Aberrant Neurogenesis in Experimental Temporal Lobe Epilepsy

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。人和实验性MTLE的组织病理学表现为海马锥体 齿状回神经元丢失、齿状回颗粒细胞(DGC)层分散和DGC轴突重塑 称为苔藓纤维发芽(MFS)。最近的工作发现了更多涉及DGC的病理 实验性MTLE：肺门和门部异位部位的持续性肺门基底树突状细胞(HBD)和DGC 分子层。值得注意的是，这些异常源于紊乱的神经发生，如DGC神经发生 会持续一生。这些发现导致了一种想法，即致痫侮辱导致了这种异常。 新生儿DGC的整合。这一观点得到了形态和电生理学证据的支持 异常的神经发生导致网络过度兴奋。相比之下，其他研究表明，通常情况下 完整的成人出生的DGC通过在状态后恢复抑制来补偿致痫的过度兴奋 癫痫(SE)所致损伤。 利用匹罗卡品的大鼠癫痫模型，我们最近发现，只有发育中的，不成熟的， DGC是癫痫发生过程中DGC可塑性异常的原因，包括MFS和 HBD和异位DGC。来自我们实验室和其他实验室的数据也表明，分泌的 癫痫大鼠海马区发育线索卷曲蛋白参与实验性神经母细胞的异常迁移 MTLE和DGC层在人MTLE中的分散。基于这些数据，我们建议测试以下内容 假设：1)只有在损伤时未完全成熟的DGC或损伤后生成的DGC才是脆弱的 对于SE诱导的可塑性，齿状回卷曲蛋白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整合异常，导致 海马区过度兴奋性和癫痫发作；阻止神经发生或DGC异常整合因此将 改善癫痫状态。我们提出了三个具体目标来检验这些假说。目标1是确定 无论Reelin信号改变是否导致DGC祖细胞异常迁移或HBD在完整或 癫痫样齿状回。目标2是描述不同发育阶段DGC的脆弱性 (从SE时成熟的到SE后出生的)到SE诱导的可塑性，并检查内在特性 癫痫发生过程中发育的DGC整合正常或异常的网络影响。在AIM 3，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。这些目标的进展将为成人神经发生的调控提供洞察力，威尔 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方法 抑制MTLE患者癫痫发生或认知障碍的策略。

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.