Mossy cell control of adult neurogenesis in epilepsy

癫痫是由大脑内神经元兴奋和抑制的不平衡引起的。其中最 常见的癫痫形式是颞叶癫痫(TLE)，很大比例的TLE患者是 难治性的。TLE与细胞丢失、胶质增生、神经发生改变、轴突萌发、 和突触重组，在人类和动物模型的TLE。这些变化在中描述得最好 在癫痫中变得过度兴奋的海马体，可以作为癫痫发作的起始焦点 TLE。在啮齿动物模型中，TLE中成年出生的神经元增殖增加，并且 这些新神经元异常地整合到神经元回路中，并被认为有助于 癫痫的发生。谷氨酸能信号和突触的形成是正常成熟、突触形成的关键 成体出生的齿状颗粒细胞(DGC)的整合和存活，最近的一项研究表明，肺门 苔藓细胞是成年出生的DGC的第一个谷氨酸能输入细胞。有趣的是，这些海马体苔藓 癫痫发作后，细胞也非常容易发生凋亡。这表明苔藓细胞在 癫痫持续状态可改变成体出生的DGCs的成熟和突触形成，从而导致 这些细胞可能通过对癫痫后神经发生的影响而在癫痫的发病机制中发挥关键作用。这 该提案将调查苔藓细胞如何有助于成人的正常成熟和网络整合- 以及苔藓细胞的丢失是否有助于突触的异常整合、成熟 以及成年出生的DGC在癫痫中的存活率。此外，我们还将直接测试苔藓细胞的挽救情况 丢失可防止神经发生的改变和癫痫的发展。我们将使用苔藓细胞特异体 使用药物遗传学、白喉选择性地改变苔藓细胞活性和存活率的Cre驱动小鼠系 毒素介导的细胞消融和凋亡抑制，并评估成年出生的DGC突触的变化 融合与生存。此外，我们将把这些技术与成熟的匹罗卡品结合起来。 TLE模型，评估苔藓细胞死亡对成年出生的DGC成熟和癫痫发生的影响。我们 假设苔藓细胞活动对成年婴儿的正常融合、成熟和存活至关重要 颗粒细胞和苔藓细胞丢失的减少将恢复这些特征并减少癫痫的发生 小鼠癫痫持续状态后。这项研究不仅将极大地提高我们对苔藓作用的理解 细胞参与神经发生和癫痫，但可能导致许多新的治疗策略的发展 难治性癫痫的类型。

Epilepsy results from an imbalance in neuronal excitation and inhibition within the brain. One of the most common forms of epilepsy is temporal lobe epilepsy (TLE), and a large percentage of TLE patients are refractory to medical treatment. TLE is associated with cell loss, gliosis, altered neurogenesis, axon sprouting, and synaptic reorganization in both humans and animal models of TLE. These changes are best described in the hippocampus, which becomes hyperexcitable in epilepsy and can serve as an initiating seizure focus in TLE. In rodent models, there is increased proliferation of adult-born neurons in the hippocampus in TLE, and these new neurons integrate abnormally into neuronal circuits and are believed to contribute to epileptogenesis. Glutamatergic signaling and synapse formation are critical for the proper maturation, synaptic integration, and survival of adult-born dentate granule cells (DGCs), and a recent study demonstrated that hilar mossy cells serve as the first glutamatergic inputs to adult-born DGCs. Interestingly, these hippocampal mossy cells are also highly susceptible to apoptosis after seizures. This suggests that the loss of mossy cells after status epilepticus could alter the maturation and synapse formation by adult-born DGCs and thus the loss of these cells may be a critical step in pathogenesis of epilepsy via its effect on post-seizure neurogenesis. This proposal will investigate how mossy cells contribute to the normal maturation and network integration of adult- born granule cells, and whether mossy cell loss contributes to the abnormal synaptic integration, maturation, and survival of adult-born DGCs in epilepsy. In addition, we will directly test whether the rescue of mossy cell loss prevents alterations in neurogenesis and the development of epilepsy. We will use a mossy cell specific Cre driver mouse line to selectively modify mossy cell activity and survival using pharmacogenetics, diphtheria toxin-mediated cell ablation, and inhibition of apoptosis, and assess changes in adult-born DGC synaptic integration and survival. Additionally, we will combine these techniques with the well-established pilocarpine model of TLE, to assess how mossy cell death affects adult-born DGC maturation and epileptogenesis. We hypothesize that mossy cell activity is critical for proper integration, maturation, and survival of adult-born granule cells and that a reduction in mossy cell loss will restore these features and reduce epileptogenesis after status epilepticus in mice. This study will not only greatly improve our understanding of the role of mossy cells in neurogenesis and epilepsy, but could lead to the development of new therapeutic strategies for many types of refractory epilepsies.