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: 10618036
• 负责人: Amy L. Brewster
• 金额: $ 32.48万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618036
• 关键词: Acute; Antiepileptic Agents; Apoptosis; Attenuated; Biochemical; 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; 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; drug repurposing; 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

项目摘要 癫痫病是一种癫痫病，通常与认知障碍合并。长时间连续癫痫发作 （状态癫痫; 弱势神经元网络（例如海马的神经元网络）中的突触连通性。广泛的证据 支持通过麸 来自许多细胞内信号传导级联反应的兴奋性，凋亡和异常激活与 通常导致癫痫发作的神经元过度兴奋性。尽管有这些发现，但机制的机制 直接影响神经过度兴奋性仍然难以捉摸。 SE和SE组织病理学的重要标志 癫痫是小胶质细胞的激活，该小胶质细胞介导神经炎症和吞噬反应。很好 知道小胶质细胞介导的神经炎症机制有助于癫痫发作。但是，差距仍然存在 关于其吞噬反应的潜在作用。在SE小胶质细胞中和之后进行多个物理 与皮质和海马树突的接触，这是我们最近在人类难治中发现的现象 癫痫。这些接触可能导致树突结构的吞噬作用，从而改变 神经元连通性。最近的研究发现，来自免疫完成的C1Q和C3蛋白 系统发送“饮食”信号，将小胶质细胞引导至正常的吞噬吞噬外鼻外突触 发展大脑。此外，C1Q和C3与海马的病理去除有关 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有所增加 在实验模型中，顽固性人类癫痫和SE之后的mRNA和蛋白水平。因此，我们 假设癫痫发作引起的免疫完成系统的激活有助于海马 促进神经元/网络过度刺激性，癫痫发作和记忆缺陷的突触dondRITIC修饰。 我们将追求以下目标，AIM1：表征完成激活和相关响应 SE和TLE的小鼠模型； AIM2：确定SE诱导的C3激活对神经元的贡献 在小鼠TLE模型中，海马的突触齿状变化； AIM3：确定 SE诱导的C3激活对癫痫发作和海马依赖性记忆的贡献在小鼠中定义 TLE的模型。这项研究将为理解先天性的吞噬作用提供强大的框架 免疫完成系统和小胶质细胞在SE诱导的癫痫电路产生中。我们的科学 发现可能会提供直接调节的潜在治疗价值的证据 补充级联反应减弱癫痫病的癫痫发作和认知合并症。重要的是，因为FDA- 我们的研究 可以提供证据，以快速跟踪这些药物在癫痫中使用的重新利用。 1