Molecular Neurobiology

, Volume 42, Issue 3, pp 151–160 | Cite as

Molecular Neurobiology of Lead (Pb2+): Effects on Synaptic Function

Article

Abstract

Lead (Pb2+) is a ubiquitous environmental neurotoxicant that continues to threaten public health on a global scale. Epidemiological studies have demonstrated detrimental effects of Pb2+ on childhood IQ at very low levels of exposure. Recently, a mechanistic understanding of how Pb2+ affects brain development has begun to emerge. The cognitive effects of Pb2+ exposure are believed to be mediated through its selective inhibition of the N-methyl-d-aspartate receptor (NMDAR). Studies in animal models of developmental Pb2+ exposure exhibit altered NMDAR subunit ontogeny and disruption of NMDAR-dependent intracellular signaling. Additional studies have reported that Pb2+ exposure inhibits presynaptic calcium (Ca2+) channels and affects presynaptic neurotransmission, but a mechanistic link between presynaptic and postsynaptic effects has been missing. Recent work has suggested that the presynaptic and postsynaptic effects of Pb2+ exposure are both due to inhibition of the NMDAR by Pb2+, and that the presynaptic effects of Pb2+ may be mediated by disruption of NMDAR activity-dependent signaling of brain-derived neurotrophic factor (BDNF). These findings provide the basis for the first working model to describe the effects of Pb2+ exposure on synaptic function. Here, we review the neurotoxic effects of Pb2+ exposure and discuss the known effects of Pb2+ exposure in light of these recent findings.

Keywords

Lead Neurotoxicology NMDA Receptor BDNF Synaptogenesis Neurotransmission 

References

  1. 1.
    Byers RK, Lord EE (1943) Late effects of lead poisoning on mental development. Am J Dis Child 66:471–494Google Scholar
  2. 2.
    Gilbert SG, Weiss B (2006) A rationale for lowering the blood lead action level from 10 to 2 microg/dl. Neurotoxicology 27:693–701PubMedCrossRefGoogle Scholar
  3. 3.
    Needleman HL, Gatsonis CA (1990) Low-level lead exposure and the IQ of children. A meta-analysis of modern studies. JAMA 263:673–678PubMedCrossRefGoogle Scholar
  4. 4.
    Canfield RL, Henderson CR Jr, Cory-Slechta D, Cox C, Jusko TA, Lanphear BP (2003) Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N Engl J Med 348:1517–1526PubMedCrossRefGoogle Scholar
  5. 5.
    Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, Canfield RL, Dietrich KN, Bornschein R, Greene T, Rothenberg SJ, Needleman HL, Schnaas L, Wasserman G, Graziano J, Roberts R (2005) Low-level environmental lead exposure and children’s intellectual function: an international pooled analysis. Environ Health Perspect 113:894–899PubMedCrossRefGoogle Scholar
  6. 6.
    Jusko TA, Henderson CR, Lanphear BP, Cory-Slechta DA, Parsons PJ, Canfield RL (2008) Blood lead concentrations <10 microg/dl and child intelligence at 6 years of age. Environ Health Perspect 116:243–248PubMedCrossRefGoogle Scholar
  7. 7.
    Hu H, Tellez-Rojo MM, Bellinger D, Smith D, Ettinger AS (2006) Fetal lead exposure at each stage of pregnancy as a predictor of infant mental development. Environ Health Perspect 114:1730–1735PubMedGoogle Scholar
  8. 8.
    Miranda ML, Kim D, Galeano MA, Paul CJ, Hull AP, Morgan SP (2007) The relationship between early childhood blood lead levels and performance on end-of-grade tests. Environ Health Perspect 115:1242–1247PubMedCrossRefGoogle Scholar
  9. 9.
    Needleman HL, Riess JA, Tobin MJ, Biesecker GE, Greenhouse JB (1996) Bone lead levels and delinquent behavior. JAMA 275:363–369PubMedCrossRefGoogle Scholar
  10. 10.
    Leviton A, Bellinger D, Allred EH, Rabinowitz M, Needleman H, Schoenbaum S (1993) Pre- and postnatal low-level lead exposure and children’s dysfunction in school. Environ Res 60:30–43PubMedCrossRefGoogle Scholar
  11. 11.
    Roy A, Bellinger D, Hu H, Schwartz J, Ettinger AS, Wright RO, Bouchard M, Palaniappan K, Balakrishnan K (2009) Lead exposure and behavior among young children in Chennai, India. Environ Health Perspect 117:1607–1611PubMedGoogle Scholar
  12. 12.
    Bellinger D, Leviton A, Allred E, Rabinowitz M (1994) Pre- and postnatal lead exposure and behavior problems in school-aged children. Env Res 66:12–30CrossRefGoogle Scholar
  13. 13.
    Froehlich TE, Lanphear BP, Auinger P, Hornung R, Epstein JN, Braun J, Kahn RS (2009) Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder. Pediatrics 124:E1054–E1063PubMedCrossRefGoogle Scholar
  14. 14.
    United States Centers for Disease Control and Prevention (2002) Managing elevated blood lead levels among young children: recommendations from the advisory committee on childhood lead poisoning prevention. CDC, AtlantaGoogle Scholar
  15. 15.
    Rogan WJ, Dietrich KN, Ware JH, Dockery DW, Salganik M, Radcliffe J, Jones RL, Ragan NB, Chisolm JJ, Rhoads GG (2001) The effect of chelation therapy with succimer on neuropsyhological development in children exposed to lead. N Engl J Med 344:1421–1426PubMedCrossRefGoogle Scholar
  16. 16.
    Dietrich KN, Ware JH, Salganik M, Radcliffe J, Rogan WJ, Rhoads GG, Fay ME, Davoli CT, Denckla MB, Bornschein RL, Schwarz D, Dockery DW, Adubato S, Jones RL (2004) Effect of chelation therapy on the neuropsychological and behavioral development of lead-exposed children after school entry. Pediatrics 114:19–26PubMedCrossRefGoogle Scholar
  17. 17.
    White LD, Cory-Slechta DA, Gilbert ME, Tiffany-Castiglioni E, Zawia NH, Virgolini M, Rossi-George A, Lasley SM, Qian YC, Basha R (2007) New and evolving concepts in the neurotoxicology of lead. Toxicol Appl Pharmacol 225:1–27PubMedCrossRefGoogle Scholar
  18. 18.
    Dietrich KN, Ris MD, Succop PA, Berger OG, Bornschein RL (2001) Early exposure to lead and juvenile delinquency. Neurotoxicol Teratol 23:511–518PubMedCrossRefGoogle Scholar
  19. 19.
    Needleman HL, McFarland C, Ness RB, Fienberg SE, Tobin MJ (2002) Bone lead levels in adjudicated delinquents. A case control study. Neurotoxicol Teratol 24:711–717PubMedCrossRefGoogle Scholar
  20. 20.
    Wright JP, Dietrich KN, Ris MD, Hornung RW, Wessel SD, Lanphear BP, Ho M, Rae MN (2008) Association of prenatal and childhood blood lead concentrations with criminal arrests in early adulthood. PLoS Med 5:0732–0740CrossRefGoogle Scholar
  21. 21.
    Nevin R (2000) How lead exposure relates to temporal changes in IQ, violent crime, and unwed pregancy. Environ Res 83:1–22PubMedCrossRefGoogle Scholar
  22. 22.
    Nevin R (2007) Understanding international crime trends: the legacy of preschool lead exposure. Environ Res 104:315–336PubMedCrossRefGoogle Scholar
  23. 23.
    Stretesky PB, Lynch MJ (2001) The relationship between lead exposure and homicide. Arch Pediatr Adolesc Med 155:579–582PubMedGoogle Scholar
  24. 24.
    Cecil KM, Brubaker CJ, Adler CM, Dietrich KN, Altaye M, Egelhoff JC, Wessel S, Elangovan I, Hornung R, Jarvis K, Lanphear BP (2008) Decreased brain volume in adults with childhood lead exposure. PLoS Med 5:0741–0749CrossRefGoogle Scholar
  25. 25.
    Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683PubMedCrossRefGoogle Scholar
  26. 26.
    Morris RGM, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319:774–776PubMedCrossRefGoogle Scholar
  27. 27.
    Tsien JZ, Huerta PT, Tonegawa S (1996) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87:1327–1338PubMedCrossRefGoogle Scholar
  28. 28.
    Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136PubMedCrossRefGoogle Scholar
  29. 29.
    Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39PubMedCrossRefGoogle Scholar
  30. 30.
    Chen C, Tonegawa S (1997) Molecular genetic analysis of synaptic plasticity, activity-dependent neural development, learning, and memory in the mammalian brain. Annu Rev Neurosci 20:157–184PubMedCrossRefGoogle Scholar
  31. 31.
    Monaghan DT, Holets VR, Toy DW, Cotman CW (1983) Anatomical distributions of four pharmacologically distinct 3H-l-glutamate binding sites. Nature 306:176–179PubMedCrossRefGoogle Scholar
  32. 32.
    Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12:529–540PubMedCrossRefGoogle Scholar
  33. 33.
    Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizuno N, Nakanishi S (1991) Molecular cloning and characterization of the rat NMDA receptor. Nature 354:31–37PubMedCrossRefGoogle Scholar
  34. 34.
    Durand GM, Gregor P, Zheng Z, Bennett MVL, Uhl GR, Zukin RS (1992) Cloning of an apparent splice variant of the rat N-methyl-d-aspartate receptor NMDAR1 with altered sensitivity to polyamines and activators of protein kinase C. Proc Natl Acad Sci USA 89:9359–9363PubMedCrossRefGoogle Scholar
  35. 35.
    Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seebur PH (1992) Heteromeric NMDA receptors: Molecular and functional distinction of subtypes. Science 256:1217–1221PubMedCrossRefGoogle Scholar
  36. 36.
    Ishii T, Moriyoshi K, Sugihara H, Sakurada K, Kadotani H, Yokoi M, Akazawa C, Shigemoto R, Mizuno N, Masu M, Nakanishi S (1993) Molecular characterization of the family of the N-methyl-d-aspartate receptor subunits. J Biol Chem 268:2836–2843PubMedGoogle Scholar
  37. 37.
    Al Hallaq RA, Conrads TP, Veenstra TD, Wenthold RJ (2007) NMDA di-heteromeric receptor populations and associated proteins in rat hippocampus. J Neurosci 27:8334–8343PubMedCrossRefGoogle Scholar
  38. 38.
    Soriano FX, Martel MA, Papadia S, Vaslin A, Baxter P, Rickman C, Forder J, Tymianski M, Duncan R, Aarts M, Clarke PGH, Wyllie DJA, Hardingham GE (2008) Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand. J Neurosci 28:10696–10710PubMedCrossRefGoogle Scholar
  39. 39.
    Hardingham GE (2006) 2B synaptic or extrasynaptic determines signaling from the NMDA receptor. J Physiol 572:614–615PubMedGoogle Scholar
  40. 40.
    Hardingham GE, Fukunaga Y, Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5:405–414PubMedGoogle Scholar
  41. 41.
    Kim MJ, Dunah AW, Wang YT, Sheng M (2005) Differential roles of NR2A and NR2B containing NMDA receptors in RAS-ERD signaling and AMPA receptor trafficking. Neuron 46:745–760PubMedCrossRefGoogle Scholar
  42. 42.
    Tovar K, Westbrook GL (1999) The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci 19:4180–4188PubMedGoogle Scholar
  43. 43.
    Alkondon M, Alberto CS, Radhakrishnan V, Aronstam RS, Albuquerque EX (1990) Selective blockade of NMDA-activated channel currents may be implicated in learning deficits caused by lead. FEBS Lett 261:124–130PubMedCrossRefGoogle Scholar
  44. 44.
    Guilarte TR, Miceli RC (1992) Age-dependent effects of lead on [3H]MK-801 binding to the NMDA receptor-gated ionophore: in vitro and in vivo studies. Neurosci Lett 148:27–30PubMedCrossRefGoogle Scholar
  45. 45.
    Rachline J, Perin-Dureau F, Le Goff A, Neyton J, Paoletti P (2005) The micromolar zinc-binding domain on the NMDA receptor subunit NR2B. J Neurosci 25:308–317PubMedCrossRefGoogle Scholar
  46. 46.
    Paoletti P, Perin-Dureau F, Fayyazuddin A, Le Goff A, Callebaut I, Neyton J (2000) Molecular organization of a zinc binding N-terminal modulatory domain in a NMDA receptor subunit. Neuron 28:911–925PubMedCrossRefGoogle Scholar
  47. 47.
    Jett DA, Kuhlmann A, Guilarte TR (1996) Intrahippocampal administration of lead (Pb) impairs performance of rats in the Morris water maze. Pharmacol Biochem Behav 57:263–269CrossRefGoogle Scholar
  48. 48.
    Kuhlmann AC, McGlothan JL, Guilarte TR (1997) Developmental lead exposure causes spatial learning deficits in adult rats. Neurosci Lett 233:101–104PubMedCrossRefGoogle Scholar
  49. 49.
    Guilarte TR, Toscano CD, McGlothan JL, Weaver SA (2003) Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure. Ann Neurol 53:50–56PubMedCrossRefGoogle Scholar
  50. 50.
    Gavazzo P, Zanardi I, Baranowska-Bosiacka I, Marchetti C (2008) Molecular determinants of Pb2+ interaction with NMDA receptor channels. Neurochem Int 52:329–337PubMedCrossRefGoogle Scholar
  51. 51.
    Yamada Y, Ujihara H, Sada H, Ban T (1995) Pb2+ reduces the current from NMDA receptors expressed in Xenopus oocytes. FEBS Lett 377:390–392PubMedCrossRefGoogle Scholar
  52. 52.
    Guilarte TR, Miceli RC, Jett DA (1995) Biochemical evidence of an interaction of lead at the zinc allosteric sites of the NMDA receptor complex: effects of neuronal development. Neurotoxicology 16:63–71PubMedGoogle Scholar
  53. 53.
    Fayyazuddin A, Villarroel A, Le Goff A, Lerma J, Neyton J (2000) Four residues of the extracellular N-terminal domain of the NR2A subunit control high-affinity Zn2+ binding to NMDA receptors. Neuron 25:685–694CrossRefGoogle Scholar
  54. 54.
    Lasley SM, Gilbert ME (1999) Lead inhibits the rat N-methyl-d-aspartate receptor channel by binding to a site distinct from the zinc allosteric site. Toxicol Appl Pharmacol 159:224–233PubMedCrossRefGoogle Scholar
  55. 55.
    Omelchenko IA, Nelson CS, Marino JL, Allen CN (1996) The sensitivity of N-methyl-d-aspartate receptors to lead inhibition is dependent on the receptor subunit composition. J Pharmacol Exp Ther 278:15–20PubMedGoogle Scholar
  56. 56.
    Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR (2000) N-methyl-d-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning. Neuroscience 99:233–242PubMedCrossRefGoogle Scholar
  57. 57.
    Nihei MK, Guilarte TR (1999) NMDAR-2A subunit protein expression is reduced in the hippocampus of rats exposed to Pb2+ during development. Mol Brain Res 66:42–49PubMedCrossRefGoogle Scholar
  58. 58.
    Guilarte TR, McGlothan JL (1998) Hippocampal NMDA receptor mRNA undergoes subunit specific changes during developmental lead exposure. Brain Res 790:98–107PubMedCrossRefGoogle Scholar
  59. 59.
    Xy Z, Liu AP, Ruan DY, Liu J (2002) Effect of developmental lead exposure on the expression of specific NMDA receptor subunit mRNAs in the hippocampus of neonatal rats by digoxigenin-labeled in situ hybridization histochemistry. Neurotoxicol Teratol 24:149–160CrossRefGoogle Scholar
  60. 60.
    Guilarte TR, McGlothan JL, Nihei MK (2000) Hippocampal expression of N-methyl-d-aspartate receptor (NMDAR1) subunit splice variant mRNA is altered by developmental exposure to Pb2+. Mol Brain Res 76:299–305PubMedCrossRefGoogle Scholar
  61. 61.
    Guilarte TR, McGlothan JL (2003) Selective decrease in NR1 subunit splice variant mRNA in the hippocampus of Pb2+-exposed rats: implications for synaptic targeting and cell surface expression of NMDAR complexes. Mol Brain Res 113:37–43PubMedCrossRefGoogle Scholar
  62. 62.
    Toscano CD, Hashemzadeh-Gargari H, McGlothan JL, Guilarte TR (2002) Developmental Pb2+ exposure alters NMDAR subtypes and reduces CREB phosphorylation in the rat brain. Dev Brain Res 139:217–226CrossRefGoogle Scholar
  63. 63.
    Toscano CD, Guilarte TR (2005) Lead neurotoxicity: from exposure to molecular effects. Brain Res Rev 49:529–555PubMedCrossRefGoogle Scholar
  64. 64.
    Xu SZ, Rajanna B (2006) Glutamic acid reverses Pb2+-induced reductions of NMDAR receptor subunits in vitro. Neurotoxicology 27:169–175PubMedCrossRefGoogle Scholar
  65. 65.
    Chung HJ, Huang YH, Lau LF, Huganir RL (2004) Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand. J Neurosci 24:10248–10259PubMedCrossRefGoogle Scholar
  66. 66.
    Lee MC, Yasuda R, Ehlers MD (2010) Metaplasticity at single glutamatergic synapses. Neuron 66:859–870PubMedCrossRefGoogle Scholar
  67. 67.
    Cordova FM, Rodrigues LS, Giocomelli MBO, Oliveira CS, Posser T, Dunkley PR, Leal RB (2004) Lead stimulates ERK1/2 and p38MAPK phosphorylation in the hippocampus of immature rats. Brain Res 998:65–72PubMedCrossRefGoogle Scholar
  68. 68.
    Toscano CD, O’Callaghan JP, Guilarte TR (2005) Calcium/calmodulin-dependent protein kinase II activity and expression are altered in the hippocampus of Pb2+-exposed rats. Brain Res 1044:51–58PubMedCrossRefGoogle Scholar
  69. 69.
    Toscano CD, McGlothan JL, Guilarte TR (2003) Lead exposure alters cyclic-AMP response element binding protein phosphorylation and binding activity in the developing rat brain. Dev Brain Res 145:219–228CrossRefGoogle Scholar
  70. 70.
    Athos J, Impey S, Pineda VV, Chen X, Storm DR (2002) Hippocampal CRE-mediated gene expression is required for contextual memory formation. Nat Neurosci 5:1119–1120PubMedCrossRefGoogle Scholar
  71. 71.
    Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schultz G, Silva AJ (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79:59–68PubMedCrossRefGoogle Scholar
  72. 72.
    Kim KA, Chakraborti T, Golstein G, Johnston M, Bressler J (2002) Exposure to lead elevates induction of zif268 and ARC mRNA in rats after electroconvulsive shock: the involvement of protein kinase C. J Neurosci Res 69:268–277PubMedCrossRefGoogle Scholar
  73. 73.
    Lasley SM, Gilbert ME (2002) Rat hippocampal glutamate and GABA release exhibit biphasic effects as a function of chronic lead exposure level. Toxicol Sci 66:139–147PubMedCrossRefGoogle Scholar
  74. 74.
    Lasley SM, Gilbert ME (1996) Presynaptic glutamatergic function in dentate gyrus in vivo is diminished by chronic exposure to inorganic lead. Brain Res 736:125–134PubMedCrossRefGoogle Scholar
  75. 75.
    Xiao C, Gu Y, Zhou CY, Wang L, Zhang MM, Ruan DY (2006) Pb2+ impairs GABAergic synaptic transmission in rat hippocampal slices: a possible involvement of presynaptic calcium channels. Brain Res 1088:93–100PubMedCrossRefGoogle Scholar
  76. 76.
    Braga MFM, Pereira EFR, Albuquerque EX (1999) Nanomolar concentrations of lead inhibit glutamatergic and GABAergic transmission in hippocampal neurons. Brain Res 826:22–34PubMedCrossRefGoogle Scholar
  77. 77.
    Neal AP, Stansfield KH, Worley PF, Thompson RE, Guilarte TR (2010) Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: potential role of NMDA receptor-dependent BDNF signaling. Toxicol Sci 116:249–263PubMedCrossRefGoogle Scholar
  78. 78.
    Bouton CMLS, Frelin LP, Forde CE, Godwin HA, Pevsner J (2001) Synaptotagmin i is a molecular target for lead. J Neurochem 76:1724–1735PubMedCrossRefGoogle Scholar
  79. 79.
    Chicka MC, Hui E, Lui H, Chapman ER (2008) Synaptotagmin arrests the snare complex before triggering fast, efficient membrane fusion in response to Ca2+. Nat Struct Mol Biol 15:827–835PubMedCrossRefGoogle Scholar
  80. 80.
    Chao SH, Suzuki Y, Zysk JR, Cheung WY (1984) Activation of calmodulin by various metal cations as a function of ionic radius. Mol Pharmacol 26:75–82PubMedGoogle Scholar
  81. 81.
    Garza A, Vega R, Soto E (2006) Cellular mechanisms of lead neurotoxicity. Med Sci Monit 12:RA57–RA65PubMedGoogle Scholar
  82. 82.
    Habermann E, Crowell K, Janicki P (1983) Lead and other metals can substitute for Ca2+ in calmodulin. Arch Toxicol 54:61–70PubMedCrossRefGoogle Scholar
  83. 83.
    Kern M, Wisniewski M, Cabell L, Audesirk G (2000) Inorganic lead and calcium interact positively in activation of calmodulin. Neurotoxicology 3:353–363Google Scholar
  84. 84.
    Kern M, Audesirk G (2000) Stimulatory and inhibitory effects of inorganic lead on calcineurin. Toxicology 150:171–178PubMedCrossRefGoogle Scholar
  85. 85.
    Simons TJB (1993) Lead-calcium interactions in cellular lead toxicity. Neurotoxicology 14:77–86PubMedGoogle Scholar
  86. 86.
    Sun X, Tian X, Tomsig JL, Suszkiw JB (1999) Analysis of differential effects of Pb2+ on protein kinase C isozymes. Toxicol Appl Pharmacol 156:40–45PubMedCrossRefGoogle Scholar
  87. 87.
    Toscano CD, Schanne FAX (2000) Lead-induced activation of protein kinase C in rat brain cortical synaptosomes. Ann NY Acad Sci 919:307–311PubMedCrossRefGoogle Scholar
  88. 88.
    Long GJ, Rosen JF, Schanne FAX (1994) Lead activation of protein kinase C from rat brain. J Biol Chem 269:834–837PubMedGoogle Scholar
  89. 89.
    Bressler J, Kim KA, Chakraborti T, Goldstein G (1999) Molecular mechanisms of lead neurotoxicity. Neurochem Res 24:595–600PubMedCrossRefGoogle Scholar
  90. 90.
    Marchetti C (2003) Molecular targets of lead in brain neurotoxicity. Neurotox Res 5:221–236PubMedCrossRefGoogle Scholar
  91. 91.
    Richardt G, Federolf G, Habermann E (1986) Affinity of heavy metal ions to intracellular Ca2+-binding proteins. Biochem Pharmacol 35:1331–1335PubMedCrossRefGoogle Scholar
  92. 92.
    Peng S, Hajela RK, Atchison WD (2002) Characteristics of block by Pb2+ of function of human neuronal L-, N-, and R-type Ca2+ channels transiently expressed in human embryonic kidney 293 cells. Mol Pharmacol 62:1418–1430PubMedCrossRefGoogle Scholar
  93. 93.
    Xu J, He L, Wu LG (2007) Role of Ca2+ channels in short-term synaptic plasticity. Curr Opin Neurobiol 17:352–359PubMedCrossRefGoogle Scholar
  94. 94.
    Bacci A, Coco S, Pravettoni E, Schenk U, Armano S, Frassoni C, Verderio C, De Camilli P, Matteoli M (2001) Chronic blockade of glutamate receptors enhances presynaptic release and downregulates the interaction between synaptophysin-synaptobrevin-vesicle-associated-membrane protein 2. J Neurosci 21:6588–6596PubMedGoogle Scholar
  95. 95.
    Verderio C, Coco S, Pravettoni E, Bacci A, Matteoli M (1999) Synaptogenesis in hippocampal cultures. Cell Mol Life Sci 55:1448–1462PubMedCrossRefGoogle Scholar
  96. 96.
    Fitzsimonds RM, Poo MM (1998) Retrograde signaling in the development and modification of synapses. Physiol Rev 78:143–170PubMedGoogle Scholar
  97. 97.
    Cohen-Cory S, Kidane AH, Shirkey NJ, Marshak S (2010) Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Nev Neurobiol 70:271–288Google Scholar
  98. 98.
    Walz C, Jungling KL, Gottmann K (2006) Presynaptic plasticity in an immature neocortical network requires NMDA receptor activation and BDNF release. J Neurophysiol 96:3512–3516PubMedCrossRefGoogle Scholar
  99. 99.
    Hartmann M, Heumann R, Lessmann V (2001) Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J 20:5887–5897PubMedCrossRefGoogle Scholar
  100. 100.
    Jiang X, Tian F, Mearow K, Okagaki P, Lipsky RH, Marini AM (2005) The excitoprotective effect of N-methyl-d-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. J Neurochem 94:713–722PubMedCrossRefGoogle Scholar
  101. 101.
    Matsuda N, Lu H, Fukata Y, Noritake J, Gao H, Mukherjee S, Nemoto T, Fukata M, Mm P (2009) Differential activity-dependent secretion of brain-derived neurotrophic factor from axon to dendrite. J Neurosci 29:14185–14198PubMedCrossRefGoogle Scholar
  102. 102.
    Kolarow R, Brigadski T, Lessmann V (2007) Postsynaptic secretion of BDNF and NT-3 from hippocampal neurons depends on calcium-calmodulin kinase II signaling and proceeds via delayed fusion pore opening. J Neurosci 27:10350–10364PubMedCrossRefGoogle Scholar
  103. 103.
    Madara JC, Levine ES (2008) Presynaptic and postsynaptic NMDA receptors mediate distinct effects of brain-derived neurotrophic factor on synaptic transmission. J Neurosci 100:3175–3184Google Scholar
  104. 104.
    Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T (2007) Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res 85:525–535PubMedCrossRefGoogle Scholar
  105. 105.
    Vanhoutte P, Bading H (2003) Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signaling and BDNF gene regulation. Curr Opin Neurobiol 13:366–371PubMedCrossRefGoogle Scholar
  106. 106.
    Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20:709–726PubMedCrossRefGoogle Scholar
  107. 107.
    Shieh PB, Hu SC, Bobb K, Timmusk T, Ghosh A (1998) Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 20:727–740PubMedCrossRefGoogle Scholar
  108. 108.
    Metsis M, Timmusk T, Arenas E, Persson H (1993) Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation. Proc Natl Acad Sci USA 90:8802–8806PubMedCrossRefGoogle Scholar
  109. 109.
    Chen Q, He S, Hu XL, Yu J, Zhou Y, Zheng J, Zhang S, Zhang C, Duan WH, Xiong ZQ (2007) Differential roles of NR2A- and NR2N-containing NMDA receptors in activity-dependent brain-derived neurotrophic factor gene regulation and limbic epileptogenesis. J Neurosci 27:542–552PubMedCrossRefGoogle Scholar
  110. 110.
    Tartaglia N, Du J, Tyler WJ, Neale E, Pozzo-Miller L, Lu B (2001) Protein synthesis-dependent and -independent regulation of hippocampal synapses by brain-derived neurotrophic factor. J Biol Chem 276:37585–37593PubMedCrossRefGoogle Scholar
  111. 111.
    Caldeira MV, Melo CV, Pereira DB, Carvalho RF, Carvalho AL, Duarte CB (2007) BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons. Mol Cell Neurosci 35:208–219PubMedCrossRefGoogle Scholar
  112. 112.
    Small DL, Murray CL, Mealing GA, Poulter MO, Buchan AM, Morley P (1998) Brain derived neurotrophic factor induction of N-methyl-d-aspartate receptor subunit NR2A expression in cultured rat cortical neurons. Neurosci Lett 252:211–214PubMedCrossRefGoogle Scholar
  113. 113.
    Margottil E, Domenici L (2003) NR2A but not NR2B n-methyl-d-aspartate receptor subunit is altered in the visual cortex of BDNF-knock-out mice. Cell Mol Neurobiol 23:165–174PubMedCrossRefGoogle Scholar
  114. 114.
    Pozzo-Miller LD, Gottschalk W, Zhang L, McDermott K, Du J, Gopalakrishnan R, Oho C, Sheng ZH, Lu B (1999) Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci 19:4972–4983PubMedGoogle Scholar
  115. 115.
    Ehlers MD (2003) Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci 6:231–242PubMedCrossRefGoogle Scholar
  116. 116.
    Perez-Otano I, Ehlers MD (2005) Homeostatic plasticity and NMDA receptor trafficking. Trends Neurosci 28:229–238PubMedCrossRefGoogle Scholar
  117. 117.
    Rao A, Craig AM (1997) Activity regulates the synaptic localization of the NMDA receptor in hippocampal neurons. Neuron 19:801–812PubMedCrossRefGoogle Scholar
  118. 118.
    Hu B, Nikolakopoulou AM, Cohen-Cory S (2005) BDNF stabilizes synapses and maintains the structural complexity of optic axons in vivo. Development 132:4285–4298PubMedCrossRefGoogle Scholar
  119. 119.
    Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99–125PubMedCrossRefGoogle Scholar
  120. 120.
    Lovinger DM, White G, Weight FF (1983) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243:1721–1724CrossRefGoogle Scholar
  121. 121.
    Rice D, Barone S Jr (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans to animal models. Environ Health Perspect 108:511–533PubMedCrossRefGoogle Scholar
  122. 122.
    Carpenter-Hyland EP, Woodward JJ, Chandler LJ (2004) Chronic ethanol induces synaptic but not extrasynaptic targeting of NMDA receptors. J Neurosci 24:7859–7868PubMedCrossRefGoogle Scholar
  123. 123.
    Qiang M, Denny AD, Ticku MK (2007) Chronic intermittent ethanol treatment selectively alters N-methyl-d-aspartate receptor subunit surface expression in cultured cortical neurons. Mol Pharmacol 72:95–102PubMedCrossRefGoogle Scholar
  124. 124.
    Roberto M, Treistman SN, Pietrzykowski AZ, Weiner J, Galindo R, Mameli M, Valenzuela F, Zhu PJ, Lovinger D, Zhang TA, Hendricson AH, Morrisett R, Siggins GR (2006) Actions of acute and chronic ethanol on presynaptic terminals. Alcohol Clin Exp Res 30:222–232PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyMichigan State UniversityEast LansingUSA
  2. 2.Department of Environmental Health Sciences, Mailman School of Public HealthColumbia UniversityNew YorkUSA

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