Inhibitory Network Plasticity in Neurological Disease

项目概述：在超过300,000名首次发病的患者中，有三分之一的人患有颞叶癫痫(TLE 癫痫和30%以上的病例对导致严重残疾的药物具有抵抗力。存在一个 首次发作和癫痫发展之间的治疗时间窗表明改善了 从机制上了解早期的病理过程可能有助于预防癫痫的发生和 相关的共病。而海马齿状回硬化是晚期TLE细胞的特征 在侮辱进展后不久，齿状回就会发生丢失、网络重组和抑制不足的情况 去TLE。特别是，限制GC活性吞吐的齿状抑制门在早期就受到了损害 收购TLE。然而，是什么细胞和电路组成了齿状抑制门，以及它是如何形成的 癫痫发作后的损害尚不完全清楚。最近，一类新的神经元-半月颗粒细胞 (SGCs)被认为是持续齿状反馈抑制的驱动因素。尽管SGC样神经细胞 在包括人类在内的多种物种中观察到，并在行为、发育、分子 SGCs的身份和连接性尚不清楚，因此很难确定它们在齿状功能中的作用 和疾病。与SGCS输入和输出连接不同的有限文献和我们的试点数据 颗粒细胞表明它们在齿状突起中起着独特的作用。这项研究将检验这一假设 SGCs来自一个平行的齿状回路，它加强了正常大脑中的抑制作用。我们进一步建议 癫痫发作后细胞和网络的变化损害了SGC介导的抑制和增强其兴奋性 导致癫痫和记忆缺陷的影响。结合形态计量学，Patch-Seq转录学， 实验性癫痫转基因小鼠的电和光生理学及计算 建模将使我们能够检验上述假设。目标1将定义SGC的细胞和电路身份 并确定分子标记。目标2将确定SGC兴奋回路是否得到加强 癫痫持续状态后反馈抑制回路受损。最后，目标3将检查正常和 癫痫发作诱导SGCs的发育及其在齿状记忆加工中的作用。完工后 这些研究将消除齿状回路如何在行为和行为中发挥作用的具体知识空白 癫痫，与NINDS任务保持一致，并提供防止齿状突变性崩溃所需的信息 在癫痫发作后不久进行抑制，防止癫痫和记忆并存的发展。

Project Summary: Temporal lobe epilepsy (TLE) develops in a third of over 300,000 patients with a first seizure and over 30% of cases are resistant to drugs contributing to a significant disability. Presence of a therapeutic time window between the initial insult and development of epilepsy suggests that improved mechanistic understanding of early pathological process may enable prevention of epileptogenesis and associated co-morbidities. While sclerosis of the hippocampal dentate gyrus characterizes late stage TLE, cell loss, network reorganization and deficient inhibition in the dentate gyrus occur soon after insults that progress to TLE. In particular, the dentate inhibitory gate which limits GC activity throughput is compromised early in acquired TLE. However, what cells and circuits make up the dentate inhibitory gate and how this is compromised after seizures is not fully understood. Recently, a new class of neurons, semilunar granule cells (SGCs) were proposed as drivers of sustained dentate feedback inhibition. Although SGC-like neuros are observed in multiple species including humans and are activated during behaviors, the development, molecular identity, and connectivity of SGCs are not known making it difficult to determine their role in dentate function and disease. The limited literature and our pilot data that SGCs input and output connections are distinct from granule cells indicating that they play a unique role in dentate processing. This study will test the hypothesis that SGCs from a parallel dentate circuit that strengthens inhibition in the normal brain. We further propose that cellular and network changes after seizures compromise SGC mediated inhibition and augment their excitatory effects contributing to epilepsy and memory deficits. Combining morphometry, Patch-seq transcriptomics, electro- and optophysiology in transgenic mouse lines subject to experimental epilepsy and computational modeling will allow us to test the above hypothesis. Aim 1 will define the cellular and circuit identity of SGCs and determine molecular markers. Aim 2 will determine if the SGC excitatory circuit is strengthened and feedback inhibitory circuit compromised after status epilepticus. Finally, Aim 3 will examine the normal and seizure-induced development of SGCs and their contribution to dentate memory processing. On completion the studies will eliminate specific knowledge gaps in how the dentate circuit functions in behaviors and epilepsy, in keeping with the NINDS mission, and provide information needed to prevent collapse of dentate inhibition soon after seizures and prevent development of epilepsy and memory co-morbidities.