Rajayer Salil R, Smith Stephen M
Section of Pulmonary, Critical Care, Allergy, and Sleep Medicine, VA Portland Health Care System, 3710 SW U.S. Veterans Hospital Road, R&D 24, Portland, OR, 97239, USA.
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.
Intensive Care Med Exp. 2023 Oct 14;11(1):71. doi: 10.1186/s40635-023-00557-9.
Neurological manifestations of severe coronavirus infections, including SARS-CoV-2, are wide-ranging and may persist following virus clearance. Detailed understanding of the underlying changes in brain function may facilitate the identification of therapeutic targets. We directly tested how neocortical function is impacted by the specific panel of cytokines that occur in coronavirus brain infection. Using the whole-cell patch-clamp technique, we determined how the five cytokines (TNFα, IL-1β, IL-6, IL-12p40 and IL-15 for 22-28-h) at concentrations matched to those elicited by MHV-A59 coronavirus brain infection, affected neuronal function in cultured primary mouse neocortical neurons.
We evaluated how acute cytokine exposure affected neuronal excitability (propensity to fire action potentials), membrane properties, and action potential characteristics, as well as sensitivity to changes in extracellular calcium and magnesium (divalent) concentration. Neurovirulent cytokines increased spontaneous excitability and response to low divalent concentration by depolarizing the resting membrane potential and hyperpolarizing the action potential threshold. Evoked excitability was also enhanced by neurovirulent cytokines at physiological divalent concentrations. At low divalent concentrations, the change in evoked excitability was attenuated. One hour after cytokine removal, spontaneous excitability and hyperpolarization of the action potential threshold normalized but membrane depolarization and attenuated divalent-dependent excitability persisted.
Coronavirus-associated cytokine exposure increases spontaneous excitability in neocortical neurons, and some of the changes persist after cytokine removal.
包括严重急性呼吸综合征冠状病毒2（SARS-CoV-2）在内的严重冠状病毒感染的神经学表现多种多样，且在病毒清除后可能持续存在。深入了解脑功能的潜在变化可能有助于确定治疗靶点。我们直接测试了冠状病毒脑感染中出现的特定细胞因子组如何影响新皮质功能。使用全细胞膜片钳技术，我们确定了浓度与小鼠肝炎病毒A59（MHV-A59）冠状病毒脑感染所引发的浓度相匹配的五种细胞因子（22 - 28小时的肿瘤坏死因子α、白细胞介素-1β、白细胞介素-6、白细胞介素-12p40和白细胞介素-15）如何影响原代培养的小鼠新皮质神经元的神经元功能。
我们评估了急性细胞因子暴露如何影响神经元兴奋性（产生动作电位的倾向）、膜特性、动作电位特征，以及对细胞外钙和镁（二价离子）浓度变化的敏感性。具有神经毒性的细胞因子通过使静息膜电位去极化和使动作电位阈值超极化，增加了自发兴奋性和对低二价离子浓度的反应。在生理二价离子浓度下，具有神经毒性的细胞因子也增强了诱发兴奋性。在低二价离子浓度下，诱发兴奋性的变化减弱。去除细胞因子1小时后，自发兴奋性和动作电位阈值的超极化恢复正常，但膜去极化和减弱的二价离子依赖性兴奋性仍然存在。
冠状病毒相关的细胞因子暴露增加了新皮质神经元的自发兴奋性，并且在去除细胞因子后，一些变化仍然存在。
