• Xiao-Min Li, Fan Su, Mu-Huo Ji, Guang-Fen Zhang, Li-Li Qiu, Min Jia, Jun Gao, Zhongcong Xie, and Jian-Jun Yang.
• 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.).
• Anesthesiology. 2014 Jul 1; 121 (1): 79-88.

BackgroundA 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.MethodsFourteen-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.ResultsThe 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.ConclusionDisruption 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.

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