Wu Xin-Miao, Shi Cui-Na, Liu Kai, Hu Xiao-Yi, He Qiu-Li, Yao Hao, Fan Di, Ma Da-Qing, Yang Jian-Jun, Shen Jin-Chun, Ji Mu-Huo
Department of Anesthesiology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Perioperative and Systems Medicine Laboratory and Department of Anesthesiology, National Clinical Research Center for Child Health, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.
Brain Behav Immun. 2025 Aug;128:416-428. doi: 10.1016/j.bbi.2025.04.027. Epub 2025 Apr 24.
Neuroinflammation is one of crucial pathogenic mechanisms underlying Alzheimer's disease, sepsis-associated encephalopathy, and postoperative cognitive dysfunction. These diseases or conditions are often accompanied by typical clinical manifestations of cognitive impairments, including impaired learning and memory but underlying mechanisms are unknown. Hence, effective treatments are not available. In the current study, mice received intraperitoneal administrations of LPS (0.5 mg/kg, daily, Escherichia coliO55:B5) for seven consecutive days and after which, different cohorts were used for behavioral assessments with open field, Y maze, and novel object recognition test or for electrophysiology recordings of mEPSC, mIPSC or LTP in ex vivo preparations. Their hippocampi were harvested for immunostaining or Western blotting of PSD95, vGLUT1, vGAT, gephyrin, PV, and SST. In vivo optical fiber calcium recording was used to evaluate the neuronal excitability. During the early stage of neuroinflammation induced by LPS, there was a decrease of excitatory afferent synapses and transmission in the CA1. During the later stage of neuroinflammation, there was an increase of inhibitory afferent synapses and transmission in the CA1, resulting in excessive inhibition on excitatory neurons. Both of them contributed to the decreased hippocampal neuronal excitability and impaired LTP, ultimately leading to cognitive impairments. Overexpression of CREB in the early stage or inactivation of PV-positive interneurons in the later stage in the CA1 both improved cognitive impairments. Our work suggests that negating decreased excitatory and increased inhibitory afferent in the hippocampus may improve cognitive impairments relate to neuroinflammation associated with neurological diseases.
神经炎症是阿尔茨海默病、脓毒症相关性脑病和术后认知功能障碍的关键致病机制之一。这些疾病或状况通常伴有认知障碍的典型临床表现，包括学习和记忆受损，但其潜在机制尚不清楚。因此，目前尚无有效的治疗方法。在本研究中，小鼠连续7天腹腔注射脂多糖（0.5mg/kg，每日，大肠杆菌O55:B5），之后，不同组用于旷场、Y迷宫和新物体识别测试的行为评估，或用于离体标本中微小兴奋性突触后电流（mEPSC）、微小抑制性突触后电流（mIPSC）或长时程增强（LTP）的电生理记录。取其海马进行免疫染色或对突触后密度蛋白95（PSD95）、囊泡谷氨酸转运体1（vGLUT1）、囊泡GABA转运体（vGAT）、gephyrin、小白蛋白（PV）和生长抑素（SST）进行蛋白质免疫印迹分析。采用体内光纤钙记录来评估神经元兴奋性。在脂多糖诱导的神经炎症早期，CA1区兴奋性传入突触和传递减少。在神经炎症后期，CA1区抑制性传入突触和传递增加，导致对兴奋性神经元的过度抑制。两者均导致海马神经元兴奋性降低和LTP受损，最终导致认知障碍。在早期过表达环磷腺苷效应元件结合蛋白（CREB）或在后期使CA1区PV阳性中间神经元失活均能改善认知障碍。我们的研究表明，消除海马中兴奋性传入减少和抑制性传入增加可能改善与神经疾病相关的神经炎症所致的认知障碍。
