Neurotoxicity Research

, Volume 21, Issue 1, pp 128–141 | Cite as

Zinc and the ERK Kinases in the Developing Brain

  • J. R. Nuttall
  • P. I. OteizaEmail author
Review Article


This article reviews evidence in support of the hypothesis that impaired activation of the extracellular signal-regulated kinases (ERK1/2) contributes to the disruptions in neurodevelopment associated with zinc deficiency. These kinases are implicated in major events of brain development, including proliferation of progenitor cells, neuronal migration, differentiation, and apoptotic cell death. In humans, mutations in ERK1/2 genes have been associated with neuro-cardio-facial-cutaneous syndromes. ERK1/2 deficits in mice have revealed impaired neurogenesis, altered cellularity, and behavioral abnormalities. Zinc is an important modulator of ERK1/2 signaling. Conditions of both zinc deficiency and excess affect ERK1/2 phosphorylation in fetal and adult brains. Hypophosphorylation of ERK1/2, associated with decreased zinc availability in cell cultures, is accompanied by decreased proliferation and an arrest of the cell cycle at the G0/G1 phase. Zinc and ERK1/2 have both been shown to modulate neural progenitor cell proliferation and cell death in the brain. Furthermore, behavioral deficits resulting from developmental zinc deficiency are similar to those observed in mice with decreased ERK1/2 signaling. For example, impaired performance on behavioral tests of learning and memory; such as the Morris water maze, fear conditioning, and the radial arm maze; has been reported in both animals exposed to developmental zinc deficiency and transgenic mice with decreased ERK signaling. Future study should clarify the mechanisms through which a dysregulation of ERK1/2 may contribute to altered brain development associated with dietary zinc deficiency and with conditions that limit zinc availability.


Zinc Brain ERK Brain development Zinc deficiency MAPK Neuron 



Attention deficit-hyperactivity disorder


Brain-derived neurotrophic factor


cAMP-responsive element binding protein


C-terminal Src kinase


Embryonic day


Extracellular signal-regulated kinases


Glial fibrillary acidic protein


G-protein coupled receptor 39


c-Jun N-terminal kinases


Mitogen activated protein kinase


Mitogen activated ERK kinase


Matrix metalloproteinases


Neuro-cardio-facial-cutaneous syndromes


N-methyl-d-aspartate sensitive glutamate receptor


Postnatal day


Rat cortical neurons


Src family kinases


Son of sevenless


Tropomyosin-receptor-kinase B



This study was supported by grants from the University of California, Davis, and NIH (grant # HD 01743), USA.


  1. Adamo AM, Zago MP, Mackenzie GG, Aimo L, Keen CL, Keenan A, Oteiza PI (2010) The role of zinc in the modulation of neuronal proliferation and apoptosis. Neurotoxic Res 17:1–14Google Scholar
  2. Adlard PA, Parncutt JM, Finkelstein DI, Bush AI (2010) Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer’s disease? J Neurosci 30:1631–1636PubMedGoogle Scholar
  3. Aimo L, Cherr GN, Oteiza PI (2010a) Low extracellular zinc increases neuronal oxidant production through NADPH oxidase and nitric oxide synthase activation. Free Radic Biol Med 48:1577–1587PubMedGoogle Scholar
  4. Aimo L, Mackenzie GG, Keenan AH, Oteiza PI (2010b) Gestational zinc deficiency affects the regulation of transcription factors AP-1, NF-kappaB and NFAT in fetal brain. J Nutr Biochem 21:1069–1075PubMedGoogle Scholar
  5. Akhondzadeh S, Mohammadi MR, Khademi M (2004) Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial [ISRCTN64132371]. BMC Psychiatry 4:9PubMedGoogle Scholar
  6. Alessandrini A, Namura S, Moskowitz MA, Bonventre JV (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci USA 96:12866–12869PubMedGoogle Scholar
  7. Amani R, Saeidi S, Nazari Z, Nematpour S (2010) Correlation between dietary zinc intakes and its serum levels with depression scales in young female students. Biol Trace Elem Res 137:150–158PubMedGoogle Scholar
  8. Andrews RC (1992) An update of the zinc deficiency theory of schizophrenia. Identification of the sex determining system as the site of action of reproductive zinc deficiency. Med Hypotheses 38:284–291PubMedGoogle Scholar
  9. Apgar J (1968) Effect of zinc deficiency on parturition in the rat. Am J Physiol 215:160–163PubMedGoogle Scholar
  10. Arnold LE, DiSilvestro RA (2005) Zinc in attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 15:619–627PubMedGoogle Scholar
  11. Arnold LE, Bozzolo H, Hollway J, Cook A, DiSilvestro RA, Bozzolo DR, Crowl L, Ramadan Y, Williams C (2005) Serum zinc correlates with parent- and teacher- rated inattention in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 15:628–636PubMedGoogle Scholar
  12. Arnold LE, Disilvestro RA, Bozzolo D, Bozzolo H, Crowl L, Fernandez S, Ramadan Y, Thompson S, Mo X, Abdel-Rasoul M, Joseph E (2011) Zinc for attention-deficit/hyperactivity disorder: placebo-controlled double-blind pilot trial alone and combined with amphetamine. J Child Adolesc Psychopharmacol 21:1–19PubMedGoogle Scholar
  13. Azman MS, Wan Saudi WS, Ilhami M, Mutalib MS, Rahman MT (2009) Zinc intake during pregnancy increases the proliferation at ventricular zone of the newborn brain. Nutr Neurosci 12:9–12PubMedGoogle Scholar
  14. Bentley ME, Caulfield LE, Ram M, Santizo MC, Hurtado E, Rivera JA, Ruel MT, Brown KH (1997) Zinc supplementation affects the activity patterns of rural Guatemalan infants. J Nutr 127:1333–1338PubMedGoogle Scholar
  15. Besser L, Chorin E, Sekler I, Silverman WF, Atkin S, Russell JT, Hershfinkel M (2009) Synaptically released zinc triggers metabotropic signaling via a zinc-sensing receptor in the hippocampus. J Neurosci 29:2890–2901PubMedGoogle Scholar
  16. Bhutta ZA, Black RE, Brown KH, Gardner JM, Gore S, Hidayat A, Khatun F, Martorell R, Ninh NX, Penny ME, Rosado JL, Roy SK, Ruel M, Sazawal S, Shankar A (1999) Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Zinc Investigators’ Collaborative Group. J Pediatr 135:689–697PubMedGoogle Scholar
  17. Bilici M, Yildirim F, Kandil S, Bekaroglu M, Yildirmis S, Deger O, Ulgen M, Yildiran A, Aksu H (2004) Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry 28:181–190PubMedGoogle Scholar
  18. Black MM (2003) The evidence linking zinc deficiency with children’s cognitive and motor functioning. J Nutr 133:1473S–1476SPubMedGoogle Scholar
  19. Boulton TG, Nye SH, Robbins DJ, Ip NY, Radziejewska E, Morgenbesser SD, DePinho RA, Panayotatos N, Cobb MH, Yancopoulos GD (1991) ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65:663–675PubMedGoogle Scholar
  20. Brenton DP, Jackson MJ, Young A (1981) Two pregnancies in a patient with acrodermatitis enteropathica treated with zinc sulphate. Lancet 2:500–502PubMedGoogle Scholar
  21. Briefel RR, Bialostosky K, Kennedy-Stephenson J, McDowell MA, Ervin RB, Wright JD (2000) Zinc intake of the U.S. population: findings from the third National Health and Nutrition Examination Survey, 1988–1994. J Nutr 130:1367S–1373SPubMedGoogle Scholar
  22. Brown KH, Peerson JM, Rivera J, Allen LH (2002) Effect of supplemental zinc on the growth and serum zinc concentrations of prepubertal children: a meta-analysis of randomized controlled trials. Am J Clin Nutr 75:1062–1071PubMedGoogle Scholar
  23. Brunet A, Roux D, Lenormand P, Dowd S, Keyse S, Pouyssegur J (1999) Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry. EMBO J 18:664–674PubMedGoogle Scholar
  24. Charest DL, Mordret G, Harder KW, Jirik F, Pelech SL (1993) Molecular cloning, expression, and characterization of the human mitogen-activated protein kinase p44erk1. Mol Cell Biol 13:4679–4690PubMedGoogle Scholar
  25. Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT (2001) Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50:260–265PubMedGoogle Scholar
  26. Choi YS, Cho HY, Hoyt KR, Naegele JR, Obrietan K (2008) IGF-1 receptor-mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus. Glia 56:791–800PubMedGoogle Scholar
  27. Chowanadisai W, Kelleher SL, Lonnerdal B (2005) Maternal zinc deficiency reduces NMDA receptor expression in neonatal rat brain, which persists into early adulthood. J Neurochem 94:510–519PubMedGoogle Scholar
  28. Cieslik K, Sowa-Kucma M, Ossowska G, Legutko B, Wolak M, Opoka W, Nowak G (2011) Chronic unpredictable stress-induced reduction in the hippocampal brain-derived neurotrophic factor (BDNF) gene expression is antagonized by zinc treatment. Pharmacol Rep 63:537–543PubMedGoogle Scholar
  29. Cole TB, Wenzel HJ, Kafer KE, Schwartzkroin PA, Palmiter RD (1999) Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc Natl Acad Sci USA 96:1716–1721PubMedGoogle Scholar
  30. Cole TB, Martyanova A, Palmiter RD (2001) Removing zinc from synaptic vesicles does not impair spatial learning, memory, or sensorimotor functions in the mouse. Brain Res 891:253–265PubMedGoogle Scholar
  31. Corniola RS, Tassabehji NM, Hare J, Sharma G, Levenson CW (2008) Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms. Brain Res 1237:52–61PubMedGoogle Scholar
  32. Corona C, Masciopinto F, Silvestri E, Viscovo AD, Lattanzio R, Sorda RL, Ciavardelli D, Goglia F, Piantelli M, Canzoniero LM, Sensi SL (2010) Dietary zinc supplementation of 3×Tg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction. Cell Death Dis 1:e91PubMedGoogle Scholar
  33. Coyle P, Tran N, Fung JN, Summers BL, Rofe AM (2009) Maternal dietary zinc supplementation prevents aberrant behaviour in an object recognition task in mice offspring exposed to LPS in early pregnancy. Behav Brain Res 197:210–218PubMedGoogle Scholar
  34. Creson TK, Hao Y, Engel S, Shen Y, Hamidi A, Zhuo M, Manji HK, Chen G (2009) The anterior cingulate ERK pathway contributes to regulation of behavioral excitement and hedonic activity. Bipolar Disord 11:339–350PubMedGoogle Scholar
  35. Davies SP, Reddy H, Caivano M, Cohen P (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351:95–105PubMedGoogle Scholar
  36. DiGirolamo AM, Ramirez-Zea M, Wang M, Flores-Ayala R, Martorell R, Neufeld LM, Ramakrishnan U, Sellen D, Black MM, Stein AD (2010) Randomized trial of the effect of zinc supplementation on the mental health of school-age children in Guatemala. Am J Clin Nutr 92:1241–1250PubMedGoogle Scholar
  37. Dufner-Beattie J, Langmade SJ, Wang F, Eide D, Andrews GK (2003) Structure, function, and regulation of a subfamily of mouse zinc transporter genes. J Biol Chem 278:50142–50150PubMedGoogle Scholar
  38. Dvergsten CL, Fosmire GJ, Ollerich DA, Sandstead HH (1983) Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. I. Impaired acquisition of granule cells. Brain Res 271:217–226PubMedGoogle Scholar
  39. Dvergsten CL, Fosmire GJ, Ollerich DA, Sandstead HH (1984a) Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. II. Impaired maturation of Purkinje cells. Brain Res 318:11–20PubMedGoogle Scholar
  40. Dvergsten CL, Johnson LA, Sandstead HH (1984b) Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. III. Impaired dendritic differentiation of basket and stellate cells. Brain Res 318:21–26PubMedGoogle Scholar
  41. Engel SR, Creson TK, Hao Y, Shen Y, Maeng S, Nekrasova T, Landreth GE, Manji HK, Chen G (2009) The extracellular signal-regulated kinase pathway contributes to the control of behavioral excitement. Mol Psychiatry 14:448–461PubMedGoogle Scholar
  42. Ferguson SM, Fasano S, Yang P, Brambilla R, Robinson TE (2006) Knockout of ERK1 enhances cocaine-evoked immediate early gene expression and behavioral plasticity. Neuropsychopharmacology 31:2660–2668PubMedGoogle Scholar
  43. Franco JL, Posser T, Brocardo PS, Trevisan R, Uliano-Silva M, Gabilan NH, Santos AR, Leal RB, Rodrigues AL, Farina M, Dafre AL (2008) Involvement of glutathione, ERK1/2 phosphorylation and BDNF expression in the antidepressant-like effect of zinc in rats. Behav Brain Res 188:316–323PubMedGoogle Scholar
  44. Fyffe-Maricich SL, Karlo JC, Landreth GE, Miller RH (2011) The ERK2 mitogen-activated protein kinase regulates the timing of oligodendrocyte differentiation. J Neurosci 31:843–850PubMedGoogle Scholar
  45. Gao HL, Zheng W, Xin N, Chi ZH, Wang ZY, Chen J (2009) Zinc deficiency reduces neurogenesis accompanied by neuronal apoptosis through caspase-dependent and -independent signaling pathways. Neurotoxic Res 16:416–425Google Scholar
  46. Gao HL, Xu H, Xin N, Zheng W, Chi ZH, Wang ZY (2011) Disruption of the CaMKII/CREB signaling is associated with zinc deficiency-induced learning and memory impairments. Neurotoxic Res 19:584–591Google Scholar
  47. Gardner JM, Powell CA, Baker-Henningham H, Walker SP, Cole TJ, Grantham-McGregor SM (2005) Zinc supplementation and psychosocial stimulation: effects on the development of undernourished Jamaican children. Am J Clin Nutr 82:399–405PubMedGoogle Scholar
  48. Golub MS, Keen CL, Gershwin ME, Hendrickx AG (1995) Developmental zinc deficiency and behavior. J Nutr 125:2263S–2271SPubMedGoogle Scholar
  49. Golub MS, Takeuchi PT, Keen CL, Hendrickx AG, Gershwin ME (1996) Activity and attention in zinc-deprived adolescent monkeys. Am J Clin Nutr 64:908–915PubMedGoogle Scholar
  50. Golub MS, Keen CL, Gershwin ME (2000) Moderate Zn–Fe deprivation influences behavior but not growth in adolescent Rhesus monkeys. J Nutr 130:354S–357SPubMedGoogle Scholar
  51. Gonzalez FA, Raden DL, Davis RJ (1991) Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases. J Biol Chem 266:22159–22163PubMedGoogle Scholar
  52. Halas ES, Sandstead HH (1975) Some effects of prenatal zinc deficiency on behavior of the adult rat. Pediatr Res 9:94–97PubMedGoogle Scholar
  53. Halas ES, Hunt CD, Eberhardt MJ (1986) Learning and memory disabilities in young adult rats from mildly zinc deficient dams. Physiol Behav 37:451–458PubMedGoogle Scholar
  54. Hamadani JD, Fuchs GJ, Osendarp SJ, Khatun F, Huda SN, Grantham-McGregor SM (2001) Randomized controlled trial of the effect of zinc supplementation on the mental development of Bangladeshi infants. Am J Clin Nutr 74:381–386PubMedGoogle Scholar
  55. Hamadani JD, Fuchs GJ, Osendarp SJ, Huda SN, Grantham-McGregor SM (2002) Zinc supplementation during pregnancy and effects on mental development and behaviour of infants: a follow-up study. Lancet 360:290–294PubMedGoogle Scholar
  56. Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G (2004) Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci 24:6590–6599PubMedGoogle Scholar
  57. He K, Aizenman E (2010) ERK signaling leads to mitochondrial dysfunction in extracellular zinc-induced neurotoxicity. J Neurochem 114:452–461PubMedGoogle Scholar
  58. Heffron DS, Landreth GE, Samuels IS, Mandell JW (2009) Brain-specific deletion of extracellular signal-regulated kinase 2 mitogen-activated protein kinase leads to aberrant cortical collagen deposition. Am J Pathol 175:2586–2599PubMedGoogle Scholar
  59. Holst B, Egerod KL, Schild E, Vickers SP, Cheetham S, Gerlach LO, Storjohann L, Stidsen CE, Jones R, Beck-Sickinger AG, Schwartz TW (2007) GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology 148:13–20PubMedGoogle Scholar
  60. Huang YZ, Pan E, Xiong ZQ, McNamara JO (2008) Zinc-mediated transactivation of TrkB potentiates the hippocampal mossy fiber-CA3 pyramid synapse. Neuron 57:546–558PubMedGoogle Scholar
  61. Hubbs-Tait L, Kennedy TS, Droke EA, Belanger DM, Parker JR (2007) Zinc, iron, and lead: relations to head start children’s cognitive scores and teachers’ ratings of behavior. J Am Diet Assoc 107:128–133PubMedGoogle Scholar
  62. Hunt CD, Halas ES, Sandstead HH (1984) Mild perinatal zinc-deficiency affects brain hippocampal morphology and behavior. Fed Proc 43:382Google Scholar
  63. Hurley LS, Swenerton H (1966) Congenital malformations resulting from zinc deficiency in rats. Proc Soc Exp Biol Med 123:692–696PubMedGoogle Scholar
  64. Hwang JJ, Park MH, Choi SY, Koh JY (2005) Activation of the Trk signaling pathway by extracellular zinc. Role of metalloproteinases. J Biol Chem 280:11995–12001PubMedGoogle Scholar
  65. Imamura O, Satoh Y, Endo S, Takishima K (2008) Analysis of extracellular signal-regulated kinase 2 function in neural stem/progenitor cells via nervous system-specific gene disruption. Stem Cells 26:3247–3256PubMedGoogle Scholar
  66. Imamura O, Pages G, Pouyssegur J, Endo S, Takishima K (2010) ERK1 and ERK2 are required for radial glial maintenance and cortical lamination. Genes Cells 15:1072–1088PubMedGoogle Scholar
  67. Impey S, Obrietan K, Wong ST, Poser S, Yano S, Wayman G, Deloulme JC, Chan G, Storm DR (1998) Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21:869–883PubMedGoogle Scholar
  68. Ito M, Seki T, Liu J, Nakamura K, Namba T, Matsubara Y, Suzuki T, Arai H (2010) Effects of repeated electroconvulsive seizure on cell proliferation in the rat hippocampus. Synapse 64:814–821PubMedGoogle Scholar
  69. Kanterewicz BI, Urban NN, et al (2000) The extracellular signal-regulated kinase cascade is required for NMDA receptor-independent LTP in area CA1 but not area CA3 of the hippocampus. J Neurosci 20(9):3057–3066Google Scholar
  70. Kawamoto JC, Halas ES (1984) Lasting morphologic effects of mild perinatal zinc deficiency in the adult hippocampal formation. In: Frederickson CJ, Howell GA, Kasarakis EJ (eds) The neurobiology of zinc B: deficiency, toxicity, and pathology. Alan R. Liss, Inc., New York, pp. 33–48Google Scholar
  71. Keller KA, Grider A, Coffield JA (2001) Age-dependent influence of dietary zinc restriction on short-term memory in male rats. Physiol Behav 72:339–348PubMedGoogle Scholar
  72. Ketterman JK, Li YV (2008) Presynaptic evidence for zinc release at the mossy fiber synapse of rat hippocampus. J Neurosci Res 86:422–434PubMedGoogle Scholar
  73. Kim SH, Seo MS, Jeon WJ, Yu HS, Park HG, Jung GA, Lee HY, Kang UG, Kim YS (2008) Haloperidol regulates the phosphorylation level of the MEK-ERK-p90RSK signal pathway via protein phosphatase 2A in the rat frontal cortex. Int J Neuropsychopharmacol 11:509–517PubMedGoogle Scholar
  74. Kim Y, Kim SH, Kim YS, Lee YH, Ha K, Shin SY (2011) Imipramine activates glial cell line-derived neurotrophic factor via early growth response gene 1 in astrocytes. Prog Neuropsychopharmacol Biol Psychiatry 35:1026–1032PubMedGoogle Scholar
  75. Kirksey A, Wachs TD, Yunis F, Srinath U, Rahmanifar A, McCabe GP, Galal OM, Harrison GG, Jerome NW (1994) Relation of maternal zinc nutriture to pregnancy outcome and infant development in an Egyptian village. Am J Clin Nutr 60:782–792PubMedGoogle Scholar
  76. Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW (1996) The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 272:1013–1016PubMedGoogle Scholar
  77. Kumar RA, KaraMohamed S, Sudi J, Conrad DF, Brune C, Badner JA, Gilliam TC, Nowak NJ, Cook EH Jr, Dobyns WB, Christian SL (2008) Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 17:628–638PubMedGoogle Scholar
  78. Liu H, Oteiza PI, Gershwin ME, Golub MS, Keen CL (1992) Effects of maternal marginal zinc deficiency on myelin protein profiles in the suckling rat and infant rhesus monkey. Biol Trace Elem Res 34:55–66PubMedGoogle Scholar
  79. Lopez V, Keen CL, Lanoue L (2008) Prenatal zinc deficiency: influence on heart morphology and distribution of key heart proteins in a rat model. Biol Trace Elem Res 122:238–255PubMedGoogle Scholar
  80. Mackenzie GG, Zago MP, Keen CL, Oteiza PI (2002) Low intracellular zinc impairs the translocation of activated NF-kappa B to the nuclei in human neuroblastoma IMR-32 cells. J Biol Chem 277:34610–34617PubMedGoogle Scholar
  81. Mackenzie GG, Zago MP, Erlejman AG, Aimo L, Keen CL, Oteiza PI (2006) Alpha-lipoic acid and N-acetyl cysteine prevent zinc deficiency-induced activation of NF-kappaB and AP-1 transcription factors in human neuroblastoma IMR-32 cells. Free Radic Res 40:75–84PubMedGoogle Scholar
  82. Mackenzie GG, Salvador GA, Romero C, Keen CL, Oteiza PI (2011) A deficit in zinc availability can cause alterations in tubulin thiol redox status in cultured neurons and in the developing fetal rat brain. Free Radic Biol Med 51:480–489PubMedGoogle Scholar
  83. Maes M, D’Haese PC, Scharpe S, D’Hondt P, Cosyns P, De Broe ME (1994) Hypozincemia in depression. J Affect Disord 31:135–140PubMedGoogle Scholar
  84. Maes M, Vandoolaeghe E, Neels H, Demedts P, Wauters A, Meltzer HY, Altamura C, Desnyder R (1997) Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness. Biol Psychiatry 42:349–358PubMedGoogle Scholar
  85. Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, Kubera M, Bob P, Lerer B, Maj M (2009) The inflammatory & neurodegenerative (I & ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 24:27–53PubMedGoogle Scholar
  86. Mazzucchelli C, Vantaggiato C, Ciamei A, Fasano S, Pakhotin P, Krezel W, Welzl H, Wolfer DP, Pages G, Valverde O, Marowsky A, Porrazzo A, Orban PC, Maldonado R, Ehrengruber MU, Cestari V, Lipp HP, Chapman PF, Pouyssegur J, Brambilla R (2002) Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory. Neuron 34:807–820PubMedGoogle Scholar
  87. McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Basecke J, Libra M, Stivala F, Milella M, Tafuri A, Lunghi P, Bonati A, Martelli AM (2008) Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia 22:708–722PubMedGoogle Scholar
  88. McLoughlin IJ, Hodge JS (1990) Zinc in depressive disorder. Acta Psychiatr Scand 82:451–453PubMedGoogle Scholar
  89. Mebratu Y, Tesfaigzi Y (2009) How ERK1/2 activation controls cell proliferation and cell death: is subcellular localization the answer? Cell Cycle 8:1168–1175PubMedGoogle Scholar
  90. Miller FD, Gauthier AS (2007) Timing is everything: making neurons versus glia in the developing cortex. Neuron 54:357–369PubMedGoogle Scholar
  91. Minichiello L (2009) TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 10:850–860PubMedGoogle Scholar
  92. Molnar P, Nadler JV (2001) Synaptically-released zinc inhibits N-methyl-d-aspartate receptor activation at recurrent mossy fiber synapses. Brain Res 910:205–207PubMedGoogle Scholar
  93. Nakashima AS, Dyck RH (2009) Zinc and cortical plasticity. Brain Res Rev 59:347–373PubMedGoogle Scholar
  94. Namura S, Iihara K, Takami S, Nagata I, Kikuchi H, Matsushita K, Moskowitz MA, Bonventre JV, Alessandrini A (2001) Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia. Proc Natl Acad Sci USA 98:11569–11574PubMedGoogle Scholar
  95. Neary JT, Whittemore SR, Bu Y, Mehta H, Shi YF (2001) Biochemical mechanisms of action of Hypericum LI 160 in glial and neuronal cells: inhibition of neurotransmitter uptake and stimulation of extracellular signal regulated protein kinase. Pharmacopsychiatry 34(Suppl 1):S103–S107PubMedGoogle Scholar
  96. Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547PubMedGoogle Scholar
  97. Nowak G, Siwek M, Dudek D, Zieba A, Pilc A (2003) Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study. Pol J Pharmacol 55:1143–1147PubMedGoogle Scholar
  98. Pascoli V, Valjent E, Corbille AG, Corvol JC, Tassin JP, Girault JA, Herve D (2005) cAMP and extracellular signal-regulated kinase signaling in response to d-amphetamine and methylphenidate in the prefrontal cortex in vivo: role of beta 1-adrenoceptors. Mol Pharmacol 68:421–429PubMedGoogle Scholar
  99. Penland JG, Sandstead HH, Alcock NW, Dayal HH, Chen XC, Li JS, Zhao F, Yang JJ (1997) A preliminary report: effects of zinc and micronutrient repletion on growth and neuropsychological function of urban Chinese children. J Am Coll Nutr 16:268–272PubMedGoogle Scholar
  100. Qi X, Lin W, Li J, Pan Y, Wang W (2006) The depressive-like behaviors are correlated with decreased phosphorylation of mitogen-activated protein kinases in rat brain following chronic forced swim stress. Behav Brain Res 175:233–240PubMedGoogle Scholar
  101. Qi X, Lin W, Li J, Li H, Wang W, Wang D, Sun M (2008) Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress. Neurobiol Dis 31:278–285PubMedGoogle Scholar
  102. Rantamaki T, Vesa L, Antila H, Di Lieto A, Tammela P, Schmitt A, Lesch KP, Rios M, Castren E (2011) Antidepressant drugs transactivate TrkB neurotrophin receptors in the adult rodent brain independently of BDNF and monoamine transporter blockade. PLoS One 6:e20567PubMedGoogle Scholar
  103. Reszka AA, Seger R, Diltz CD, Krebs EG, Fischer EH (1995) Association of mitogen-activated protein kinase with the microtubule cytoskeleton. Proc Natl Acad Sci USA 92:8881–8885PubMedGoogle Scholar
  104. Reus GZ, Stringari RB, Ribeiro KF, Ferraro AK, Vitto MF, Cesconetto P, Souza CT, Quevedo J (2011) Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behav Brain Res 221:166–171PubMedGoogle Scholar
  105. Rowin J, Lewis SL (2005) Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation. J Neurol Neurosurg Psychiatry 76:750–751PubMedGoogle Scholar
  106. Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen M, MacDonald E, Agerman K, Haapasalo A, Nawa H, Aloyz R, Ernfors P, Castren E (2003) Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23:349–357PubMedGoogle Scholar
  107. Samuels IS, Karlo JC, Faruzzi AN, Pickering K, Herrup K, Sweatt JD, Saitta SC, Landreth GE (2008) Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function. J Neurosci 28:6983–6995PubMedGoogle Scholar
  108. Samuels IS, Saitta SC, Landreth GE (2009) MAP’ing CNS development and cognition: an ERKsome process. Neuron 61:160–167PubMedGoogle Scholar
  109. Sandstrom B (2001) Micronutrient interactions: effects on absorption and bioavailability. Br J Nutr 85(Suppl 2):S181–S185PubMedGoogle Scholar
  110. Satoh Y, Endo S, Ikeda T, Yamada K, Ito M, Kuroki M, Hiramoto T, Imamura O, Kobayashi Y, Watanabe Y, Itohara S, Takishima K (2007) Extracellular signal-regulated kinase 2 (ERK2) knockdown mice show deficits in long-term memory; ERK2 has a specific function in learning and memory. J Neurosci 27:10765–10776PubMedGoogle Scholar
  111. Satoh Y, Endo S, Nakata T, Kobayashi Y, Yamada K, Ikeda T, Takeuchi A, Hiramoto T, Watanabe Y, Kazama T (2011) ERK2 contributes to the control of social behaviors in mice. J Neurosci 31:11953–11967PubMedGoogle Scholar
  112. Sawada T, Yokoi K (2010) Effect of zinc supplementation on mood states in young women: a pilot study. Eur J Clin Nutr 64:331–333PubMedGoogle Scholar
  113. Sazawal S, Black RE, Menon VP, Dinghra P, Caulfield LE, Dhingra U, Bagati A (2001) Zinc supplementation in infants born small for gestational age reduces mortality: a prospective, randomized, controlled trial. Pediatrics 108:1280–1286PubMedGoogle Scholar
  114. Schiavon AP, Milani H, Romanini CV, Foresti ML, Castro OW, Garcia-Cairasco N, de Oliveira RM (2010) Imipramine enhances cell proliferation and decreases neurodegeneration in the hippocampus after transient global cerebral ischemia in rats. Neurosci Lett 470:43–48PubMedGoogle Scholar
  115. Shalin SC, Zirrgiebel U, Honsa KJ, Julien JP, Miller FD, Kaplan DR, Sweatt JD (2004) Neuronal MEK is important for normal fear conditioning in mice. J Neurosci Res 75:760–770PubMedGoogle Scholar
  116. She QB, Ma WY, Zhong S, Dong Z (2002) Activation of JNK1, RSK2, and MSK1 is involved in serine 112 phosphorylation of Bad by ultraviolet B radiation. J Biol Chem 277:24039–24048PubMedGoogle Scholar
  117. Sheline YI, Gado MH, Kraemer HC (2003) Untreated depression and hippocampal volume loss. Am J Psychiatry 160:1516–1518PubMedGoogle Scholar
  118. Sindreu C, Palmiter RD, Storm DR (2011) Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory. Proc Natl Acad Sci USA 108:3366–3370PubMedGoogle Scholar
  119. Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15:1768–1777PubMedGoogle Scholar
  120. Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA (2004) JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18:189–218PubMedGoogle Scholar
  121. Suh SW, Thompson RB, Frederickson CJ (2001) Loss of vesicular zinc and appearance of perikaryal zinc after seizures induced by pilocarpine. Neuroreport 12:1523–1525PubMedGoogle Scholar
  122. Suh SW, Won SJ, Hamby AM, Yoo BH, Fan Y, Sheline CT, Tamano H, Takeda A, Liu J (2009) Decreased brain zinc availability reduces hippocampal neurogenesis in mice and rats. J Cereb Blood Flow Metab 29:1579–1588PubMedGoogle Scholar
  123. Tahmasebi Boroujeni S, Naghdi N, Shahbazi M, Farrokhi A, Bagherzadeh F, Kazemnejad A, Javadian M (2009) The effect of severe zinc deficiency and zinc supplement on spatial learning and memory. Biol Trace Elem Res 130:48–61PubMedGoogle Scholar
  124. Takeda A, Tamano H, Kan F, Itoh H, Oku N (2007) Anxiety-like behavior of young rats after 2-week zinc deprivation. Behav Brain Res 177:1–6PubMedGoogle Scholar
  125. Takeda A, Tamano H, Kan F, Hanajima T, Yamada K, Oku N (2008) Enhancement of social isolation-induced aggressive behavior of young mice by zinc deficiency. Life Sci 82:909–914PubMedGoogle Scholar
  126. Takeda A, Fuke S, Ando M, Oku N (2009) Positive modulation of long-term potentiation at hippocampal CA1 synapses by low micromolar concentrations of zinc. Neuroscience 158:585–591PubMedGoogle Scholar
  127. Tassabehji NM, Corniola RS, Alshingiti A, Levenson CW (2008) Zinc deficiency induces depression-like symptoms in adult rats. Physiol Behav 95:365–369PubMedGoogle Scholar
  128. Taubeneck MW, Daston GP, Rogers JM, Keen CL (1994) Altered maternal zinc metabolism following exposure to diverse developmental toxicants. Reprod Toxicol 8:25–40PubMedGoogle Scholar
  129. Taubeneck MW, Daston GP, Rogers JM, Gershwin ME, Ansari A, Keen CL (1995) Tumor necrosis factor-alpha alters maternal and embryonic zinc metabolism and is developmentally toxic in mice. J Nutr 125:908–919PubMedGoogle Scholar
  130. Toren P, Eldar S, Sela BA, Wolmer L, Weitz R, Inbar D, Koren S, Reiss A, Weizman R, Laor N (1996) Zinc deficiency in attention-deficit hyperactivity disorder. Biol Psychiatry 40:1308–1310PubMedGoogle Scholar
  131. Uckardes Y, Ozmert EN, Unal F, Yurdakok K (2009) Effects of zinc supplementation on parent and teacher behaviour rating scores in low socioeconomic level Turkish primary school children. Acta Paediatr 98:731–736PubMedGoogle Scholar
  132. Uriu-Adams JY, Keen CL (2010) Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development. Birth Defects Res B Dev Reprod Toxicol 89:313–325PubMedGoogle Scholar
  133. Walsh CT, Sandstead HH, Prasad AS, Newberne PM, Fraker PJ (1994) Zinc: health effects and research priorities for the 1990s. Environ Health Perspect 102(Suppl 2):5–46PubMedGoogle Scholar
  134. Wang FD, Bian W, Kong LW, Zhao FJ, Guo JS, Jing NH (2001) Maternal zinc deficiency impairs brain nestin expression in prenatal and postnatal mice. Cell Res 11:135–141PubMedGoogle Scholar
  135. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, Daly MJ (2008) Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 358:667–675PubMedGoogle Scholar
  136. Whittle N, Lubec G, Singewald N (2009) Zinc deficiency induces enhanced depression-like behaviour and altered limbic activation reversed by antidepressant treatment in mice. Amino Acids 36:147–158PubMedGoogle Scholar
  137. Xu H, Gao HL, Zheng W, Xin N, Chi ZH, Bai SL, Wang ZY (2011) Lactational zinc deficiency-induced hippocampal neuronal apoptosis by a BDNF-independent TrkB signaling pathway. Hippocampus 21:495–501PubMedGoogle Scholar
  138. Yamamoto T, Ebisuya M, Ashida F, Okamoto K, Yonehara S, Nishida E (2006) Continuous ERK activation downregulates antiproliferative genes throughout G1 phase to allow cell-cycle progression. Curr Biol 16:1171–1182PubMedGoogle Scholar
  139. Yang X, Liu L, Sternberg D, Tang L, Galinsky I, DeAngelo D, Stone R (2005) The FLT3 Internal tandem duplication mutation prevents apoptosis in interleukin-3-deprived BaF3 cells due to protein kinase A and ribosomal S6 kinase 1-mediated BAD phosphorylation at serine 112. Cancer Res 65:7338–7347PubMedGoogle Scholar
  140. Ye B, Maret W, Vallee BL (2001) Zinc metallothionein imported into liver mitochondria modulates respiration. Proc Natl Acad Sci USA 98:2317–2322PubMedGoogle Scholar
  141. Zambuzzi WF, Granjeiro JM, Parikh K, Yuvaraj S, Peppelenbosch MP, Ferreira CV (2008) Modulation of Src activity by low molecular weight protein tyrosine phosphatase during osteoblast differentiation. Cell Physiol Biochem 22:497–506PubMedGoogle Scholar
  142. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14–3–3 not BCL-X(L). Cell 87:619–628PubMedGoogle Scholar
  143. Zhang F, Wang S, Signore AP, Chen J (2007) Neuroprotective effects of leptin against ischemic injury induced by oxygen-glucose deprivation and transient cerebral ischemia. Stroke 38:2329–2336PubMedGoogle Scholar
  144. Zheng CF, Guan KL (1993) Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. J Biol Chem 268:11435–11439PubMedGoogle Scholar
  145. Zhu Y, Yang GY, Ahlemeyer B, Pang L, Che XM, Culmsee C, Klumpp S, Krieglstein J (2002) Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage. J Neurosci 22:3898–3909PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Nutrition and Department of Environmental ToxicologyUniversity of CaliforniaDavisUSA

Personalised recommendations