The Role of Inflammation in Post-stroke Epileptogenesis

 描述(申请人提供)：癫痫是一种常见的大脑侮辱的后果，如脑损伤，癫痫持续状态，以及老年人和儿童的大脑皮质中风。 尽管研究仍在进行，但目前还没有预防大脑侮辱后癫痫的治疗方法。每年，全球有1500万人罹患中风。中风之后会有一段潜伏期(几个月到几年)，在此期间，大脑会经历导致慢性癫痫发作的变化。了解癫痫的不良适应过程，从而预防或治疗潜伏期癫痫的发生发展，是癫痫研究的圣杯。我们的初步数据构成了这一建议的基础，这表明涉及神经胶质细胞的持续性炎症可能是大鼠中风后癫痫发生的关键组成部分。我们先前发现，大脑皮层卒中导致丘脑皮质系统的神经重组，丘脑在卒中后第一周内变得高度兴奋。用光基因工具沉默丘脑的“热点”，足以实时终止癫痫发作。我们以前发现这些热点与癫痫发作(在慢性卒中后癫痫发作后)有因果关系。它们与神经回路可塑性共同定位于永久性和局灶性星形胶质细胞增生症和小胶质细胞增多症有关，以及 补体级联的免疫分子C1q在导致癫痫发作的区域大量上调。众所周知，在视觉系统的正常发育过程中，C1q在突触修剪和电路可塑性方面发挥作用，但我们的发现表明，C1q可能在中风等脑损伤后的电路可塑性中发挥作用。我们的初步数据表明，改善胶质细胞增生的抗炎治疗也可以防止电路的过度兴奋和突触抑制的缺陷，通过病毒途径选择性地诱导胶质细胞增生，可以减少突触抑制的缺陷，诱导电路的过度兴奋。我们假设，神经胶质诱导的炎症和丘脑中的C1q在导致中风到癫痫的适应不良的细胞和电路可塑性中起关键作用。本研究的目的是确定胶质细胞增多症在丘脑皮质系统致痫回路重组中的作用。我们将结合细胞生理学、系统神经科学和生物工程来确定中风后胶质增生和/或阻断C1q活动是否可以防止癫痫的发生，以及在慢性癫痫阶段(即癫痫发生后)扰乱胶质增生和阻断C1q活动是否足以“回到过去”来改变疾病和治愈癫痫。该项目可能导致癫痫(丘脑胶质细胞增多症和C1q)的新生物标记物，以及预防中风等脑损伤后癫痫的新疗法。

 DESCRIPTION (provided by applicant): Epilepsy is a common consequence of brain insults, such as brain injuries, status epilepticus, and cerebrocortical stroke in the elderly and children. Despite ongoing research, there are no treatments that prevent epilepsy after brain insults. Each year, 15 million people worldwide suffer a stroke. Stroke is followed by a latent period (month to years) during which the brain goes through changes leading to the onset of chronic epilepsy. Understanding the maladaptive process so the development of epilepsy ("epileptogenesis") during the latent period can be prevented or treated is the holy grail of epilepsy research. Our preliminary data that form the basis of this proposal suggest that persistent inflammation involving glial cells may be a key component of epileptogenesis after stroke in rats. We previously found that cerebrocortical stroke leads to neural reorganization in the thalamocortical system and that the thalamus becomes hyperexcitable within the first week after stroke. Silencing the thalamic "hot spot" with optogenetic tools is sufficient to abort the epileptic seizures in real-time. We previously showed these hot spots to be causally involved in epileptic seizures (after the onset of chronic post-stroke epilepsy). They are associated with neural circuit plasticity co-localized with a permanent and focal astrogliosis and microgliosis and a massive upregulation of C1q, an immune molecule of the complement cascade, in the region that is causally involved in epileptic seizures. C1q is known for its role in synaptic pruning and circuit plasticity during normal development in the visual system, but our findings suggest that C1q may have a role in circuit plasticity after brain insults such as stroke. Our pilot data indicae that anti-inflammatory treatments that modify the gliosis also prevent the circuit hyperexcitabilit and deficits in synaptic inhibition and that selectively inducing gliosis via viral approaches phenocopies the deficits in synaptic inhibition and induces circuit hyperexcitability. We hypothesize that the glial-induced inflammation and C1q in the thalamus have key roles in the maladaptive cellular and circuit plasticity that leads from stroke to epilepsy. The goal of the proposed research is to determine the role of gliosis in epileptogenic circuit reorganization in th thalamocortical system. We will combine cellular physiology, systems neuroscience, and bioengineering to determine whether gliosis and/or blocking C1q actions after stroke will prevent epileptogenesis and whether disrupting the gliosis and blocking C1q actions during the chronic epileptic phase (i.e., after epilepsy has developed) will be sufficient to "go back in time" to modify the disease and cure epilepsy. This project may lead to novel biomarkers in epilepsy (thalamic gliosis and C1q) and novel treatments to prevent epilepsy after brain lesions, such as stroke.