A role for the complement system in seizure induced neuronal and dendritic injury

补体系统在癫痫引起的神经元和树突损伤中的作用

• 批准号: 9898484
• 负责人: Amy L. Brewster
• 金额: $ 33.39万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898484
• 关键词: Acute; Antiepileptic Agents; Apoptosis; Attenuated; Biochemical; Biological; Brain; Cognitive; Cognitive deficits; Complement; Complement 1q; Complement 3a; Complement 3b; Complement 5a; Complement Activation; Complement Inactivators; DLG4 gene; Dendrites; Dendritic Spines; Development; Eating; Electroencephalogram; Electrophysiology (science); Epilepsy; Excision; Experimental Models; FDA approved; Generations; Glutamates; Hippocampus (Brain); Histologic; Histopathology; Human; Immune; Immunologics; Impairment; Individual; Inflammatory; Injury; Intractable Epilepsy; Knockout Mice; Link; Measures; Mediating; Memory; Memory Loss; Memory impairment; Messenger RNA; Microglia; Modeling; Modification; Mus; Neurodegenerative Disorders; Neurons; Pathologic; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Physiological; Predisposition; Proteins; Research; Risk; Role; Seizures; Signal Transduction; Status Epilepticus; Structure; Synapses; System; Temporal Lobe Epilepsy; Testing; Therapeutic; Time; Virus Diseases; age related; behavior test; cognitive disability; cognitive function; comorbidity; complement system; excitotoxicity; immune activation; inflammatory marker; mouse model; neuroinflammation; neuron loss; neuropathology; receptor; relating to nervous system; response; therapeutic target

Project Summary Epilepsy is a seizure disorder that is often comorbid with cognitive disabilities. Prolonged-continuous seizures (status epilepticus; SE) increase the risk for the development of temporal lobe epilepsy (TLE) by remodeling synaptic connectivity in vulnerable neuronal networks such as those of the hippocampus. Extensive evidence supports that SE-induced hippocampal synaptodendritic remodeling orchestrated through glutamate excitotoxicity, apoptosis, and aberrant activation from a number of intracellular signaling cascades is linked to the neuronal hyperexcitability that often results in seizures. Despite these findings, the mechanisms that directly impact neural hyperexcitability remain elusive. A prominent hallmark in the histopathology of SE and epilepsy is activation of microglia, which mediate neuroinflammatory and phagocytic responses. It is well known that microglia-mediated neuroinflammatory mechanisms contribute to seizures; however, a gap remains on the potential role of their phagocytic responses. During and after SE microglia make multiple physical contacts with cortical and hippocampal dendrites, a phenomenon that we recently found in human refractory epilepsy. These contacts may result in the phagocytosis of dendritic structures and thereby modification of neuronal connectivity. Recent studies discovered that C1q and C3 proteins from the immune complement system send “eat-me” signals that guide microglia to phagocytose extranumerary synapses in the normal developing brain. In addition, C1q and C3 are associated with the pathological removal of hippocampal synaptic structures in models of neurodegenerative disorders. We and others found increases in C1q-C3 mRNA and protein levels in intractable human epilepsy and after SE in experimental models. Therefore, we hypothesized that seizure-induced activation of the immune complement system contributes to hippocampal synaptodendritic modifications that promote neuronal/network hyperexcitability, seizures, and memory deficits. We will pursue the following Aims, Aim1: To characterize complement activation and associated responses in a mouse model of SE and TLE; Aim2: To determine the contribution of SE-induced C3 activation to neuronal and synaptodendritic changes in the hippocampus in a mouse model of TLE; Aim3: To determine the contribution of SE-induced C3 activation to seizures and hippocampal-dependent memory deficits in a mouse model of TLE. This study will provide a strong framework for understanding the phagocytic role of the innate immune complement system and microglia in the SE-induced generation of epileptic circuits. Our scientific discoveries are likely to provide evidence for the potential therapeutic value of directly modulating the complement cascade to attenuate seizures and cognitive comorbidities in epilepsy. Importantly, because FDA- approved complement inhibitors are currently being used for immunological illnesses in humans, our study may provide evidence to fast track the repurposing of these drugs for their use in epilepsy. 1

项目概要 癫痫是一种癫痫病，通常与认知障碍共存。长时间持续性癫痫发作 （癫痫持续状态；SE）通过重塑增加发生颞叶癫痫 (TLE) 的风险 脆弱神经元网络（例如海马体）中的突触连接。大量证据 支持 SE 诱导的海马突触树突重塑是通过谷氨酸协调的 兴奋性毒性、细胞凋亡和许多细胞内信号级联的异常激活与 神经元过度兴奋，常常导致癫痫发作。尽管有这些发现，但机制 直接影响神经过度兴奋的因素仍然难以捉摸。 SE 组织病理学的一个显着特征 癫痫是小胶质细胞的激活，它介导神经炎症和吞噬反应。很好 已知小胶质细胞介导的神经炎症机制会导致癫痫发作；但仍存在差距 关于其吞噬反应的潜在作用。 SE小胶质细胞在产生多种物理作用期间和之后 与皮质和海马树突的接触，这是我们最近在人类难治性中发现的一种现象 癫痫。这些接触可能导致树突结构的吞噬作用，从而修饰 神经元连接。最近的研究发现，来自免疫补体的 C1q 和 C3 蛋白 系统发送“吃我”信号，引导小胶质细胞吞噬正常情况下的额外突触 正在发育的大脑。此外，C1q和C3与海马的病理性切除有关。 神经退行性疾病模型中的突触结构。我们和其他人发现 C1q-C3 增加 实验模型中难治性人类癫痫和 SE 后的 mRNA 和蛋白质水平。因此，我们 假设癫痫发作诱导的免疫补体系统激活有助于海马 促进神经元/网络过度兴奋、癫痫发作和记忆缺陷的突触树突修饰。 我们将追求以下目标，目标 1：表征补体激活和相关反应 SE和TLE小鼠模型；目标 2：确定 SE 诱导的 C3 激活对神经元的贡献 以及 TLE 小鼠模型海马突触树突的变化；目标 3：确定 SE 诱导的 C3 激活对小鼠癫痫发作和海马依赖性记忆缺陷的影响 TLE 模型。这项研究将为理解先天吞噬细胞的作用提供一个强有力的框架。 SE 诱导的癫痫回路生成中的免疫补体系统和小胶质细胞。我们的科学 这些发现可能为直接调节的潜在治疗价值提供证据 补体级联反应可减轻癫痫发作和认知合并症。重要的是，因为 FDA- 我们的研究表明，已批准的补体抑制剂目前正用于治疗人类免疫性疾病 可能会提供证据来快速追踪这些药物用于治疗癫痫的用途。 1