The Role of Inflammation in Post-stroke Epileptogenesis

炎症在中风后癫痫发生中的作用

• 批准号: 10318906
• 负责人: Jeanne T Paz
• 金额: $ 18.9万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318906
• 关键词: Anatomy; Animal Model; Animals; Anti-Inflammatory Agents; Back; Biological Markers; Biomedical Engineering; Blocking Antibodies; Brain; Brain Injuries; Cell physiology; Cerebral cortex; Child; Chronic; Complement; Complement 1q; Data; Development; Disease; Elderly; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Etiology; Genetic; Gliosis; Goals; Hot Spot; Immune; Impaired health; In Vitro; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injections; Injury; Lasers; Lead; Lesion; Link; Measures; Modeling; Molecular; Neuroglia; Neurosciences; Outcome; Pharmacology; Phase; Phenocopy; Prevention; Process; Proteins; Rattus; Recovery of Function; Research; Role; Seizures; Slice; Source; Status Epilepticus; Stroke; Synapses; System; Technology; Testing; Thalamic structure; Therapeutic; Time; Up-Regulation; Viral; Visual system structure; Work; astrogliosis; complement pathway; cytokine; disability; experimental study; in vivo; insight; neural circuit; novel; novel marker; optogenetics; parent grant; patch clamp; post stroke; prevent; relating to nervous system; stroke model; synaptic inhibition; synaptic pruning; tool

PROJECT SUMMARY/ABSTRACT OF PARENT GRANT 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 data that formed 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 data indicate that anti- inflammatory treatments that modify the gliosis also prevent the circuit hyperexcitability and deficits in synaptic inhibition and that selectively inducing gliosis via viral approaches phenocopies the changes 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 and mainly the complement pathway in epileptogenic circuit reorganization in the thalamocortical system. We combine cellular physiology, systems neuroscience, and bioengineering to determine whether blocking gliosis and/or C1q actions after stroke will prevent epileptogenesis and whether blocking gliosis and/or 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.

项目概要/赠款摘要 癫痫是脑损伤的常见后果，如脑损伤、癫痫持续状态和皮质功能障碍。 老年人和儿童中风。尽管正在进行研究，但没有治疗方法可以预防癫痫， 脑侮辱。每年，全世界有1500万人患中风。中风后有一个潜伏期（月 在此期间，大脑经历了导致慢性癫痫发作的变化。理解 适应不良的过程，因此癫痫的发展（“癫痫发生”）在潜伏期可以是 是癫痫研究的圣杯。 我们的数据构成了这一提议的基础，表明涉及神经胶质细胞的持续性炎症可能是一个重要的因素。 大鼠中风后癫痫发生的关键组成部分。我们以前发现，皮质性中风导致 在丘脑皮质系统的神经重组和丘脑变得过度兴奋内 中风后第一周用光遗传学工具沉默丘脑“热点”足以中止癫痫 实时捕捉我们以前表明这些热点与癫痫发作有因果关系（在癫痫发作后）。 慢性中风后癫痫的发作）。它们与神经回路可塑性有关， 永久性和局灶性星形胶质细胞增生和小胶质细胞增生以及C1 q的大量上调，C1 q是一种免疫分子， 补体级联反应，在癫痫发作的因果关系涉及的区域。C1 q以其在以下方面的作用而闻名： 突触修剪和电路可塑性在视觉系统的正常发展，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。我们的数据表明，抗- 改变神经胶质增生的炎症治疗也能防止神经回路的过度兴奋和突触神经元的缺陷。 抑制和通过病毒途径选择性诱导胶质增生的方法复制了突触抑制的变化 并引起电路过度兴奋。 我们推测，胶质细胞诱导的炎症反应和丘脑中的C1 q在适应不良中起关键作用。 细胞和电路可塑性导致中风癫痫。拟议研究的目标是 确定神经胶质增生的作用，主要是癫痫电路重组中的补体途径 在丘脑皮质系统中。我们结合联合收割机细胞生理学，系统神经科学和生物工程， 确定阻断脑卒中后神经胶质增生和/或C1 q活动是否能预防癫痫发生，以及 在慢性癫痫期阻断神经胶质增生和/或C1 q作用（即，癫痫发作后）， 足以“回到过去”来改变疾病并治愈癫痫。该项目可能会导致新的生物标志物 在癫痫（丘脑神经胶质增生和C1 q）和新的治疗，以防止癫痫后脑损伤，如 中风

项目成果

Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome.

Scn1a-Dravet 综合征中增强的网状丘脑破裂和癫痫发作。

• DOI: 10.1016/j.celrep.2019.01.037
• 发表时间: 2019
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Ritter-Makinson,Stefanie;Clemente-Perez,Alexandra;Higashikubo,Bryan;Cho,FrancesS;Holden,StephanieS;Bennett,Eric;Chkhaidze,Ana;EelkmanRooda,OscarHJ;Cornet,Marie-Coralie;Hoebeek,FreekE;Yamakawa,Kazuhiro;Cilio,MariaRoberta;Delo
• 通讯作者: Delo

Distinct Thalamic Reticular Cell Types Differentially Modulate Normal and Pathological Cortical Rhythms.

• DOI: 10.1016/j.celrep.2017.05.044
• 发表时间: 2017-06-06
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Clemente-Perez A;Makinson SR;Higashikubo B;Brovarney S;Cho FS;Urry A;Holden SS;Wimer M;Dávid C;Fenno LE;Acsády L;Deisseroth K;Paz JT
• 通讯作者: Paz JT