Aberrant Neurogenesis in Experimental Temporal Lobe Epilepsy

描述（由申请方提供）：内侧颞叶癫痫（mTLE）是一种常见的癫痫综合征，通常表现为药物耐药性癫痫发作。人类和实验性mTLE的组织学显示海马锥体和齿状门神经元损失、齿状颗粒细胞（DGC）层分散和被称为苔藓纤维发芽（MFS）的DGC轴突重塑。最近的研究发现了实验性mTLE中涉及DGC的其他病理学：持续的门基底树突（HBD）和门和分子层中异位位置的DGC。值得注意的是，这些异常是由神经发生紊乱引起的，因为DGC神经发生在整个生命中持续存在。这些发现导致了这样的想法，即致痫性损伤导致新生儿DGC的异常整合。形态学和电生理学证据支持这一观点，即异常神经发生诱导网络过度兴奋。相反，其他研究表明，正常整合的成人出生的DGC通过恢复癫痫持续状态（SE）诱导的损伤后的抑制来补偿致癫痫性过度兴奋。 使用大鼠匹鲁卡品癫痫模型，我们最近发现，只有发展中，而不是成熟的，DGC负责异常DGC可塑性在癫痫发生，包括MFS和HBDs和异位DGC的存在。来自我们实验室和其他实验室的数据还表明，癫痫海马中分泌的发育线索reelin的表达减少有助于实验性mTLE中的异常神经母细胞迁移，以及人类mTLE中的DGC层分散。基于这些数据，我们提出了以下假设：1）只有在损伤时未完全成熟的DGC或损伤后产生的DGC才容易受到SE诱导的可塑性的影响，并且齿状回reelin表达的缺失是这种可塑性的某些形式的基础; 2）大多数脆弱的DGC或其祖细胞在癫痫发生过程中异常整合，导致海马过度兴奋和癫痫发作;因此，阻断神经发生或异常DGC整合将改善癫痫状态。我们提出了3个具体目标来测试这些假设。目的1是确定是否改变reelin信号转导导致异常DGC祖细胞迁移或HBD形成在完整的或癫痫齿状回。目的2是表征不同发育阶段（从SE成熟到SE后出生）的DGC对SE诱导的可塑性的脆弱性，并研究癫痫发生过程中正常或异常整合的DGC的内在特性和网络影响。在目标3中，我们建议确定衰减发育中的DGC的异常整合是否会抑制癫痫发生。在这些目标的进展将提供洞察成人神经发生的调节，将确定异常神经发生在癫痫的功能作用，并可能导致新的治疗策略，以抑制癫痫或认知功能障碍的mTLE。 公共卫生相关性：颞叶癫痫（TLE）是一种常见的癫痫，通常对抗癫痫药物具有耐药性，需要手术治疗。患者通常因频繁癫痫发作和相关的记忆障碍而残疾。我们有证据表明，导致实验性TLE的损伤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，以及正常化其行为是否会阻止癫痫的发展。因此，在这方面的进展可能提供新的治疗方法，以防止TLE后脑损伤。

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.