Aberrant Neurogenesis in Experimental Temporal Lobe Epilepsy

描述(申请人提供)：内侧颞叶癫痫(MTLE)是一种常见的癫痫综合征，通常表现为耐药癫痫发作。人和实验性MTLE的组织病理学显示，海马区锥体和齿状肺门神经元丢失，齿状颗粒细胞(DGC)层分散，DGC轴突重塑，称为苔藓纤维发芽(MFS)。最近的工作发现了实验性MTLE中涉及DGC的其他病理：持续性肺门基底树突状细胞(HBD)和位于肺门和分子层异位位置的DGC。值得注意的是，这些异常是由无序的神经发生引起的，因为DGC神经发生贯穿一生。这些发现导致了一种想法，即致痫侮辱会导致新生DGC的异常整合。这一观点得到了形态和电生理学证据的支持，即异常的神经发生会导致网络过度兴奋。相反，其他工作表明，正常整合的成年出生的DGC通过在癫痫持续状态(SE)诱导的损伤后恢复抑制来补偿致痫过度兴奋。利用匹罗卡品的大鼠癫痫模型，我们最近发现，在癫痫发生过程中，DGC只在发育中而不成熟，导致DGC可塑性异常，包括MFS、HBDS和异位DGC的存在。我们实验室和其他实验室的数据也表明，癫痫患者海马中分泌的发育线索reelin的表达减少，导致实验性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，我们建议检验以下假设：1)只有损伤时未完全成熟的DGC或损伤后生成的DGC才容易受到SE诱导的可塑性，而齿状回Reelin表达的缺失是这种可塑性的某些形式；以及2)大多数脆弱的DGC或其前体细胞在癫痫发生过程中整合异常，导致海马过度兴奋和癫痫发作；因此，阻止神经发生或DGC异常整合将改善癫痫状态。我们提出了三个具体目标来检验这些假说。目的1是确定Reelin信号改变是否导致完整或癫痫齿状回DGC前体迁移或HBD形成的异常。目的2研究不同发育阶段(从SE时成熟到SE后出生的DGC)对SE诱导的可塑性的易感性，以及在癫痫发生过程中发育中的DGC整合正常或异常的内在特性和网络影响。在目标3中，我们建议确定减弱发育中的DGC的异常整合是否会抑制癫痫的发生。这些目标的进展将有助于深入了解成人神经发生的调控，将确定异常神经发生在癫痫中的功能作用，并可能导致抑制MTLE癫痫发生或认知障碍的新治疗策略。 公共卫生相关性：颞叶癫痫(TLE)是一种常见的癫痫，通常对抗癫痫药物耐药，需要手术治疗。患者通常会因频繁的癫痫发作和相关的记忆障碍而致残。我们有证据表明，损伤导致实验性TLE诱导成年海马神经干细胞产生错位和异常的新神经细胞。我们建议确定神经干细胞改变的潜在机制，以及使其行为正常化是否会阻止癫痫的发展。因此，这一领域的进展可能会为预防大脑侮辱后的TLE提供新的治疗方法。

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.