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

Overview

Journal Anesthesiology

Specialty Anesthesiology

Date 2014 Mar 5

PMID 24589481

Citations 30

Authors

Xiao-Min Li

Fan Su

Mu-Huo Ji

Guang-Fen Zhang

Li-Li Qiu

Min Jia

Jun Gao

Zhongcong Xie

Jian-Jun Yang

Affiliations

Soon will be listed here.

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.

Citing Articles

Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway.

Dao J, Zhang W, Liu C, Li Q, Qiao C, Cui C Front Pharmacol. 2025; 16:1528604.

PMID: 39959423 PMC: 11825806. DOI: 10.3389/fphar.2025.1528604.

Alteration in Neuregulin 1/ERbB4 in Absence Epilepsy: Regulatory Effect on TRPV1 Expression.

Talebi F, Ghorbani S, Alizadeh L, Akhlaghi F, Sadat Moeeni S, Karimzadeh F Basic Clin Neurosci. 2023; 13(6):777-788.

PMID: 37323956 PMC: 10262282. DOI: 10.32598/bcn.2021.731.2.

Dysfunction of NRG1/ErbB4 Signaling in the Hippocampus Might Mediate Long-term Memory Decline After Systemic Inflammation.

Gao Y, Wu X, Zhou Z, Liu P, Yang J, Ji M Mol Neurobiol. 2023; 60(6):3210-3226.

PMID: 36840846 DOI: 10.1007/s12035-023-03278-y.

Isoflurane Rescue Schizophrenia-Related Deficits through Parvalbumin-Positive Neurons in the Dentate Gyrus.

Peng H, Jia J, Lu Y, Zheng H Biomedicines. 2022; 10(11).

PMID: 36359279 PMC: 9687200. DOI: 10.3390/biomedicines10112759.

Relevance of Cortical and Hippocampal Interneuron Functional Diversity to General Anesthetic Mechanisms: A Narrative Review.

Speigel I, Hemmings Jr H Front Synaptic Neurosci. 2022; 13:812905.

PMID: 35153712 PMC: 8825374. DOI: 10.3389/fnsyn.2021.812905.

References

Wen L, Lu Y, Zhu X, Li X, Woo R, Chen Y . Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci U S A. 2010; 107(3):1211-6. PMC: 2824309. DOI: 10.1073/pnas.0910302107. View

Mason S, Noel-Storr A, Ritchie C . The impact of general and regional anesthesia on the incidence of post-operative cognitive dysfunction and post-operative delirium: a systematic review with meta-analysis. J Alzheimers Dis. 2010; 22 Suppl 3:67-79. DOI: 10.3233/JAD-2010-101086. View

Wan Y, Xu J, Meng F, Bao Y, Ge Y, Lobo N . Cognitive decline following major surgery is associated with gliosis, β-amyloid accumulation, and τ phosphorylation in old mice. Crit Care Med. 2010; 38(11):2190-8. DOI: 10.1097/CCM.0b013e3181f17bcb. View

Shen X, Dong Y, Xu Z, Wang H, Miao C, Soriano S . Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology. 2013; 118(3):502-15. PMC: 3580002. DOI: 10.1097/ALN.0b013e3182834d77. View

Fisahn A, Neddens J, Yan L, Buonanno A . Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. Cereb Cortex. 2008; 19(3):612-8. PMC: 2638818. DOI: 10.1093/cercor/bhn107. View

Kwon O, Longart M, Vullhorst D, Hoffman D, Buonanno A . Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses. J Neurosci. 2005; 25(41):9378-83. PMC: 6725708. DOI: 10.1523/JNEUROSCI.2100-05.2005. View

Cibelli M, Rei Fidalgo A, Terrando N, Ma D, Monaco C, Feldmann M . Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol. 2010; 68(3):360-8. PMC: 4836445. DOI: 10.1002/ana.22082. View

Chen Y, Zhang M, Yin D, Wen L, Ting A, Wang P . ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proc Natl Acad Sci U S A. 2010; 107(50):21818-23. PMC: 3003111. DOI: 10.1073/pnas.1010669107. View

Culley D, Baxter M, Yukhananov R, Crosby G . Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats. Anesthesiology. 2004; 100(2):309-14. DOI: 10.1097/00000542-200402000-00020. View

10.

Bryson G, Wyand A . Evidence-based clinical update: general anesthesia and the risk of delirium and postoperative cognitive dysfunction. Can J Anaesth. 2006; 53(7):669-77. DOI: 10.1007/BF03021625. View

11.

Fuchs E, Zivkovic A, Cunningham M, Middleton S, LeBeau F, Bannerman D . Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior. Neuron. 2007; 53(4):591-604. DOI: 10.1016/j.neuron.2007.01.031. View

12.

Eto K, Hommyo A, Yonemitsu R, Abe S . ErbB4 signals Neuregulin1-stimulated cell proliferation and c-fos gene expression through phosphorylation of serum response factor by mitogen-activated protein kinase cascade. Mol Cell Biochem. 2010; 339(1-2):119-25. DOI: 10.1007/s11010-009-0375-z. View

13.

Lin D, Zuo Z . Isoflurane induces hippocampal cell injury and cognitive impairments in adult rats. Neuropharmacology. 2011; 61(8):1354-9. PMC: 3189329. DOI: 10.1016/j.neuropharm.2011.08.011. View

14.

Mei L, Xiong W . Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008; 9(6):437-52. PMC: 2682371. DOI: 10.1038/nrn2392. View

15.

Wei H, Liang G, Yang H, Wang Q, Hawkins B, Madesh M . The common inhalational anesthetic isoflurane induces apoptosis via activation of inositol 1,4,5-trisphosphate receptors. Anesthesiology. 2008; 108(2):251-60. DOI: 10.1097/01.anes.0000299435.59242.0e. View

16.

Saab B, MacLean A, Kanisek M, Zurek A, Martin L, Roder J . Short-term memory impairment after isoflurane in mice is prevented by the α5 γ-aminobutyric acid type A receptor inverse agonist L-655,708. Anesthesiology. 2010; 113(5):1061-71. DOI: 10.1097/ALN.0b013e3181f56228. View

17.

Pitcher G, Kalia L, Ng D, Goodfellow N, Yee K, Lambe E . Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nat Med. 2011; 17(4):470-8. PMC: 3264662. DOI: 10.1038/nm.2315. View

18.

Moller J, Cluitmans P, Rasmussen L, Houx P, Rasmussen H, Canet J . Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998; 351(9106):857-61. DOI: 10.1016/s0140-6736(97)07382-0. View

19.

Fazzari P, Paternain A, Valiente M, Pla R, Lujan R, Lloyd K . Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature. 2010; 464(7293):1376-80. DOI: 10.1038/nature08928. View

20.

Rammes G, Starker L, Haseneder R, Berkmann J, Plack A, Zieglgansberger W . Isoflurane anaesthesia reversibly improves cognitive function and long-term potentiation (LTP) via an up-regulation in NMDA receptor 2B subunit expression. Neuropharmacology. 2008; 56(3):626-36. DOI: 10.1016/j.neuropharm.2008.11.002. View