLE, and DGC layer dispersion in human mTLE. Based on these data, we propose to test the following hypotheses: 1) Only DGCs not fully mature at the time of injury or those generated after injury are vulnerable to SE-induced plasticity, and loss of dentate gyrus reelin expression underlies some forms of this plasticity; and 2) Most vulnerable DGCs or their progenitors integrate abnormally during epileptogenesis, leading to hippocampal hyperexcitability and seizures; blocking neurogenesis or aberrant DGC integration therefore will ameliorate the epileptic state. We propose 3 specific aims to test these hypotheses. Aim 1 is to determine whether altered reelin signaling leads to aberrant DGC progenitor migration or HBD formation in the intact or epileptic dentate gyrus. Aim 2 is to characterize the vulnerability of DGCs at different developmental stages (ranging from mature at SE to those born after SE) to SE-induced plasticity, and to examine intrinsic properties and network influences of developing DGCs integrating normally or aberrantly during epileptogenesis. In Aim 3, we propose to determine whether attenuating aberrant integration of developing DGCs will suppress epileptogenesis. Progress in these aims will provide insight into the regulation of adult neurogenesis, will determine the functional role of aberrant neurogenesis in epilepsy, and may lead to novel therapeutic strategies to inhibit epileptogenesis or cognitive impairment in mTLE. PUBLIC HEALTH RELEVANCE: Temporal lobe epilepsy (TLE) is a common epilepsy that is often resistant to antiepileptic medications and requires surgical therapy. Patients are typically disabled by frequent seizures and associated memory impairment. We have evidence that injury leading to experimental TLE induces adult hippocampal neural stem cells to generate misplaced and abnormal new nerve cells. We propose to determine the mechanisms underlying the neural stem cell alterations and whether normalizing their behavior blocks epilepsy development. Progress in this area therefore may offer novel treatments to prevent TLE after brain insults.