Archives of Toxicology

, Volume 92, Issue 4, pp 1407–1419 | Cite as

Lanthanum chloride reduces lactate production in primary culture rat cortical astrocytes and suppresses primary co-culture rat cortical astrocyte-neuron lactate transport

  • Yaling Sun
  • Jinghua Yang
  • Xiaoyu Hu
  • Xiang Gao
  • Yingqi Li
  • Miao Yu
  • Shiyu Liu
  • Xiaobo Lu
  • Cuihong Jin
  • Shengwen Wu
  • Yuan Cai
Inorganic Compounds


Lanthanum (La) can impair learning memory and induce behavioral abnormalities in animals. However, the mechanism underlying these adverse effects of La is still elusive. It has been demonstrated that lactate derived from astrocytes is the major energy source for neurons during long-term memory (LTM) formation and the deficiency of lactate supply can result in LTM damage. However, little work has been done with respect to the impact of La on the lactate production in astrocytes and astrocyte-neuron lactate transport (ANLT). Herein, experiments were undertaken to explore if there was such an adverse effect of La. Primary culture rat cortical astrocytes and primary co-culture rat cortical astrocyte-neuron were treated with (0.125, 0.25 and 0.5 mM) lanthanum chloride (LaCl3) for 24 h. The results showed that LaCl3 treatment significantly downregulated the mRNA and protein expression of glucose transporter 1 (GLUT1), glycogen synthase (GS), glycogen phosphorylase (GP), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1, 2 and 4 (MCT 1 2 and 4); upregulated the mRNA and protein expression of lactate dehydrogenase B (LDHB); and decreased the glycogen level, total LDH and GP activity, GS/p-GS ratio and lactate contents. Moreover, rolipram (20, 40 μM) or forskolin (20, 40 μM) could increase the lactate content by upregulating GP expression and the GS/p-GS ratio, as well as antagonize the effects of La. These results suggested that La-induced learning-memory damage was probably related to its suppression of lactate production in astrocytes and ANLT. This study provides some novel clues for clarifying the mechanism underlying the neurotoxicity of La.


Lanthanum Lactate production Astrocyte-neuron lactate transport Long-term memory 





Astrocyte-neuron lactate transport


Long-term memory


Lanthanum chloride


Glucose transporter 1


Glycogen synthase


Glycogen phosphorylase


Lactate dehydrogenase


Monocarboxylate transporter







This work was supported by the National Nature Science Foundation of China (nos. 81273117 and 81673220 and 81373024). All experiments were conducted in compliance with the APPIVE guidelines.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.


  1. Andreev VA et al (2007) Measurement of the muon capture rate in hydrogen gas and determination of the proton’s pseudoscalar coupling gP. Phys Rev Lett 99:032002. CrossRefPubMedGoogle Scholar
  2. Belanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14:724–738. CrossRefPubMedGoogle Scholar
  3. Benarroch EE (2014) Brain glucose transporters: implications for. Neurol Dis Neurol 82:1374–1379. Google Scholar
  4. Blokland A, Schreiber R, Prickaerts J (2006) Improving memory: a role for phosphodiesterases. Curr Pharm Des 12:2511–2523CrossRefPubMedGoogle Scholar
  5. Bouskila M et al (2010) Allosteric regulation of glycogen synthase controls glycogen synthesis in muscle. Cell Metab 12:456–466. CrossRefPubMedGoogle Scholar
  6. Chen Z (2004) The hormesis effect of rare earths and potential impact of application in agriculture on the agriculture environment. Rural Ecol Environ 20:1–5 (in Chinese) Google Scholar
  7. Chen Z (2005) Brain accumulation, toxicity and potential hazards to human health in rare earths. Rural Ecol Environ 72:73–80 (in Chinese) Google Scholar
  8. Choeiri C, Staines W, Miki T, Seino S, Messier C (2005) Glucose transporter plasticity during memory processing. Neuroscience 130:591–600. CrossRefPubMedGoogle Scholar
  9. Chuquet J, Quilichini P, Nimchinsky EA, Buzsaki G (2010) Predominant enhancement of glucose uptake in astrocytes versus neurons during activation of the somatosensory cortex. J Neurosci 30:15298–15303. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Clarke LE, Barres BA (2013) Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 14:311–321. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cm C, George MA (2016) The popliteal vein thrombosis in a pediatric patient: a case report. J Orthop Case Rep 6:72–74. PubMedPubMedCentralGoogle Scholar
  12. Daneman R, Prat A (2015) The blood–brain barrier. Cold Spring Harb Perspect Biol. 7:a020412. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Dawson DM, Goodfriend TL, Kaplan NO (1964) Lactic dehydrogenases: functions of the two types rates of synthesis of the two major forms can be correlated with metabolic differentiation. Science 143:929–933CrossRefPubMedGoogle Scholar
  14. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 88:6368–6371CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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. Wei sheng yan jiu = J Hyg Res 33:23–28Google Scholar
  16. Fellin T, Pascual O, Haydon PG (2006) Astrocytes coordinate synaptic networks: balanced excitation and inhibition. Physiology 21:208–215. CrossRefPubMedGoogle Scholar
  17. Ghosh A, Highton D, Kolyva C, Tachtsidis I, Elwell CE, Smith M (2017) Hyperoxia results in increased aerobic metabolism following acute brain injury. J Cereb Blood Flow Metab 37:2910–2920. CrossRefPubMedGoogle Scholar
  18. Gibbs ME (2015) Role of glycogenolysis in memory and learning: regulation by noradrenaline, serotonin and ATP. Front Integr Neurosci. 9:70 PubMedGoogle Scholar
  19. Gibbs ME, Hertz L (2008) Inhibition of astrocytic energy metabolism by d-lactate exposure impairs memory. Neurochem Int 52:1012–1018. CrossRefPubMedGoogle Scholar
  20. Gibbs ME, O’Dowd BS, Hertz E, Hertz L (2006) Astrocytic energy metabolism consolidates memory in young chicks. Neuroscience 141:9–13. CrossRefPubMedGoogle Scholar
  21. Gramowski A, Jugelt K, Schroder OH, Weiss DG, Mitzner S (2011) Acute functional neurotoxicity of lanthanum(III) in primary cortical networks. Toxicol Sci 120:173–183. CrossRefPubMedGoogle Scholar
  22. Greenberg CC, Jurczak MJ, Danos AM, Brady MJ (2006) Glycogen branches out: new perspectives on the role of glycogen metabolism in the integration of metabolic pathways. Am J Physiol Endocrinol Metab 291:E1–E8. CrossRefPubMedGoogle Scholar
  23. Hartline DK (2011) The evolutionary origins of glia. Glia 59:1215–1236. CrossRefPubMedGoogle Scholar
  24. Heitland P, Koster HD (2006) Biomonitoring of 30 trace elements in urine of children and adults by ICP-MS. Clin Chim Acta 365:310–318. CrossRefPubMedGoogle Scholar
  25. Jakoby P, Schmidt E, Ruminot I, Gutierrez R, Barros LF, Deitmer JW (2014) Higher transport and metabolism of glucose in astrocytes compared with neurons: a multiphoton study of hippocampal and cerebellar tissue slices. Cereb Cortex 24:222–231. CrossRefPubMedGoogle Scholar
  26. Jancic D, Lopez de Armentia M, Valor LM, Olivares R, Barco A (2009) Inhibition of cAMP response element-binding protein reduces neuronal excitability and plasticity, and triggers neurodegeneration. Cereb Cortex 19:2535–2547. CrossRefPubMedGoogle Scholar
  27. Jiang C et al (2014) Low glucose utilization and neurodegenerative changes caused by sodium fluoride exposure in rat’s developmental brain. Neuromol Med 16:94–105. CrossRefGoogle Scholar
  28. Jin M, Huang Y, Hu Y, Qiao M, Wang X (2014) Rare earth elements content and health risk assessment of soil and crops in typical rare earth mine area in Jiangxi Province. Acta Sci Circumst 34:3084–3093Google Scholar
  29. Kettenmann H, Verkhratsky A (2008) Neuroglia: the 150 years after. Trends Neurosci 31:653–659. CrossRefPubMedGoogle Scholar
  30. Li N, Duan Y, Zhou M, Liu C, Hong F (2009) The effects of lanthanoid on the structure–function of lactate dehydrogenase from mice heart Biol. Trace Elem Res 132:164–175. CrossRefGoogle Scholar
  31. Libao R, Xiaoyan W, Qing X, Jingxiu L, Zhuo H, Ying D, Jingyu W (2007) Study on the correlation of light rare earth elements content in rat brain tissue. Chin J Anal Lab. Google Scholar
  32. Liu H et al (2014) Lanthanum chloride impairs spatial memory through ERK/MSK1 signaling pathway of hippocampus in rats. Neurochem Res 39:2479–2491. CrossRefPubMedGoogle Scholar
  33. Lu W et al (2015) Changes in lactate content and monocarboxylate transporter 2 expression in Abeta(2)(5)(-)(3)(5)-treated rat model of Alzheimer’s disease. Neurol Sci 36:871–876. CrossRefPubMedGoogle Scholar
  34. Lundgaard I et al (2015) Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism. Nat Commun 6:6807. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Machler P et al (2016) In vivo evidence for a lactate gradient from astrocytes to neurons. Cell Metab 23:94–102. CrossRefPubMedGoogle Scholar
  36. Magistretti PJ, Allaman I (2015) A cellular perspective on brain energy metabolism and functional imaging. Neuron 86:883–901. CrossRefPubMedGoogle Scholar
  37. Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2:679–689. CrossRefPubMedGoogle Scholar
  38. Matsui T, Omuro H, Liu YF, Soya M, Shima T, McEwen BS, Soya H (2017) Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity. Proc Natl Acad Sci USA 114:6358–6363. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Newman LA, Korol DL, Gold PE (2011) Lactate produced by glycogenolysis in astrocytes regulates memory processing. PloS One. Google Scholar
  40. Obel LF, Muller MS, Walls AB, Sickmann HM, Bak LK, Waagepetersen HS, Schousboe A (2012) Brain glycogen-new perspectives on its metabolic function and regulation at the subcellular level. Front Neuroenerg 4:3. CrossRefGoogle Scholar
  41. Oz G et al (2007) Human brain glycogen content and metabolism: implications on its role in brain energy metabolism. Am J Physiol Endocrinol Metab 292:E946–E951. CrossRefPubMedGoogle Scholar
  42. Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci USA 91:10625–10629CrossRefPubMedPubMedCentralGoogle Scholar
  43. Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, Magistretti PJ (2007) Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55:1251–1262. CrossRefPubMedGoogle Scholar
  44. Pfeiffer B, Elmer K, Roggendorf W, Reinhart PH, Hamprecht B (1990) Immunohistochemical demonstration of glycogen phosphorylase in rat brain slices. Histochemistry 94:73–80CrossRefPubMedGoogle Scholar
  45. Pierre K, Pellerin L (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 94:1–14. CrossRefPubMedGoogle Scholar
  46. Roach PJ et al (1998) Novel aspects of the regulation of glycogen storage. J Basic Clin Physiol Pharmacol 9:139–151CrossRefPubMedGoogle Scholar
  47. Rutten K, Lieben C, Smits L, Blokland A (2007a) The PDE4 inhibitor rolipram reverses object memory impairment induced by acute tryptophan depletion in the rat. Psychopharmacology (Berl) 192:275–282. CrossRefGoogle Scholar
  48. Rutten K, Prickaerts J, Hendrix M, van der Staay FJ, Sik A, Blokland A (2007b) Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors. Eur J Pharmacol 558:107–112. CrossRefPubMedGoogle Scholar
  49. Shammas FV, Engeset A (1986) Glycogen content and PAS staining pattern of human megakaryocytes. Scand J Haematol 37:237–242CrossRefPubMedGoogle Scholar
  50. Steinman MQ, Gao V, Alberini CM (2016) The role of lactate-mediated metabolic coupling between astrocytes and neurons in long-term memory formation. Front Integr Neurosci 10:10 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144:810–823. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Swanson RA, Choi DW (1993) Glial glycogen stores affect neuronal survival during glucose deprivation in vitro. J Cereb Blood Flow Metab 13:162–169. CrossRefPubMedGoogle Scholar
  53. Tabatabaei Shafiei M, Carvajal Gonczi CM, Rahman MS, East A, Francois J, Darlington PJ (2014) Detecting glycogen in peripheral blood mononuclear cells with periodic acid schiff staining. J Vis Exp. PubMedPubMedCentralGoogle Scholar
  54. Tadi M, Allaman I, Lengacher S, Grenningloh G, Magistretti PJ (2015) Learning-induced gene expression in the hippocampus reveals a role of neuron -astrocyte metabolic coupling in long term memory. PloS One 10:e0141568. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Temple S (2001) The development of neural stem cells. Nature 414:112–117. CrossRefPubMedGoogle Scholar
  56. Wang DD, Bordey A (2008) The astrocyte odyssey. Progress Neurobiol 86:342–367. Google Scholar
  57. Wang J et al (2007) Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 168:176–185. CrossRefPubMedGoogle Scholar
  58. Wyss MT, Jolivet R, Buck A, Magistretti PJ, Weber B (2011) In vivo evidence for lactate as a neuronal energy source. J Neurosci 31:7477–7485. CrossRefPubMedGoogle Scholar
  59. Xiaofei L, Zhibiao C, yonghe Z, Zhiqiang C (2013) Evaluation of rare earth elements content and health risk of soil and vegetables in rare earth mining area. J Environ Sci:835–843Google Scholar
  60. Yang J et al (2009) Lanthanum chloride impairs memory, decreases pCaMK IV, pMAPK and pCREB expression of hippocampus in rats. Toxicol Lett 190:208–214. CrossRefPubMedGoogle Scholar
  61. Yang J, Liu Q, Qi M, Lu S, Wu S, Xi Q, Cai Y (2013) Lanthanum chloride promotes mitochondrial apoptotic pathway in primary cultured rat astrocytes. Environ Toxicol 28:489–497. CrossRefPubMedGoogle Scholar
  62. Zhang XJ, Li TY, Liu YX, Chen J, Qu P, Wei XP, He J (2010) Primary culture of rat hippocampal neurons and detection of the neuronal excitability. Nan fang yi ke da xue xue bao = J South Med Univ 30:2080–2083Google Scholar
  63. Zhang L et al (2017a) The effect of nuclear factor erythroid 2-related factor/antioxidant response element signalling pathway in the lanthanum chloride-induced impairment of learning and memory in rats. J Neurochem 140:463–475. CrossRefPubMedGoogle Scholar
  64. Zhang L et al (2017b) Activation of Nrf2/ARE signaling pathway attenuates lanthanum chloride induced injuries in primary rat astrocytes. Metallomics 9:1120–1131. CrossRefPubMedGoogle Scholar
  65. Zhao Y, Yang J, QufangLiu, Jin C, Wu S, Wang C, Cai Y (2013) Effects of lanthanum on the spatial learning, memory,c AMP content and PKA expression in the hippocampus of rats. J Toxicol:321–324Google Scholar
  66. Zheng L et al (2013) Lanthanum chloride impairs spatial learning and memory and downregulates NF-kappaB signalling pathway in rats. Arch Toxicol 87:2105–2117. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Yaling Sun
    • 1
  • Jinghua Yang
    • 1
  • Xiaoyu Hu
    • 1
  • Xiang Gao
    • 1
  • Yingqi Li
    • 1
  • Miao Yu
    • 1
  • Shiyu Liu
    • 1
  • Xiaobo Lu
    • 1
  • Cuihong Jin
    • 1
  • Shengwen Wu
    • 1
  • Yuan Cai
    • 1
  1. 1.Department of Toxicology, School of Public HealthChina Medical UniversityShenyangPeople’s Republic of China

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