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Anesthesiology:
doi: 10.1097/ALN.0000000000000191
Perioperative Medicine: Basic Science

Disruption of Hippocampal Neuregulin 1–ErbB4 Signaling Contributes to the Hippocampus-dependent Cognitive Impairment Induced by Isoflurane in Aged Mice

Li, Xiao-Min M.D.; Su, Fan M.D., Ph.D.; Ji, Mu-Huo M.D.; Zhang, Guang-Fen M.D.; Qiu, Li-Li M.D.; Jia, Min M.D.; Gao, Jun M.D., Ph.D.; Xie, Zhongcong M.D., Ph.D.; Yang, Jian-Jun M.D., Ph.D.

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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.
Conclusion: 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.

© 2014 American Society of Anesthesiologists, Inc.

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