Skip to main content
SpringerLink
Log in

Toll-Like Receptor 4 Deficiency Ameliorates Propofol-Induced Impairments of Cognitive Function and Synaptic Plasticity in Young Mice

  • Original Article
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Propofol is one of the most used intravenous anesthetic agents, which is widely used in clinical anesthesia induction and maintenance of pediatric patients. Exposure of the developing brain to propofol has been reported to lead to adverse brain changes, which in turn can induce persistent behavioral abnormalities in adulthood. However, the mechanisms by which propofol exposure in the developing brain induces cognitive impairment remain unclear. Here we report that repeated propofol exposure during the second postnatal week impairs spatial learning and memory in young mice. The reduced excitatory synaptic function and synaptogenesis in hippocampal CA1 neurons underlie this cognitive impairment. Propofol exposure specifically activates Toll-like receptor 4 (TLR4)-myeloid differentiation primary response protein 88 (MyD88)-NF-κB signaling pathway. TLR4 deficiency recues propofol exposure-induced synaptic function and cognitive deficits in young mice. Thus, we provide evidence that the activation of the TLR4-mediated pathway by propofol exposure may serve as a crucial trigger for the cognitive impairment in young adulthood caused by repeated exposure to propofol in the developing brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Rappaport B, Mellon RD, Simone A, Woodcock J (2011) defining safe use of anesthesia in children. New Engl J Med 364(15):1387–1390. https://doi.org/10.1056/NEJMp1102155

    Article  CAS  PubMed  Google Scholar 

  2. Istaphanous GK, Loepke AW (2009) General anesthetics and the developing brain. Curr Opin Anaesthesiol 22(3):368–373. https://doi.org/10.1097/aco.0b013e3283294c9e

    Article  PubMed  Google Scholar 

  3. Loepke AW, Soriano SG (2008) An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg 106(6):1681–1707. https://doi.org/10.1213/ane.0b013e318167ad77

    Article  PubMed  Google Scholar 

  4. Bercker S, Bert B, Bittigau P, Felderhoff-Muser U, Buhrer C, Ikonomidou C et al (2009) Neurodegeneration in newborn rats following propofol and sevoflurane anesthesia. Neurotox Res 16(2):140–147. https://doi.org/10.1007/s12640-009-9063-8

    Article  CAS  PubMed  Google Scholar 

  5. Wan J, Shen CM, Wang Y, Wu QZ, Wang YL, Liu Q et al (2021) Repeated exposure to propofol in the neonatal period impairs hippocampal synaptic plasticity and the recognition function of rats in adulthood. Brain Res Bull 169:63–72. https://doi.org/10.1016/j.brainresbull.2021.01.007

    Article  CAS  PubMed  Google Scholar 

  6. Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H (2008) The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neurosci Ther 14(2):95–106. https://doi.org/10.1111/j.1527-3458.2008.00043.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wagner M, Ryu YK, Smith SC, Patel P, Mintz CD (2014) Review: effects of anesthetics on brain circuit formation. J Neurosurg Anesthesiol 26(4):358–362. https://doi.org/10.1097/ANA.0000000000000118

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yu D, Jiang Y, Gao J, Liu B, Chen P (2013) Repeated exposure to propofol potentiates neuroapoptosis and long-term behavioral deficits in neonatal rats. Neurosci Lett 534:41–46. https://doi.org/10.1016/j.neulet.2012.12.033

    Article  CAS  PubMed  Google Scholar 

  9. Creeley C, Dikranian K, Dissen G, Martin L, Olney J, Brambrink A (2013) Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth 110(Suppl 1):i29–i38. https://doi.org/10.1093/bja/aet173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang C, Allegaert K, Peeters MY, Tibboel D, Danhof M, Knibbe CA (2014) The allometric exponent for scaling clearance varies with age: a study on seven propofol datasets ranging from preterm neonates to adults. Br J Clin Pharmacol 77(1):149–159. https://doi.org/10.1111/bcp.12180

    Article  CAS  PubMed  Google Scholar 

  11. Cattano D, Young C, Straiko MM, Olney JW (2008) Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg 106(6):1712–1714. https://doi.org/10.1213/ane.0b013e318172ba0a

    Article  CAS  PubMed  Google Scholar 

  12. Liang C, Du F, Cang J, Xue Z (2018) Pink1 attenuates propofol-induced apoptosis and oxidative stress in developing neurons. J Anesth 32(1):62–69. https://doi.org/10.1007/s00540-017-2431-2

    Article  PubMed  Google Scholar 

  13. Davidson AJ (2011) Anesthesia and neurotoxicity to the developing brain: the clinical relevance. Paediatr Anaesth 21(7):716–721

    Article  PubMed  Google Scholar 

  14. Wang YJ, Guo XY, Wang J (2017) Influences of repeated propofol anesthesia on hippocampal apoptosis and long-term learning and memory abilities of neonatal rats. Beijing Da Xue Bao Yi Xue Ban 49(2):310–314 https://www.ncbi.nlm.nih.gov/pubmed/28416843.

    CAS  Google Scholar 

  15. Zhang S, Liang Z, Sun W, Pei L (2017) Repeated propofol anesthesia induced downregulation of hippocampal miR-132 and learning and memory impairment of rats. Brain Res 1670:156–164. https://doi.org/10.1016/j.brainres.2017.04.011

    Article  CAS  PubMed  Google Scholar 

  16. Barak B, Feldman N, Okun E (2014) Toll-like receptors as developmental tools that regulate neurogenesis during development: an update. Front Neurosci-Switz 8:272. https://doi.org/10.3389/fnins.2014.00272

    Article  Google Scholar 

  17. Okun E, Griffioen KJ, Mattson MP (2011) Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 34(5):269–281. https://doi.org/10.1016/j.tins.2011.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM et al (2010) Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 16(4):413–419. https://doi.org/10.1038/nm.2127

    Article  CAS  PubMed  Google Scholar 

  19. Shen Y, Qin H, Chen J, Mou L, He Y, Yan Y et al (2016) Postnatal activation of TLR4 in astrocytes promotes excitatory synaptogenesis in hippocampal neurons. J Cell Biol 215(5):719–734. https://doi.org/10.1083/jcb.201605046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nishiyama J (2019) Plasticity of dendritic spines: Molecular function and dysfunction in neurodevelopmental disorders. Psychiatry Clin Neurosci 73(9):541–550. https://doi.org/10.1111/pcn.12899

    Article  PubMed  Google Scholar 

  21. Zhang CY, Du J, Zhang R, Jin J, Qiao LY (2020) Erythropoietin attenuates propofol-induced hippocampal neuronal cell injury in developing rats by inhibiting toll-like receptor 4 expression. Neurosci Lett 716:134647. https://doi.org/10.1016/j.neulet.2019.134647

    Article  CAS  PubMed  Google Scholar 

  22. Huang C, Ng OT, Chu JM, Irwin MG, Hu X, Zhu S et al (2019) Differential effects of propofol and dexmedetomidine on neuroinflammation induced by systemic endotoxin lipopolysaccharides in adult mice. Neurosci Lett 707:134309. https://doi.org/10.1016/j.neulet.2019.134309

    Article  CAS  PubMed  Google Scholar 

  23. Gong HY, Zheng F, Zhang C, Chen XY, Liu JJ, Yue XQ (2016) Propofol protects hippocampal neurons from apoptosis in ischemic brain injury by increasing GLT-1 expression and inhibiting the activation of NMDAR via the JNK/Akt signaling pathway. Int J Mol Med 38(3):943–950. https://doi.org/10.3892/ijmm.2016.2663

    Article  CAS  PubMed  Google Scholar 

  24. He Y, Wei M, Wu Y, Qin H, Li W, Ma X et al (2019) Amyloid beta oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate. Nature Commun 10(1):1193. https://doi.org/10.1038/s41467-019-09114-z

    Article  CAS  Google Scholar 

  25. Li C, Yan Y, Cheng J, Xiao G, Gu J, Zhang L et al (2016) Toll-like receptor 4 deficiency causes reduced exploratory behavior in mice under approach-avoidance conflict. Neurosci Bull 32(2):127–136. https://doi.org/10.1007/s12264-016-0015-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen J, He Y, Wu Y, Zhou H, Su LD, Li WN et al (2018) Single ethanol withdrawal regulates extrasynaptic delta-GABAA receptors via PKCdelta activation. Front Mol Neurosci 11:141. https://doi.org/10.3389/fnmol.2018.00141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee SH, Simonetta A, Sheng M (2004) Subunit rules governing the sorting of internalized AMPA receptors in hippocampal neurons. Neuron 43(2):221–236. https://doi.org/10.1016/j.neuron.2004.06.015

    Article  CAS  PubMed  Google Scholar 

  28. Chidambaram SB, Rathipriya AG, Bolla SR, Bhat A, Ray B, Mahalakshmi AM et al (2019) Dendritic spines: revisiting the physiological role. Prog Neuropsychopharmacol Biol Psychiatry 92:161–193. https://doi.org/10.1016/j.pnpbp.2019.01.005

    Article  CAS  PubMed  Google Scholar 

  29. Sloan SA, Barres BA (2014) Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders. Curr Opin Neurobiol 27:75–81. https://doi.org/10.1016/j.conb.2014.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Waites CL, Craig AM, Garner CC (2005) Mechanisms of vertebrate synaptogenesis. Annu Rev Neurosci 28:251–274. https://doi.org/10.1146/annurev.neuro.27.070203.144336

    Article  CAS  PubMed  Google Scholar 

  31. Allen NJ, Eroglu C (2017) Cell biology of astrocyte-synapse interactions. Neuron 96(3):697–708. https://doi.org/10.1016/j.neuron.2017.09.056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang M, Suo L, Yang S, Zhang W (2021) CircRNA 001372 Reduces inflammation in propofol-induced neuroinflammation and neural apoptosis through PIK3CA/Akt/NF-kappaB by miRNA-148b-3p. J Invest Surg 34(11):1167–1177. https://doi.org/10.1080/08941939.2020.1771639

    Article  PubMed  Google Scholar 

  33. Jiang P, Jiang Q, Yan Y, Hou ZQ, Luo DX (2021) Propofol ameliorates neuropathic pain and neuroinflammation through PPAR gamma up-regulation to block Wnt/beta-catenin pathway. Neurol Res 43(1):71–77. https://doi.org/10.1080/01616412.2020.1823107

    Article  CAS  PubMed  Google Scholar 

  34. Liu PF, Gao T, Li TZ, Yang YT, Xu YX, Xu ZP et al (2021) Repeated propofol exposure-induced neuronal damage and cognitive impairment in aged rats by activation of NF-kappaB pathway and NLRP3 inflammasome. Neurosci Lett 740:135461. https://doi.org/10.1016/j.neulet.2020.135461

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Yi Shen for the comments on this manuscript. We thank the excellent technical assistant of the Imaging Facility at Zhejiang University School of Medicine.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81971874 to LDS), the Special Fund for Basic Scientific Research of Zhejiang University (226-2023-00100 to LDS), the Medical Science and Technology Project of Zhejiang Province (2021KY836 and 2017KY503 to QDD), the Traditional Chinese Medical Science and Technology Project of Zhejiang Province of China (2017ZB032 to QDD), and the Natural Science Foundation of Zhejiang Province (Y20H280055 to CYS).

Author information

Authors and Affiliations

  1. Department of Rheumatology and Immunology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310006, China

    Qiao-Ding Dai, Li-Ping Xu, Yan Zhang & Na Lin

  2. Neuroscience Care Unit (Key Laboratory of Multiple Organ Failure, China National Ministry of Education), The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Rd 88#, Hangzhou, 310009, China

    Kang-Song Wu, Yao Jiang & Li-Da Su

  3. Key Laboratory of the Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou, 310009, China

    Yao Jiang & Li-Da Su

  4. College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Chong-Yu Shao

Authors
  1. Qiao-Ding Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kang-Song Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li-Ping Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Na Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chong-Yu Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Li-Da Su
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors listed contributed immensely to this study. QDD, LDS and CYS conceived and designed the experiments. QDD, KSW, LPX and YJ performed the experiments. LPX, YZ and NL analyzed the data. QDD, LDS and CYS wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Li-Da Su.

Ethics declarations

Ethics Approval

All animal procedures were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Experimentation Ethics Committee of Zhejiang University.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 582 kb)

ESM 2

(DOCX 29 kb)

ESM 3

(XLSX 75542 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dai, QD., Wu, KS., Xu, LP. et al. Toll-Like Receptor 4 Deficiency Ameliorates Propofol-Induced Impairments of Cognitive Function and Synaptic Plasticity in Young Mice. Mol Neurobiol 61, 519–532 (2024). https://doi.org/10.1007/s12035-023-03606-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03606-2

Keywords

Search

Navigation