Skip to main content
SpringerLink
Log in

Lanthanum Impairs Learning and Memory by Activating Microglia in the Hippocampus of Mice

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Lanthanum can induce neurotoxicity and impair cognitive function; therefore, research on the mechanism by which the ability to learning and memory is decreased by lanthanum is vitally important for protecting health. Microglia are a type of neuroglia located throughout the brain and spinal cord that play an important role in the central nervous system. When overactive, these cells can cause the excessive production of inflammatory cytokines that can damage neighboring neurons. The purpose of this study was to explore the effect of lanthanum in the form of lanthanum chloride (LaCl3) on learning and the memory of mice and determine whether there is a relationship between hippocampal neurons or learning and memory damage and excessive production of inflammatory cytokines. Four groups of pregnant Chinese Kun Ming mice were exposed to 0, 18, 36, or 72 mM LaCl3 in their drinking water during lactation. The offspring were then exposed to LaCl3 in the breast milk at birth until weaning and then exposed to these concentrations in their drinking water for 2 months after weaning. The results showed that LaCl3 impaired learning and memory in mice and injured their neurons, activated the microglia, and significantly overregulated the mRNA and protein expression of tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1, and nitric oxide in the hippocampus. The results of this study suggest that lanthanum can impair learning and memory in mice, possibly by over-activating the microglia.

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 used to support the findings of this study are available from the corresponding author upon request.

Code Availability

Not applicable.

References

  1. Yang J, Liu Q, Zhang L, Wu S, Qi M, Lu S, Xi Q, Cai Y (2009) Lanthanum chloride impairs memory, decreases pCaMK IV, pMAPK and pCREB expression of hippocampus in rats. Toxicol Lett 190(2):208–214. https://doi.org/10.1016/j.toxlet.2009.07.016

    Article  CAS  PubMed  Google Scholar 

  2. Feng L, He X, Xiao H, Li Z, Li F, Liu N, Chai Z, Zhao Y, Zhang Z (2007) Ytterbium and trace element distribution in brain and organic tissues of offspring rats after prenatal and postnatal exposure to ytterbium. Biol Trace Elem Res 117(1-3):89–104. https://doi.org/10.1007/BF02698086

    Article  CAS  PubMed  Google Scholar 

  3. Fan G, Yuan Z, Zheng H, Liu Z (2004) Study on the effects of exposure to rare earth elements and health-responses in children aged 7-10 years. Journal of Hygiene Research 33(1):23–28 (in Chisese)

  4. Xu H (2004) The progress of resource, environment and health in China. Peking University Medical Press, Beijing, pp. 43–64 (in Chisese)

  5. Feng L, Xiao H, He X, Li Z, Li F, Liu N, Zhao Y, Huang Y, Zhang Z, Chai Z (2006) Neurotoxicological consequence of long-term exposure to lanthanum. Toxicol Lett 165(2):112–120. https://doi.org/10.1016/j.toxlet.2006.02.003

    Article  CAS  PubMed  Google Scholar 

  6. Feng L, Xiao H, He X, Li Z, Li F, Liu N, Chai Z, Zhao Y, Zhang Z (2006) Long-term effects of lanthanum intake on the neurobehavioral development of the rat. Neurotoxicol Teratol 28(1):119–124. https://doi.org/10.1016/j.ntt.2005.10.007

    Article  CAS  PubMed  Google Scholar 

  7. Hu X, Yang J, Sun Y, Gao X, Zhang L, Li Y, Yu M, Liu S, Lu X, Jin C, Wu S, Cai Y (2018) Lanthanum chloride impairs memory in rats by disturbing the glutamate-glutamine cycle and over-activating NMDA receptors. Food Chem Toxicol 113:1–13. https://doi.org/10.1016/j.fct.2018.01.023

  8. Valente LA, Begg LR, Filiano AJ (2019) Updating neuroimmune targets in central nervous system dysfunction. Trends Pharmacol Sci 40(7):482–494. https://doi.org/10.1016/j.tips.2019.04.013

    Article  CAS  PubMed  Google Scholar 

  9. Geirsdottir L, David E, Keren-Shaul H, Weiner A, Bohlen SC, Neuber J, Balic A, Giladi A, Sheban F, Dutertre CA, Pfeifle C, Peri F, Raffo-Romero A, Vizioli J, Matiasek K, Scheiwe C, Meckel S, Matz-Rensing K, van der Meer F, Thormodsson FR, Stadelmann C, Zilkha N, Kimchi T, Ginhoux F, Ulitsky I, Erny D, Amit I, Prinz M (2019) Cross-species single-cell analysis reveals divergence of the primate microglia program. Cell 179(7):1609–1622 e1616. https://doi.org/10.1016/j.cell.2019.11.010

    Article  CAS  PubMed  Google Scholar 

  10. Hou BR, Jiang C, Wang ZN, Ren HJ (2020) Exosome-mediated crosstalk between microglia and neural stem cells in the repair of brain injury. Neural Regen Res 15(6):1023–1024. https://doi.org/10.4103/1673-5374.270302

    Article  PubMed  Google Scholar 

  11. Yan L, Yang J, Yu M, Lu Y, Huang L, Wang J, Lu X, Jin C, Wu S, Cai Y (2019) Lanthanum chloride induces neuron damage by activating the nuclear factor-kappa B signaling pathway in activated microglia. Metallomics 11(7):1277–1287. https://doi.org/10.1039/c9mt00108e

    Article  CAS  PubMed  Google Scholar 

  12. Feng X, Valdearcos M, Uchida Y, Lutrin D, Maze M, Koliwad SK (2017) Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI insight 2(7):e91229. https://doi.org/10.1172/jci.insight.91229

    Article  PubMed  PubMed Central  Google Scholar 

  13. Helmy A, Guilfoyle MR, Carpenter KLH, Pickard JD, Menon DK, Hutchinson PJ (2016) Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury. J Cereb Blood Flow Metab 36(8):1434–1448. https://doi.org/10.1177/0271678X15620204

  14. Huang LQ, Zhu GF, Deng YY, Jiang WQ, Fang M, Chen CB, Cao W, Wen MY, Han YL, Zeng HK (2014) Hypertonic saline alleviates cerebral edema by inhibiting microglia-derived TNF-alpha and IL-1beta-induced Na-K-Cl Cotransporter up-regulation. J Neuroinflammation 11:102. https://doi.org/10.1186/1742-2094-11-102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Madhu K, Prakash T (2018) Asiaticoside counteracts the in vitro activation of microglia and astrocytes: innuendo for multiple sclerosis. Biomed Pharmacother 107:303–305. https://doi.org/10.1016/j.biopha.2018.08.010

    Article  CAS  PubMed  Google Scholar 

  16. Deng W, Mandeville E, Terasaki Y, Li W, Holder J, Chuang AT, Ning M, Arai K, Lo EH, Xing C (2020) Transcriptomic characterization of microglia activation in a rat model of ischemic stroke. J Cereb Blood Flow Metab 40(1_suppl):S34–S48. https://doi.org/10.1177/0271678X20932870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG (2009) Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener 4:47. https://doi.org/10.1186/1750-1326-4-47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Blank T, Prinz M (2013) Microglia as modulators of cognition and neuropsychiatric disorders. Glia 61(1):62–70. https://doi.org/10.1002/glia.22372

    Article  PubMed  Google Scholar 

  19. D'Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36(1):60–90. https://doi.org/10.1016/s0165-0173(01)00067-4

    Article  CAS  PubMed  Google Scholar 

  20. Zhu W, Xu S, Shao P, Zhang H, Wu D, Yang W, Feng J (1997) Bioelectrical activity of the central nervous system among populations in a rare earth element area. Biol Trace Elem Res 57(1):71–77. https://doi.org/10.1007/BF02803871

    Article  CAS  PubMed  Google Scholar 

  21. Summers MJ, Crowe SF, Ng KT (1996) Administration of lanthanum chloride following a reminder induces a transient loss of memory retrieval in day-old chicks. Brain Res Cogn Brain Res 4(2):109–119

    Article  CAS  Google Scholar 

  22. Che Y, Cui Y, Jiang X (2009) Effects of lanthanum chloride administration in prenatal stage on one-trial passive avoidance learning in chicks. Biol Trace Elem Res 127(1):37–44. https://doi.org/10.1007/s12011-008-8225-5

    Article  CAS  PubMed  Google Scholar 

  23. Yang J, Liu Q, Wu S, Xi Q, Cai Y (2012) Effects of lanthanum chloride on glutamate level, intracellular calcium concentration and caspases expression in the rat hippocampus. BioMetals 26(1):43–59. https://doi.org/10.1007/s10534-012-9593-z

    Article  CAS  PubMed  Google Scholar 

  24. Rezaie P, Male D (2002) Mesoglia & microglia--a historical review of the concept of mononuclear phagocytes within the central nervous system. J Hist Neurosci 11(4):325–374. https://doi.org/10.1076/jhin.11.4.325.8531

    Article  PubMed  Google Scholar 

  25. Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1):151–170

    Article  CAS  Google Scholar 

  26. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19(8):312–318

    Article  CAS  Google Scholar 

  27. Wang F, Cui N, Yang L, Shi L, Li Q, Zhang G, Wu J, Zheng J, Jiao B (2015) Resveratrol rescues the impairments of hippocampal neurons stimulated by microglial over-activation in vitro. Cell Mol Neurobiol 35(7):1003–1015. https://doi.org/10.1007/s10571-015-0195-5

    Article  CAS  PubMed  Google Scholar 

  28. Wang HL, Ma RH, Fang H, Xue ZG, Liao QW (2015) Impaired spatial learning memory after isoflurane anesthesia or appendectomy in aged mice is associated with microglia activation. J Cell Death 8:9–19. https://doi.org/10.4137/JCD.S30596

    Article  PubMed  PubMed Central  Google Scholar 

  29. Fetler L, Amigorena S (2005) Neuroscience. Brain under surveillance: the microglia patrol. Science 309(5733):392–393. https://doi.org/10.1126/science.1114852

    Article  CAS  PubMed  Google Scholar 

  30. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318. https://doi.org/10.1126/science.1110647

    Article  CAS  PubMed  Google Scholar 

  31. Landreth GE (2009) Microglia in central nervous system diseases. J Neuroimmune Pharmacol 4(4):369–370. https://doi.org/10.1007/s11481-009-9173-3

  32. Taetzsch T, Block ML (2013) Pesticides, microglial NOX2, and Parkinson’s disease. J Biochem Mol Toxicol 27(2):137–149. https://doi.org/10.1002/jbt.21464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Malm TM, Jay TR, Landreth GE (2015) The evolving biology of microglia in Alzheimer’s disease. Neurotherapeutics 12(1):81–93. https://doi.org/10.1007/s13311-014-0316-8

  34. Verina T, Kiihl SF, Schneider JS, Guilarte TR (2011) Manganese exposure induces microglia activation and dystrophy in the substantia nigra of non-human primates. Neurotoxicology 32(2):215–226. https://doi.org/10.1016/j.neuro.2010.11.003

    Article  CAS  PubMed  Google Scholar 

  35. Kumawat KL, Kaushik DK, Goswami P, Basu A (2014) Acute exposure to lead acetate activates microglia and induces subsequent bystander neuronal death via caspase-3 activation. Neurotoxicology 41:143–153. https://doi.org/10.1016/j.neuro.2014.02.002

    Article  CAS  PubMed  Google Scholar 

  36. Hu Z, Yu F, Gong P, Qiu Y, Zhou W, Cui Y, Li J, Chen H (2014) Subneurotoxic copper(II)-induced NF-kappaB-dependent microglial activation is associated with mitochondrial ROS. Toxicol Appl Pharmacol 276(2):95–103. https://doi.org/10.1016/j.taap.2014.01.020

    Article  CAS  PubMed  Google Scholar 

  37. Pisanu A, Lecca D, Mulas G, Wardas J, Simbula G, Spiga S, Carta AR (2014) Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-gamma agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson's disease. Neurobiol Dis 71:280–291. https://doi.org/10.1016/j.nbd.2014.08.011

    Article  CAS  PubMed  Google Scholar 

  38. Lloyd RV, Hanna PM, Mason RP (1997) The origin of the hydroxyl radical oxygen in the Fenton reaction. Free Radic Biol Med 22(5):885–888

    Article  CAS  Google Scholar 

  39. Kalehua AN, Nagel JE, Whelchel LM, Gides JJ, Pyle RS, Smith RJ, Kusiak JW, Taub DD (2004) Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 are involved in both excitotoxin-induced neurodegeneration and regeneration. Exp Cell Res 297(1):197–211. https://doi.org/10.1016/j.yexcr.2004.02.031

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (Nos. 81673220, 81273117, and 81773469).

Author information

Authors and Affiliations

  1. Department of Toxicology, School of Public Health, China Medical University, No.77 Puhe road, Shenyang North New Area, Shenyang, 110122, Liaoning province, People’s Republic of China

    Licheng Yan, Jinghua Yang, Miao Yu, Wenchang Sun, Yarao Han, Xiaobo Lu, Cuihong Jin, Shengwen Wu & Yuan Cai

  2. Department of Toxicology, School of Public Health, North China University of Science and Technology, No.21 Bohai road, Caofeidian New Area, Tangshan, 063210, Hebei province, People’s Republic of China

    Licheng Yan

Authors
  1. Licheng Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinghua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenchang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yarao Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaobo Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cuihong Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shengwen Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuan Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuan Cai.

Ethics declarations

Ethics Approval and Consent to Participate

The manuscript does not contain clinical studies or patient data. All experiments and surgical procedures complied with the Guide for the Care and Use of Laboratory Animals (NIH Publication, amended in 1996). The study was approved by the Local Ethics Committee (Laboratory Animal Welfare and Ethics Committee of the China Medical University, Shenyang, China).

Consent for Publication

Not applicable.

Conflict of Interest

The authors have declared that they have no conflicts of interest.

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 25 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yan, L., Yang, J., Yu, M. et al. Lanthanum Impairs Learning and Memory by Activating Microglia in the Hippocampus of Mice. Biol Trace Elem Res 200, 1640–1649 (2022). https://doi.org/10.1007/s12011-021-02637-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-021-02637-x

Keywords

Search

Navigation