title: Neuroinflammation-Induced Downregulation of Hippocampacal Neuregulin 1-ErbB4 Signaling in the Parvalbumin Interneurons Might Contribute to Cognitive Impairment in a Mouse Model of Sepsis-Associated Encephalopathy.
abstract: Sepsis-associated encephalopathy (SAE) is a common complication associated with poor prognosis in septic patients, but the underlying mechanism remains unclear. We hypothesized that disturbed neuregulin 1 (NRG1)-ErbB4 signaling in the parvalbumin interneurons was involved in sepsis-induced cognitive impairment in a mouse model of SAE. The SAE model was induced by cecal ligation/perforation (CLP). Animals were randomly divided into the following six groups: sham + vehicle group, sham + NRG1 group, CLP + vehicle group, CLP + NRG1 group, CLP + NRG1 + AG1478 (ErbB4 inhibitor) group, and CLP + minocycline group. Behavioral tests and in vivo electrophysiology were performed at the indicated time points. The brain tissues were harvested to determine the levels of hippocampcal cytokines, IBA1-positive cells, NRG1, ErbB4, and parvalbumin. In the present study, sepsis induced the anxiety-like behavior and hippocampal-dependent cognitive impairment, as reflected by significantly increased distance spent in the open field test and decreased freezing time to context in the fear conditioning test. The abnormal behavioral changes co-occurred with significant increases in hippocampal IBA1-positive cells, IL-1β and IL-6 levels, and decreased NRG1, ErbB4, parvalbumin expressions, and evoked gamma activity. NRG1 treatment attenuated the sepsis-induced cognitive impairment and the associated biochemical markers, which were abolished by AG1478 administration. Notably, minocycline treatment attenuated neuroinflammation and mimicked the beneficial effects of NRG1 treatment. In summary, we provided additional evidence that the disruption of NRG1-ErbB4 signaling in the parvalbumin interneurons mediated by neuroinflammation might lead to abnormal gamma oscillations and thus contribute to cognitive impairment in a mouse model of SAE.
authors.affiliation: Department of Emergency and Intensive Care Medicine, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing, 210014, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Gao
authors.affiliation: Jinling Clinical Medical College of Nanjing Medical University, Nanjing, China.|Department of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.
authors.forename: Mu-Huo
authors.initials: MH
authors.lastname: Ji
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China.
authors.forename: Da-Peng
authors.initials: DP
authors.lastname: Gao
authors.affiliation: Department of Emergency and Intensive Care Medicine, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing, 210014, China.
authors.forename: Run-Hua
authors.initials: RH
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Affiliated with Nanjing University of Chinese Medicine, Nanjing, 210014, China.
authors.forename: Shao-Gang
authors.initials: SG
authors.lastname: Zhang
authors.affiliation: Jinling Clinical Medical College of Nanjing Medical University, Nanjing, China. yjyangjj@126.com.|Department of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China. yjyangjj@126.com.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China. shenjinchun1970@126.com.
authors.forename: Jin-Chun
authors.initials: JC
authors.lastname: Shen
mesh_terms: D000818:Animals; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D015536:Down-Regulation; D004660:Encephalitis / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D065818:Gamma Rhythm; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism* / Q000503:physiopathology*; D007395:Interneurons / Q000378:metabolism; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism*; D010320:Parvalbumins; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D066247:Receptor, ErbB-4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D065166:Sepsis-Associated Encephalopathy / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D010320:Parvalbumins; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4
keywords: ErbB4; cognitive impairment; neuregulin 1; neuroinflammation; sepsis