The Role of Inflammation in Post-stroke Epileptogenesis

 描述（由申请人提供）：癫痫是脑损伤的常见后果，如老年人和儿童的脑损伤、癫痫持续状态和皮质外卒中。 尽管正在进行研究，但没有预防脑损伤后癫痫的治疗方法。每年，全世界有1500万人患中风。中风之后是一个潜伏期（数月至数年），在此期间，大脑经历了导致慢性癫痫发作的变化。了解适应不良的过程，以便在潜伏期内预防或治疗癫痫的发展（“癫痫发生”），是癫痫研究的圣杯。 我们的初步数据构成了这一提议的基础，表明涉及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，大脑皮质卒中导致丘脑皮质系统的神经重组，并且丘脑在卒中后第一周内变得过度兴奋。用光遗传学工具沉默丘脑“热点”足以实时中止癫痫发作。我们以前表明这些热点与癫痫发作有因果关系（在慢性卒中后癫痫发作后）。它们与神经回路可塑性相关，与永久性和局灶性星形胶质细胞增生和小胶质细胞增生共定位， C1 q（补体级联反应的一种免疫分子）在癫痫发作的因果相关区域的大量上调。C1 q以其在视觉系统正常发育过程中的突触修剪和回路可塑性中的作用而闻名，但我们的研究结果表明，C1 q可能在脑损伤（如中风）后的回路可塑性中发挥作用。我们的试点数据表明，改变神经胶质增生的抗炎治疗还可以预防回路过度兴奋和突触抑制缺陷，并且通过病毒方法选择性诱导神经胶质增生可以模拟突触抑制缺陷并诱导回路过度兴奋。 我们假设，神经胶质诱导的炎症和丘脑中的C1 q在导致中风至癫痫的适应不良的细胞和回路可塑性中起关键作用。这项研究的目的是确定胶质增生在丘脑皮质系统致痫性回路重组中的作用。我们将结合联合收割机细胞生理学、系统神经科学和生物工程来确定卒中后神经胶质增生和/或阻断C1 q作用是否会预防癫痫发生，以及在慢性癫痫阶段（即，在癫痫已经发展之后）将足以“回到过去”以修改疾病和治愈癫痫。该项目可能导致癫痫的新生物标志物（丘脑胶质细胞增生和C1 q）和预防脑损伤（如中风）后癫痫的新治疗方法。

 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.