Kai Liu , Yu-zhu Gao , Xin-miao Wu , Xiao-yi Hu , Cui-na Shi , Qiu-li He , Hai-peng Wu , Hao Yao , Da-qing Ma , Jian-jun Yang , Mu-huo Ji
{"title":"在神经炎症诱导的小鼠认知障碍中,小胶质细胞对 PNNs 的吞噬介导了 PV 阳性中间神经元功能障碍和相关的伽马振荡。","authors":"Kai Liu , Yu-zhu Gao , Xin-miao Wu , Xiao-yi Hu , Cui-na Shi , Qiu-li He , Hai-peng Wu , Hao Yao , Da-qing Ma , Jian-jun Yang , Mu-huo Ji","doi":"10.1016/j.neuropharm.2024.110205","DOIUrl":null,"url":null,"abstract":"<div><div>Neuroinflammation, characterized by activation of glial cells, plays a critical role in central nervous system disorders. However, the precise mechanisms of neuroinflammation contributing to cognitive impairment remain elusive. Perineuronal nets (PNNs) are extracellular matrixes that envelop the cell bodies and dendrites of parvalbumin (PV)-positive interneurons and may be mediated by apolipoprotein E <em>(ApoE</em>) gene. To investigate whether disruption of PNNs associated with <em>ApoE</em> is implicated in neuroinflammation-induced cognitive impairment, we established a neuroinflammation model by administering lipopolysaccharides (LPS) at 0.5 mg/kg for 7 consecutive days. Cognitive function was assessed using the open field, Y-maze, and novel object recognition tests, and neural oscillations were also recorded. Furthermore, differentially expressed genes in microglia within the hippocampus were identified through single-cell RNA sequencing analysis. Overexpression of hyaluronan and proteoglycan link protein 1 (<em>Hapln1</em>) and <em>ApoE</em> knockdown were carried out through adeno-associated virus (AAV) injection to C57BL/6J mice and CX3CR1-CreERT2 mice, respectively. It was found that LPS-induced neuroinflammation impaired cognitive function by reducing PNNs and PV-positive interneurons’ outputs, as well as disrupting gamma (γ) oscillations in the hippocampal CA1. Overexpression of <em>Hapln1</em> was able to restore PV-positive interneurons and γ oscillations, ultimately alleviating the cognitive impairment. Mechanistically, LPS-triggered microglial activation leads to the phagocytosis of PNNs, a process influenced by <em>ApoE</em>. Notably, prevention of PNNs engulfment through targeting microglial <em>ApoE</em> in the CA1 improved cognitive impairment. Collectively, our study suggested that microglial phagocytosis of PNNs plays a key role in neuroinflammation-induced cognitive impairment, which is probably mediated by the <em>ApoE</em>.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Microglia phagocytosis of PNNs mediates PV-positive interneuron dysfunction and associated gamma oscillations in neuroinflammation-induced cognitive impairment in mice\",\"authors\":\"Kai Liu , Yu-zhu Gao , Xin-miao Wu , Xiao-yi Hu , Cui-na Shi , Qiu-li He , Hai-peng Wu , Hao Yao , Da-qing Ma , Jian-jun Yang , Mu-huo Ji\",\"doi\":\"10.1016/j.neuropharm.2024.110205\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Neuroinflammation, characterized by activation of glial cells, plays a critical role in central nervous system disorders. However, the precise mechanisms of neuroinflammation contributing to cognitive impairment remain elusive. Perineuronal nets (PNNs) are extracellular matrixes that envelop the cell bodies and dendrites of parvalbumin (PV)-positive interneurons and may be mediated by apolipoprotein E <em>(ApoE</em>) gene. To investigate whether disruption of PNNs associated with <em>ApoE</em> is implicated in neuroinflammation-induced cognitive impairment, we established a neuroinflammation model by administering lipopolysaccharides (LPS) at 0.5 mg/kg for 7 consecutive days. Cognitive function was assessed using the open field, Y-maze, and novel object recognition tests, and neural oscillations were also recorded. Furthermore, differentially expressed genes in microglia within the hippocampus were identified through single-cell RNA sequencing analysis. Overexpression of hyaluronan and proteoglycan link protein 1 (<em>Hapln1</em>) and <em>ApoE</em> knockdown were carried out through adeno-associated virus (AAV) injection to C57BL/6J mice and CX3CR1-CreERT2 mice, respectively. It was found that LPS-induced neuroinflammation impaired cognitive function by reducing PNNs and PV-positive interneurons’ outputs, as well as disrupting gamma (γ) oscillations in the hippocampal CA1. Overexpression of <em>Hapln1</em> was able to restore PV-positive interneurons and γ oscillations, ultimately alleviating the cognitive impairment. Mechanistically, LPS-triggered microglial activation leads to the phagocytosis of PNNs, a process influenced by <em>ApoE</em>. Notably, prevention of PNNs engulfment through targeting microglial <em>ApoE</em> in the CA1 improved cognitive impairment. Collectively, our study suggested that microglial phagocytosis of PNNs plays a key role in neuroinflammation-induced cognitive impairment, which is probably mediated by the <em>ApoE</em>.</div></div>\",\"PeriodicalId\":19139,\"journal\":{\"name\":\"Neuropharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-11-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuropharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0028390824003745\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuropharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0028390824003745","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Microglia phagocytosis of PNNs mediates PV-positive interneuron dysfunction and associated gamma oscillations in neuroinflammation-induced cognitive impairment in mice
Neuroinflammation, characterized by activation of glial cells, plays a critical role in central nervous system disorders. However, the precise mechanisms of neuroinflammation contributing to cognitive impairment remain elusive. Perineuronal nets (PNNs) are extracellular matrixes that envelop the cell bodies and dendrites of parvalbumin (PV)-positive interneurons and may be mediated by apolipoprotein E (ApoE) gene. To investigate whether disruption of PNNs associated with ApoE is implicated in neuroinflammation-induced cognitive impairment, we established a neuroinflammation model by administering lipopolysaccharides (LPS) at 0.5 mg/kg for 7 consecutive days. Cognitive function was assessed using the open field, Y-maze, and novel object recognition tests, and neural oscillations were also recorded. Furthermore, differentially expressed genes in microglia within the hippocampus were identified through single-cell RNA sequencing analysis. Overexpression of hyaluronan and proteoglycan link protein 1 (Hapln1) and ApoE knockdown were carried out through adeno-associated virus (AAV) injection to C57BL/6J mice and CX3CR1-CreERT2 mice, respectively. It was found that LPS-induced neuroinflammation impaired cognitive function by reducing PNNs and PV-positive interneurons’ outputs, as well as disrupting gamma (γ) oscillations in the hippocampal CA1. Overexpression of Hapln1 was able to restore PV-positive interneurons and γ oscillations, ultimately alleviating the cognitive impairment. Mechanistically, LPS-triggered microglial activation leads to the phagocytosis of PNNs, a process influenced by ApoE. Notably, prevention of PNNs engulfment through targeting microglial ApoE in the CA1 improved cognitive impairment. Collectively, our study suggested that microglial phagocytosis of PNNs plays a key role in neuroinflammation-induced cognitive impairment, which is probably mediated by the ApoE.
期刊介绍:
Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).