Neurochemical Research

, Volume 43, Issue 4, pp 948–958 | Cite as

Inhibition of miR-219 Alleviates Arsenic-Induced Learning and Memory Impairments and Synaptic Damage Through Up-regulating CaMKII in the Hippocampus

  • Dunjia Wang
  • Xiaodong Wang
  • Xiaofang Liu
  • Liping Jiang
  • Guang Yang
  • Xiaoxia Shi
  • Cong Zhang
  • Fengyuan Piao
Original Paper


Epidemiological investigations and experimental studies indicate that chronic arsenic exposure can reduce learning and memory function. However, the underlying mechanism of this effect remains largely unknown. Emerging evidence suggests that microRNA (miRNA) play an important role in toxicant exposure and a regulatory role in cognitive function. In this study, we observed that subchronic arsenic exposure induced impairment of learning and memory and significantly up-regulated miRNA-219 (miR-219) expression in the mouse hippocampus. Furthermore, the expression of CaMKII, an experimentally validated target of miR-219, was decreased in the mice exposed to arsenic. Suppression of miR-219 by adeno-associated viral (AAV)-delivered anti-miR-219 prevented the arsenic-induced impairment of learning and memory and relieved the pathological changes in the synaptic structure of the hippocampus. Furthermore, we observed that the NMDA receptor subunit 2 (NR2) and the memory-related proteins c-Fos and c-Jun were up-regulated by inhibition of miR-219 in the mouse hippocampus. Taken together, the results of this study indicate that inhibition of miR-219 regulates arsenic-induced damage in the structure of the hippocampus and impairment of learning and memory, possibly by targeting CaMKII. Suppression of miR-219 may be a potential strategy to ameliorate arsenic-induced neurotoxicity.


Arsenic miR-219 Learning and memory Hippocampus CaMKII 



This work was supported by the Basic Research Projects of Colleges and Universities of Liaoning Province, China (LQ2017037).


  1. 1.
    Chen KL, Wu HY (1962) Epidemiologic studies on blackfoot disease. 2. A study of source of drinking water in relation to the disease. Taiwan Yi Xue Hui Za Zhi 61:611–618PubMedGoogle Scholar
  2. 2.
    Chowdhury UK, Biswas BK, Chowdhury TR, Samanta G, Mandal BK, Basu GC, Chanda CR, Lodh D, Saha KC, Mukherjee SK (2000) Groundwater arsenic contamination in Bangladesh and West Bengal, India. Environ Health Perspect 108:393–397CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Rahman M, Tondel M, Ahmad SA, Axelson O (1998) Diabetes mellitus associated with arsenic exposure in Bangladesh. Am J Epidemiol 148:198–203CrossRefPubMedGoogle Scholar
  4. 4.
    Wasserman GA, Liu X, Parvez F, Ahsan H, Factor-Litvak P, van Geen A, Slavkovich V, LoIacono NJ, Cheng Z, Hussain I (2004) Water arsenic exposure and children’s intellectual function in Araihazar, Bangladesh. Environ Health Perspect 112:1329–1333CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Wright RO, Amarasiriwardena C, Woolf AD, Jim R, Bellinger DC (2006) Neuropsychological correlates of hair arsenic, manganese, and cadmium levels in school-age children residing near a hazardous waste site. Neurotoxicology 27:210–216CrossRefPubMedGoogle Scholar
  6. 6.
    Baldissarelli LA, Capiotti KM, Bogo MR, Ghisleni G, Bonan CD (2012) Arsenic alters behavioral parameters and brain ectonucleotidases activities in zebrafish (Danio rerio). Comp Biochem Physiol C 155:566–572Google Scholar
  7. 7.
    Jing J, Zheng G, Liu M, Shen X, Zhao F, Wang J, Zhang J, Huang G, Dai P, Chen Y (2012) Changes in the synaptic structure of hippocampal neurons and impairment of spatial memory in a rat model caused by chronic arsenite exposure. Neurotoxicology 33:1230–1238CrossRefPubMedGoogle Scholar
  8. 8.
    Deng Y, Ai J, Guan X, Wang Z, Yan B, Zhang D, Liu C, Wilbanks MS, Escalon BL, Meyers SA (2014) MicroRNA and messenger RNA profiling reveals new biomarkers and mechanisms for RDX induced neurotoxicity. BMC Genomics 15(Suppl 11):S1CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    An J, Cai T, Che H, Yu T, Cao Z, Liu X, Zhao F, Jing J, Shen X, Liu M (2014) The changes of miRNA expression in rat hippocampus following chronic lead exposure. Toxicol Lett 229:158–166CrossRefPubMedGoogle Scholar
  10. 10.
    Qi Y, Zhang M, Li H, Frank JA, Dai L, Liu H, Chen G (2014) MicroRNA-29b regulates ethanol-induced neuronal apoptosis in the developing cerebellum through SP1/RAX/PKR cascade. J Biol Chem 289:10201–10210CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114CrossRefPubMedGoogle Scholar
  12. 12.
    Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng HY, Marks D, Obrietan K, Soderling TR, Goodman RH, Impey S (2008) An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci USA 105:9093–9098CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Visvanathan J, Lee S, Lee B, Lee JW, Lee SK (2007) The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev 21:744–749CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bredy TW, Lin Q, Wei W, Baker-Andresen D, Mattick JS (2011) MicroRNA regulation of neural plasticity and memory. Neurobiol Learn Mem 96:89–94CrossRefPubMedGoogle Scholar
  15. 15.
    Lee K, Kim JH, Kwon OB, An K, Ryu J, Cho K, Suh YH, Kim HS (2012) An activity-regulated microRNA, miR-188, controls dendritic plasticity and synaptic transmission by downregulating neuropilin-2. J Neurosci 32:5678–5687CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Siegel G, Saba R, Schratt G (2011) microRNAs in neurons: manifold regulatory roles at the synapse. Curr Opin Genet Dev 21:491–497CrossRefPubMedGoogle Scholar
  17. 17.
    Cheng HY, Papp JW, Varlamova O, Dziema H, Russell B, Curfman JP, Nakazawa T, Shimizu K, Okamura H, Impey S, Obrietan K (2007) microRNA modulation of circadian-clock period and entrainment. Neuron 54:813–829CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Lukiw WJ (2007) Micro-RNA speciation in fetal, adult and Alzheimer’s disease hippocampus. Neuroreport 18:297–300CrossRefPubMedGoogle Scholar
  19. 19.
    Wibrand K, Panja D, Tiron A, Ofte ML, Skaftnesmo KO, Lee CS, Pena JT, Tuschl T, Bramham CR (2010) Differential regulation of mature and precursor microRNA expression by NMDA and metabotropic glutamate receptor activation during LTP in the adult dentate gyrus in vivo. Eur J Neurosci 31:636–645CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wang F, Liu W, Jin Y, Wang F, Ma J (2015) Prenatal and neonatal exposure to perfluorooctane sulfonic acid results in aberrant changes in miRNA expression profile and levels in developing rat livers. Environ Toxicol 30:712–723CrossRefPubMedGoogle Scholar
  21. 21.
    Goto G, Hori Y, Ishikawa M, Tanaka S, Sakamoto A (2014) Changes in the gene expression levels of microRNAs in the rat hippocampus by sevoflurane and propofol anesthesia. Mol Med Rep 9:1715–1722CrossRefPubMedGoogle Scholar
  22. 22.
    Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MG, Sales N, Willoughby D, Elmen J, Hansen HF (2009) MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci USA 106:3507–3512CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wang Y, Zhao F, Liao Y, Jin Y, Sun G (2013) Effects of arsenite in astrocytes on neuronal signaling transduction. Toxicology 303:43–53CrossRefPubMedGoogle Scholar
  24. 24.
    Liu S, Piao F, Sun X, Bai L, Peng Y, Zhong Y, Ma N, Sun W (2012) Arsenic-induced inhibition of hippocampal neurogenesis and its reversibility. Neurotoxicology 33:1033–1039CrossRefPubMedGoogle Scholar
  25. 25.
    Foerch C, Arai K, Jin G, Park KP, Pallast S, van Leyen K, Lo EH (2008) Experimental model of warfarin-associated intracerebral hemorrhage. Stroke 39:3397–3404CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ferretti V, Roullet P, Sargolini F, Rinaldi A, Perri V, Del Fabbro M, Costantini VJ, Annese V, Scesa G, De Stefano ME (2010) Ventral striatal plasticity and spatial memory. Proc Natl Acad Sci USA 107:7945–7950CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Guldner FH, Ingham CA (1980) Increase in postsynaptic density material in optic target neurons of the rat suprachiasmatic nucleus after bilateral enucleation. Neurosci Lett 17:27–31CrossRefPubMedGoogle Scholar
  28. 28.
    Luceri C, Bigagli E, Pitozzi V, Giovannelli L (2017) A nutrigenomics approach for the study of anti-aging interventions: olive oil phenols and the modulation of gene and microRNA expression profiles in mouse brain. Eur J Nutr 56:865–877CrossRefPubMedGoogle Scholar
  29. 29.
    Lin SL (2015) microRNAs and fragile × syndrome. Adv Exp Med Biol 888:107–121CrossRefPubMedGoogle Scholar
  30. 30.
    Wang L, Bammler TK, Beyer RP, Gallagher EP (2013) Copper-induced deregulation of microRNA expression in the zebrafish olfactory system. Environ Sci Technol 47:7466–7474CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhang C, Li S, Sun Y, Dong W, Piao F, Piao Y, Liu S, Guan H, Yu S (2014) Arsenic downregulates gene expression at the postsynaptic density in mouse cerebellum, including genes responsible for long-term potentiation and depression. Toxicol Lett 228:260–269CrossRefPubMedGoogle Scholar
  32. 32.
    Abe M, Bonini NM (2013) MicroRNAs and neurodegeneration: role and impact. Trends Cell Biol 23:30–36CrossRefPubMedGoogle Scholar
  33. 33.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Im HI, Kenny PJ (2012) MicroRNAs in neuronal function and dysfunction. Trends Neurosci 35:325–334CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Bondy SC (2010) The neurotoxicity of environmental aluminum is still an issue. Neurotoxicology 31:575–581CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Pogue AI, Li YY, Cui JG, Zhao Y, Kruck TP, Percy ME, Tarr MA, Lukiw WJ (2009) Characterization of an NF-kappaB-regulated, miRNA-146a-mediated down-regulation of complement factor H (CFH) in metal-sulfate-stressed human brain cells. J Inorg Biochem 103:1591–1595CrossRefPubMedGoogle Scholar
  37. 37.
    Li W, He QZ, Wu CQ, Pan XY, Wang J, Tan Y, Shan XY, Zeng HC (2015) PFOS disturbs BDNF-ERK-CREB signalling in association with increased MicroRNA-22 in SH-SY5Y cells. Biomed Res Int 2015:302653PubMedPubMedCentralGoogle Scholar
  38. 38.
    Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V (2004) Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 5:R13CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Bourne JN, Harris KM (2008) Balancing structure and function at hippocampal dendritic spines. Annu Rev Neurosci 31:47–67CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    McNeill E, Van Vactor D (2012) MicroRNAs shape the neuronal landscape. Neuron 75:363–379CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Luo JH, Qiu ZQ, Shu WQ, Zhang YY, Zhang L, Chen JA (2009) Effects of arsenic exposure from drinking water on spatial memory, ultra-structures and NMDAR gene expression of hippocampus in rats. Toxicol Lett 184:121–125CrossRefPubMedGoogle Scholar
  42. 42.
    Chao HW, Tsai LY, Lu YL, Lin PY, Huang WH, Chou HJ, Lu WH, Lin HC, Lee PT, Huang YS (2013) Deletion of CPEB3 enhances hippocampus-dependent memory via increasing expressions of PSD95 and NMDA receptors. J Neurosci 33:17008–17022CrossRefPubMedGoogle Scholar
  43. 43.
    Seeburg DP, Feliu-Mojer M, Gaiottino J, Pak DT, Sheng M (2008) Critical role of CDK5 and Polo-like kinase 2 in homeostatic synaptic plasticity during elevated activity. Neuron 58:571–583CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Pan Z, Zhu LJ, Li YQ, Hao LY, Yin C, Yang JX, Guo Y, Zhang S, Hua L, Xue ZY (2014) Epigenetic modification of spinal miR-219 expression regulates chronic inflammation pain by targeting CaMKIIgamma. J Neurosci 34:9476–9483CrossRefPubMedGoogle Scholar
  45. 45.
    Sheng M, Kim MJ (2002) Postsynaptic signaling and plasticity mechanisms. Science 298:776–780CrossRefPubMedGoogle Scholar
  46. 46.
    Swulius MT, Kubota Y, Forest A, Waxham MN (2010) Structure and composition of the postsynaptic density during development. J Comp Neurol 518:4243–4260CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Moyano S, Frechilla D, Del Rio J (2004) NMDA receptor subunit and CaMKII changes in rat hippocampus induced by acute MDMA treatment: a mechanism for learning impairment. Psychopharmacology 173:337–345CrossRefPubMedGoogle Scholar
  48. 48.
    Sanhueza M, Fernandez-Villalobos G, Stein IS, Kasumova G, Zhang P, Bayer KU, Otmakhov N, Hell JW, Lisman J (2011) Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength. J Neurosci 31:9170–9178CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Lisman J, Schulman H, Cline H (2002) The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3:175–190CrossRefPubMedGoogle Scholar
  50. 50.
    Xia Z, Dudek H, Miranti CK, Greenberg ME (1996) Calcium influx via the NMDA receptor induces immediate early gene transcription by a MAP kinase/ERK-dependent mechanism. J Neurosc 16:5425–5436CrossRefGoogle Scholar
  51. 51.
    Kass-Simon G, Zompa MA, Scappaticci AA, Zackroff RV, Hufnagel LA (2009) Nucleolar binding of an anti-NMDA receptor antibody in hydra: a non-canonical role for an NMDA receptor protein? J Exp Zool A Ecol Genet Physiol 311:763–775CrossRefPubMedGoogle Scholar
  52. 52.
    Park CS, Elgersma Y, Grant SG, Morrison JH (2008) alpha-Isoform of calcium-calmodulin-dependent protein kinase II and postsynaptic density protein 95 differentially regulate synaptic expression of NR2A- and NR2B-containing N-methyl-d-aspartate receptors in hippocampus. Neuroscience 151:43–55CrossRefPubMedGoogle Scholar
  53. 53.
    Wang J, Xu W, Shao J, He Z, Ding Z, Huang J, Guo Q, Zou W (2017) miR-219-5p targets CaMKIIgamma to attenuate morphine tolerance in rats. Oncotarget 8:28203–28214PubMedPubMedCentralGoogle Scholar
  54. 54.
    Luo JH, Qiu ZQ, Zhang L, Shu WQ (2012) Arsenite exposure altered the expression of NMDA receptor and postsynaptic signaling proteins in rat hippocampus. Toxicol Lett 211:39–44CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Dunjia Wang
    • 1
  • Xiaodong Wang
    • 2
  • Xiaofang Liu
    • 3
  • Liping Jiang
    • 4
    • 5
  • Guang Yang
    • 3
  • Xiaoxia Shi
    • 1
  • Cong Zhang
    • 3
  • Fengyuan Piao
    • 1
  1. 1.Department of Occupational and Environmental HealthDalian Medical UniversityDalianPeople’s Republic of China
  2. 2.Digestive Endoscopic Department of the second Hospital of Jilin UniversityChangchunPeople’s Republic of China
  3. 3.3Department of Food Nutrition and SafetyDalian Medical UniversityDalianPeople’s Republic of China
  4. 4.4Preventive Medicine Laboratory, School of Public HealthDalian Medical UniversityDalianPeople’s Republic of China
  5. 5.Liaoning Anti-Degenerative Diseases Natural Products Engineering Research CenterDalian Medical UniversityDalianPeople’s Republic of China

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