title: Disruption of hippocampal neuregulin 1-ErbB4 signaling contributes to the hippocampus-dependent cognitive impairment induced by isoflurane in aged mice.
abstract: BACKGROUND
  A prolonged isoflurane exposure may lead to cognitive decline in rodents. Neuregulin 1 (NRG1)-ErbB4 signaling plays a key role in the modulation of hippocampal synaptic plasticity through regulating the neurotransmission. The authors hypothesized that hippocampal NRG1-ErbB4 signaling is involved in isoflurane-induced cognitive impairments in aged mice.
  
  
  METHODS
  Fourteen-month-old C57BL/6 mice were randomized to receive 100% O2 exposure, vehicle injection after 100% O2 exposure, vehicle injection after exposure to isoflurane carried by 100% O2, NRG1-β1 injection after exposure to isoflurane carried by 100% O2, and NRG1-β1 and an ErbB4 inhibitor AG1478 injection after exposure to isoflurane carried by 100% O2. Fear conditioning test was used to assess the cognitive function of mice 48-h postexposure. The brain tissues were harvested 48-h postexposure to determine the levels of NRG1, ErbB4, p-ErbB4, parvalbumin, and glutamic acid decarboxylase 67 in the hippocampus using Western blotting, enzyme-linked immunosorbent assay, and immunofluorescence.
  
  
  RESULTS
  The percentage of freezing time to context was decreased from 50.28 ± 11.53% to 30.82 ± 10.00%, and the hippocampal levels of NRG1, p-ErbB4/ErbB4, parvalbumin, and glutamic acid decarboxylase 67 were decreased from 172.79 ± 20.85 ng/g, 69.15 ± 12.20%, 101.68 ± 11.21%, and 104.71 ± 6.85% to 112.92 ± 16.65 ng/g, 42.26 ± 9.71%, 75.89 ± 10.26%, and 73.87 ± 16.89%, respectively, after isoflurane exposure. NRG1-β1 attenuated the isoflurane-induced hippocampus-dependent cognitive impairment and the declines in the hippocampal NRG1, p-ErbB4/ErbB4, parvalbumin, and glutamic acid decarboxylase 67. AG1478 inhibited the rescuing effects of NRG1-β1.
  
  
  CONCLUSIONS
  Disruption of NRG1-ErbB4 signaling in the parvalbumin-positive interneurons might, at least partially, contribute to the isoflurane-induced hippocampus-dependent cognitive impairment after exposure to isoflurane carried by 100% O2 in aged mice.
authors.affiliation: From the Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China (X.-M.L., M.-H.J., G.-F.Z., L.-L.Q., M.J., J.-J.Y.); Department of Anesthesiology, Affiliate Hospital, Shandong Medical University of Traditional Chinese Medicine, Jinan, China (F.S.); Departments of Neurobiology and Pharmacology, Key Laboratory for Neurodegenerative Disease of Jiangsu Province, Nanjing Medical University, Nanjing, China (J.G.); and Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts (Z.X.).
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Li
authors.forename: Fan
authors.initials: F
authors.lastname: Su
authors.forename: Mu-Huo
authors.initials: MH
authors.lastname: Ji
authors.forename: Guang-Fen
authors.initials: GF
authors.lastname: Zhang
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Qiu
authors.forename: Min
authors.initials: M
authors.lastname: Jia
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.forename: Zhongcong
authors.initials: Z
authors.lastname: Xie
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000375:Aging / Q000502:physiology; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology*; D015536:Down-Regulation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000187:drug effects*; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000523:psychology; D005455:Fluorescent Antibody Technique; D005968:Glutamate Decarboxylase / Q000096:biosynthesis; D006624:Hippocampus / Q000503:physiopathology*; D007276:Injections, Intraventricular; D007395:Interneurons / Q000378:metabolism; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D020890:Neuregulin-1 / Q000187:drug effects*; D010320:Parvalbumins / Q000096:biosynthesis / Q000378:metabolism; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; D020890:Neuregulin-1; D010320:Parvalbumins; D007530:Isoflurane; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1