Lead and Excitotoxicity

  • Abdur Rahman
Reference work entry


Lead (Pb2+) is a known neurotoxicant, but the mechanism of its neurotoxicity is not clearly understood. Several biochemical alterations have been shown to be caused by Pb2+ exposure in mammalian brain, but none of these changes alone can explain the mechanism of Pb2+-induced impairment of learning and memory. The most mechanistically relevant biochemical abnormalities that are directly involved in learning and memory are the excitotoxic effects caused by modulation of the N-methyl-d-aspartate-type glutamate receptors (NMDAR) in glutamatergic synapses. Pb2+ is known to affect not only the expression of the different subunits of the NMDARs but also the ontogenic developmental switch of the various NMDAR subunits that is essential for learning and memory. Overactivation of serine/threonine protein phosphatases (PPs) appears to be involved in these synaptic changes. PPs may not only affect the functions of the various subunits of the NMDAR directly by modulating the phosphorylation state of these subunits but may also affect their downstream function by modulation of the phosphorylation state of the downstream effectors like the cyclic AMP response element binding protein (CREB) and other proteins involved in this process. There is a great need to put these isolated pieces of information together and workout the exact pathway(s) that are disturbed by Pb2+.


Excitotoxicity Hippocampus Lead Learning and memory Neurotoxicity NMDAR Protein phosphatases 


  1. Alagarsamy, S., Saugstad, J., Warren, L., Mansuy, I. M., Gereau, R. W., 4th, & Conn, P. J. (2005). NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin. Neuropharmacology, 49(Suppl. 1), 135–145.PubMedCentralPubMedCrossRefGoogle Scholar
  2. Alberts, A.S., Montminy, M., Shenolikar, S., & Feramisco, J.R. (1994). Expression of a peptide inhibitor of protein phosphatase 1 increases phosphorylation and activity of CREB in NIH 3T3 fibroblasts. Mol Cell Biol 14(7), 4398–4407.PubMedCentralPubMedGoogle Scholar
  3. Altmann, L., Sveinsson, K., & Wiegand, H. (1991). Long-term potentiation in rat hippocampal slices is impaired following acute lead perfusion. Neuroscience Letters, 128, 109–112.PubMedCrossRefGoogle Scholar
  4. Altmann, L., Weinsberg, F., Sveinsson, K., Lilienthal, H., Wiegand, H., & Winneke, G. (1993). Impairment of long-term potentiation and learning following chronic lead exposure. Toxicology Letters, 66, 105–112.PubMedCrossRefGoogle Scholar
  5. Altmann, L., Gutowski, M., & Wiegand, H. (1994). Effects of maternal lead exposure on functional plasticity in the visual cortex and hippocampus of immature rats. Brain Research. Developmental Brain Research, 81(1), 50–56.PubMedCrossRefGoogle Scholar
  6. Anderson, K. A., Noeldner, P. K., Reece, K., Wadzinski, B. E., & Means, A. R. (2004). Regulation and function of the calcium/calmodulin-dependent protein kinase IV/protein serine/threonine phosphatase 2A signaling complex. The Journal of Biological Chemistry, 279(30), 31708–31716.PubMedCrossRefGoogle Scholar
  7. Antonio, M. T., & Lert, M. L. (2000). Study of the neurochemical alterations produced in discrete brain areas by perinatal low-level lead exposure. Life Sciences, 67(6), 635–642.PubMedCrossRefGoogle Scholar
  8. Atchison, W. D. (2003). Effects of toxic environmental contaminants on voltage-gated calcium channel function: From past to present. Journal of Bioenergetics and Biomembranes, 35, 507–532.PubMedCrossRefGoogle Scholar
  9. Atchison, W. D., & Narahashi, T. (1984). Mechanism of action of lead on neuromuscular junction. Neurotoxicology, 5, 267–282.PubMedGoogle Scholar
  10. Athos, J., Impey, S., Pineda, V. V., Chen, X., & Storm, D. R. (2002). Hippocampal CRE-mediated gene expression is required for contextual memory formation. Nature Neuroscience, 5, 1119–1120.PubMedCrossRefGoogle Scholar
  11. Audesirk, G. (1993). Electrophysiology of lead intoxication: Effects on voltage-sensitive ion channels. Neurotoxicology, 14, 137–147.PubMedGoogle Scholar
  12. Bellinger, D. (1995). Lead and neuropsychological function in children: Progress and problems in establishing brain– behavior relationships. Advanced Child Neuropsychology, 3, 12–45.CrossRefGoogle Scholar
  13. Bellingr, D. C., & Bellinger, A. M. (2006). Childhood lead poisoning: The torturous path from science to policy. The Journal of Clinical Investigation, 116(4), 853–857.CrossRefGoogle Scholar
  14. Bennett, P. C., Moutsoulas, P., Lawen, A., Perini, E., & Ng, K. T. (2003). Novel effects on memory observed following unilateral intracranial administration of okadaic acid, cyclosporine A, FK506 and [MeVal4]CyA. Brain Research, 988(1–2), 56–68.PubMedCrossRefGoogle Scholar
  15. Bielarczyk, H., Tian, X., & Suszkiw, J. B. (1996). Cholinergic denervation-like changes in rat hippocampus following developmental lead exposure. Brain Research, 708, 108–115.PubMedCrossRefGoogle Scholar
  16. Bliss, T. V., & Collingridge, G. L. (1993). A synaptic model of memory: Long term potentiation in the hippocampus. Nature, 361, 31–39.PubMedCrossRefGoogle Scholar
  17. Blitzer, R. D., Iyengar, R., & Landau, E. M. (2005). Postsynaptic signaling networks: Cellular cogwheels underlying long-term plasticity. Biological Psychiatry, 57(2), 113–119.PubMedCrossRefGoogle Scholar
  18. Borja-Aburto, V. H., Hertz-Picciotto, I., Lopez, M. R., Farias, P., Rios, C., & Blanco, J. (1999). Blood lead levels measured prospectively and risk of spontaneous abortion. American Journal of Epidemiology, 150, 590–597.PubMedCrossRefGoogle Scholar
  19. Bourtchuladze, R., Frenguelli, B., Blendy, J., Cioffi, D., Schultz, G., & Silva, A. J. (1994). Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell, 79, 59–68.PubMedCrossRefGoogle Scholar
  20. Bouton, C. M. L. S., Frelin, L. P., Forde, C. E., Godwin, H. A., & Pevsner, J. (2001). Synaptotagmin i is a molecular target for lead. Journal of Neurochemistry, 76, 1724–1735.PubMedCrossRefGoogle Scholar
  21. Bozdagi, O., Shan, W., Tanaka, H., Benson, D. L., & Huntley, G. W. (2000). Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. Neuron, 28, 245–259.PubMedCrossRefGoogle Scholar
  22. Braga, M. F. M., Pereira, E. F. R., & Albuquerque, E. X. (1999a). Nanomolar concentrations of lead inhibit glutamatergic and GABAergic transmission in hippocampal neurons. Brain Research, 826, 22–34.PubMedCrossRefGoogle Scholar
  23. Braga, M. F. M., Pereira, E. F. R., Marchioro, M., & Albuquerque, E. X. (1999b). Lead increases tetrodotoxin-insensitive spontaneous release of glutamate and GABA from hippocampal neurons. Brain Research, 826, 10–21.PubMedCrossRefGoogle Scholar
  24. Braga, M. F., Pereira, E. F., Mike, A., & Albuquerque, E. X. (2004). Pb2+ via protein kinase C inhibits nicotinic cholinergic modulation of synaptic transmission in the hippocampus. The Journal of Pharmacology and Experimental Therapeutics, 311(2), 700–710.PubMedCrossRefGoogle Scholar
  25. Bredt, D. S., Ferris, C. D., & Snyder, S. H. (1992). Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase; identification of flavin and calmodulin binding sites. The Journal of Biological Chemistry, 267, 10976–10981.PubMedGoogle Scholar
  26. Bressler, J., Kim, K. A., Chakraborti, T., & Goldstein, G. (1999). Molecular mechanisms of lead neurotoxicity. Neurochemical Research, 24, 595–600.PubMedCrossRefGoogle Scholar
  27. Busselberg, D., Evans, M. L., Haas, H. L., & Carpenter, D. O. (1993). Blockade of mammalian and invertebrate calcium channels by lead. Neurotoxicology, 14, 249–258.PubMedGoogle Scholar
  28. Caldeira, M. V., Melo, C. V., Pereira, D. B., Carvalho, R. F., Carvalho, A. L., & Duarte, C. B. (2007). BDNF regulates the expression and traffic of NMDA receptors in cultured hippocampal neurons. Molecular and Cellular Neurosciences, 35, 208–219.PubMedCrossRefGoogle Scholar
  29. Canfield, R. L., Henderson, C. R., Jr., Cory-Slechta, D. A., Cox, C., Jusko, T. A., & Lanphear, B. P. (2003). Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. The New England Journal of Medicine, 348, 1517–1526.PubMedCrossRefGoogle Scholar
  30. Chan, S. F., & Sucher, N. J. (2001). An NMDA receptor signaling complex with protein phosphatase 2A. The Journal of Neuroscience, 21(20), 7985–7992.PubMedGoogle Scholar
  31. Chirivia, J., Kwok, R., Lamb, N., Hagiwara, M., Montminy, M., & Goodman, R. (1993). Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature, 365, 855–859.CrossRefGoogle Scholar
  32. Chisolm, J. J., Jr. (2001). Evolution of the management and prevention of childhood lead poisoning: Dependence of advances in public health on technological advances in the determination of lead and related biochemical indicators of its toxicity. Environmental Research, 86, 111–121.PubMedCrossRefGoogle Scholar
  33. Clarkson, T. W. (1987). Metal toxicity in the central nervous system. Environmental Health Perspectives, 75, 59–64.PubMedCentralPubMedCrossRefGoogle Scholar
  34. Colbran, R. J. (2004). Targeting of calcium/calmodulin-dependent protein kinase II. The Biochemical Journal, 378, 1–16.PubMedCentralPubMedCrossRefGoogle Scholar
  35. Collingridge, G. L., & Bliss, T. V. P. (1987). NMDA receptors – Their role in long-term potentiation. Trends in Neuropharmacology, 10, 288–293.Google Scholar
  36. Collingridge, G. L., & Lester, R. A. (1989). Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacological Reviews, 41, 143–210.PubMedGoogle Scholar
  37. Cordova, F. M., Rodrigues, L. S., Giocomelli, M. B. O., Oliveira, C. S., Posser, T., Dunkley, P. R., & Leal, R. B. (2004). Lead stimulates ERK1/2 and p38MAPK phosphorylation in the hippocampus of immature rats. Brain Research, 998, 65–72.PubMedCrossRefGoogle Scholar
  38. Cornell-Bell, A. H., Finkbeiner, S. M., Cooper, M. S., & Smith, S. J. (1990). Glutamate induces calcium waves in cultured astrocytes: Long-range glial signaling. Science, 247, 470–473.PubMedCrossRefGoogle Scholar
  39. Davis, S., Vanhoutte, P., Pages, C., Caboche, J., & Laroche, S. (2000). The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. The Journal of Neuroscience, 20(12), 4563–4572.PubMedGoogle Scholar
  40. De Roo, M., Klauser, P., & Muller, D. (2008). LTP promotes a selective long-term stabilization and clustering of dendritic spines. PLoS Biology, 6, 1850–1860.Google Scholar
  41. DeMichele, S. J. (1984). Nutrition of lead. Comparative Biochemistry and Physiology A, 78(3), 401–408.CrossRefGoogle Scholar
  42. Dietrich, K. N., Ware, J. H., Salganik, M., Radcliffe, J., Rogan, W. J., Rhoads, G. G., Fay, M. E., Davoli, C. T., Denckla, M. B., Bornschein, R. L., Schwarz, D., Dockery, D. W., Adubato, S., & Jones, R. L. (2004). Effect of chelation therapy on the neuropsychological and behavioral development of lead-exposed children after school entry. Pediatrics, 114, 19–26.PubMedCrossRefGoogle Scholar
  43. Dorea, J. G. (2004). Mercury and lead during breast-feeding. The British Journal of Nutrition, 92(1), 21–40.PubMedCrossRefGoogle Scholar
  44. Downing, J. E., & Role, L. W. (1987). Activators of protein kinase C enhance acetylcholine receptor desensitization in sympathetic ganglion neurons. Proceedings of the National Academy of Sciences, 84, 7739–7743.CrossRefGoogle Scholar
  45. Durand, G. M., Gregor, P., Zheng, Z., Bennett, M. V. L., Uhl, G. R., & Zukin, R. S. (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. Proceedings of the National Academy of Sciences, 89, 9359–9363.CrossRefGoogle Scholar
  46. Ehlers, M. D. (2003). Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nature Neuroscience, 6, 231–242.PubMedCrossRefGoogle Scholar
  47. Evans, M. L., Busselberg, D., & Carpenter, D. O. (1991). Pb2+ blocks calcium currents of cultured dorsal root ganglion cells. Neuroscience Letters, 129, 103–106.PubMedCrossRefGoogle Scholar
  48. Fenster, C. P., Beckman, M. L., Parker, J. C., Sheffield, E. B., Whitworth, T. L., Quick, M. W., & Lester, R. A. (1999). Regulation of alpha4beta2 nicotinic receptor desensitization by calcium and protein kinase C. Molecular Pharmacology, 55, 432–443.PubMedGoogle Scholar
  49. Finkelstein, Y., Markowitz, M. E., & Rosen, J. F. (1998). Low-level lead-induced neurotoxicity in children: An update on central nervous system effects. Brain Research Reviews, 27, 168–176.PubMedCrossRefGoogle Scholar
  50. Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., & Tsai, L. H. (2007). Recovery of learning and memory is associated with chromatin remodelling. Nature, 447(7141), 178–182.PubMedCrossRefGoogle Scholar
  51. Gasparini, F., Lingenhöhl, K., Stoehr, N., Flor, P. J., Heinrich, M., Vranesic, I., Biollaz, M., Allgeier, H., Heckendorn, R., Urwyler, S., Varney, M. A., Johnson, E. C., Hess, S. D., Rao, S. P., Sacaan, A. I., Santori, E. M., Velicelebi, G., & Kuhn, R. (1999). 2-Methyl-6-(phenylethyl)-pyridine (MPEP), a potent, selective and systematically active mGluR5 receptor antagonist. Neuropharmacology, 38, 1493–1503.PubMedCrossRefGoogle Scholar
  52. Gavazzo, P., Gazzoli, A., Mazzolini, M., & Marchetti, C. (2001). Lead inhibition of NMDA channels in native and recombinant receptors. Neuroreport, 12(14), 3121–3125.PubMedCrossRefGoogle Scholar
  53. Gavazzo, P., Zanardi, I., Baranowska-Bosiacka, I., & Marchetti, C. (2008). Molecular determinants of Pb2+ interaction with NMDA receptor channels. Neurochemistry International, 52, 329–337.PubMedCrossRefGoogle Scholar
  54. Genoux, D., Haditsch, U., Knobloch, M., Michalon, A., Storm, D., & Mansuy, I. M. (2002). Protein phosphatase 1 is a molecular constraint on learning and memory. Nature, 418(6901), 970–975.PubMedCrossRefGoogle Scholar
  55. Genoux, D., Bezerra, P., & Montgomery, J. M. (2011). Intra-spaced stimulation and protein phosphatase 1 dictate the direction of synaptic plasticity. The European Journal of Neuroscience, 33(10), 1761–1770.PubMedCrossRefGoogle Scholar
  56. Gilbert, M. E., & Lasley, S. M. (2002). Long-term consequences of developmental exposure to lead or polychlorinated biphenyls: Synaptic transmission and plasticity in the rodent CNS. Environmental Toxicology and Pharmacology, 12, 105–117.PubMedCrossRefGoogle Scholar
  57. Gilbert, M. E., & Lasley, S. M. (2007). Developmental lead (Pb) exposure reduces the ability of the NMDA antagonist MK-801 to suppress long-term potentiation (LTP) in the rat dentate gyrus, in vivo. Neurotoxicology and Teratology, 29(2007), 385–393.PubMedCrossRefGoogle Scholar
  58. Gilbert, M. E., & Mack, C. M. (1990). The NMDA antagonist, MK-801, suppresses long-term potentiation, kindling, and kindling-induced potentiation in the perforant path of the unanesthetized rat. Brain Research, 519, 89–96.PubMedCrossRefGoogle Scholar
  59. Gilbert, M., & Mack, C. (1998). Chronic lead exposure accelerates decay of long-term potentiation in rat dentate gyrus in vivo. Brain Research, 789, 139–149.PubMedCrossRefGoogle Scholar
  60. Gilbert, M. E., Mack, C. M., & Lasley, S. M. (1996). Chronic developmental lead exposure increases the threshold for long-term potentiation in rat dentate gyrus in vivo. Brain Research, 736, 118–124.PubMedCrossRefGoogle Scholar
  61. Gilbert, M. E., Mack, C. M., & Lasley, S. M. (1999a). The influence of developmental period of lead exposure on long-term potentiation in the rat dentate gyrus in vivo. Neurotoxicology, 20, 57–70.PubMedGoogle Scholar
  62. Gilbert, M. E., Mack, M. E., & Lasley, S. M. (1999b). Developmental lead exposure reduces the magnitude of long-term potentiation: A dose–response analysis. Neurotoxicology, 20, 71–82.PubMedGoogle Scholar
  63. Goyer, R. A. (1995). Nutrition and metal toxicity. The American Journal of Clinical Nutrition, 61(Suppl), 646S–650S.PubMedGoogle Scholar
  64. Goyer, R. A., & Clarkson, T. W. (2001). Toxic effects of metals. In C. D. Klaassen (Ed.), Casarett and Doull’s toxicology: The basic science of poisons (6th ed., pp. 811–867). New York: McGraw-Hill.Google Scholar
  65. Gräff, J., Koshibu, K., Jouvenceau, A., Dutar, P., & Mansuy, I. M. (2010). Protein phosphatase 1-dependent transcriptional programs for long-term memory and plasticity. Learning & Memory, 17(7), 355–363.CrossRefGoogle Scholar
  66. Guilarte, T. R. (1997). Glutamatergic system and developmental lead neurotoxicity. Neurotoxicology, 18, 665–672.PubMedGoogle Scholar
  67. Guilarte, T. R., & McGlothan, J. L. (1998). Hippocampal NMDA receptor mRNA undergoes subunit specific changes during developmental lead exposure. Brain Research, 790, 98–107.PubMedCrossRefGoogle Scholar
  68. Guilarte, T. R., & McGlothan, J. L. (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. Brain Research. Molecular Brain Research, 113(1–2), 37–43.PubMedCrossRefGoogle Scholar
  69. Guilarte. T.R., Miceli, R.C. & Jett, D.A. (1994). Neurochemical aspects of hippocampal and cortical Pb2+ neurotoxicity. Neurotoxicology. 15(3), 459–66.PubMedGoogle Scholar
  70. Guilarte, T. R., Miceli, R. C., & Jett, D. A. (1995). Biochemical evidence of an interaction of lead at the zinc allosteric sites of the NMDA receptor complex: Effects of neuronal development. Neurotoxicology, 16, 63–71.PubMedGoogle Scholar
  71. Guilarte, T. R., McGlothan, J. L., & Nihei, M. K. (2000). Hippocampal expression of N-methyl-d-aspartate receptor (NMDAR1) subunit splice variant mRNA is altered by developmental exposure to Pb2+. Molecular Brain Research, 76, 299–305.PubMedCrossRefGoogle Scholar
  72. Gutowski, M., Altmann, L., Sveinsson, K., & Wiegand, H. (1998). Synaptic plasticity in the CA1 and CA3 hippocampal region of pre- and postnatally lead-exposed rats. Toxicology Letters, 95, 195–203.PubMedCrossRefGoogle Scholar
  73. Haege, S., Galetzka, D., Zechner, U., Haaf, T., Gamerdinger, M., Behl, C., Hiemke, C., & Schmitt, U. (2010). Spatial learning and expression patterns of PP1 mRNA in mouse hippocampus. Neuropsychobiology, 61(4), 188–196.PubMedCrossRefGoogle Scholar
  74. Hansra, G., Bornancin, F., Whelan, R., Hemmings, B. A., & Parker, P. J. (1996). 12-O-Tetradecanoylphorbol-13-acetate-induced dephosphorylation of protein kinase Calpha correlates with the presence of a membrane-associated protein phosphatase 2A heterotrimer. The Journal of Biological Chemistry, 271, 32785–32788.PubMedCrossRefGoogle Scholar
  75. Hardingham, G. E., Fukunaga, Y., & Bading, H. (2002). Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nature Neuroscience, 5(5), 405–414.PubMedGoogle Scholar
  76. Hartmann, M., Heumann, R., & Lessmann, V. (2001). Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. The EMBO Journal, 20, 5887–5897.PubMedCentralPubMedCrossRefGoogle Scholar
  77. Hashemzadeh-Gargari, H., & Guilarte, T. R. (1999). Divalent cations modulate N-methyl-d-aspartate receptor function at the glycine site. The Journal of Pharmacology and Experimental Therapeutics, 290, 1356–1362.PubMedGoogle Scholar
  78. Hassel, B., & Dingledine, R. (2006). Glutamate. In G. J. Siegel, R. W. Albers, S. T. Brady, & D. L. Price (Eds.), Basic neurochemistry: Molecular, cellular and medical aspects (7th ed., pp. 267–290). San Diego, CA: Elsevier/Academic.Google Scholar
  79. Havekes, R., Nijholt, I. M., Luiten, P. G., & Van der Zee, E. A. (2006). Differential involvement of hippocampal calcineurin during learning and reversal learning in a Y-maze task. Learning & Memory, 13(6), 753–759.CrossRefGoogle Scholar
  80. Ho, Y., Logue, E., Callaway, C. W., & DeFranco, D. B. (2007). Different mechanisms account for extracellular-signal regulated kinase activation in distinct brain regions following global ischemia and reperfusion. Neuroscience, 145(1), 248–255.PubMedCentralPubMedCrossRefGoogle Scholar
  81. Hoffmann, H., Gremme, T., Hatt, H., & Gottmann, K. (2000). Synaptic activity dependent developmental regulation of NMDA receptor subunit expression in cultured neocortical neurons. Journal of Neurochemistry, 75, 1590–1599.PubMedCrossRefGoogle Scholar
  82. Holtzman, D., Olson, J. E., DeVries, C., & Bensch, K. (1987). Lead toxicity in primary cultured cerebral astrocytes and cerebellar granular neurones. Toxicology and Applied Pharmacology, 89, 211–225.PubMedCrossRefGoogle Scholar
  83. Huang, C. C., & Hsu, K. S. (2006). Sustained activation of metabotropic glutamate receptor 5 and protein tyrosine phosphatases mediate the expression of (S)-3,5-dihydroxyphenylglycine-induced long-term depression in the hippocampal CA1 region. Journal of Neurochemistry, 96, 179–194.PubMedCrossRefGoogle Scholar
  84. Ishihara, K., Alkondon, M., Montes, J. G., & Albuquerque, E. X. (1995). Ontogenically related properties of N-methyl-d-aspartate receptors in rat hippocampal neurons and the age-specific sensitivity of developing neurons to lead. The Journal of Pharmacology and Experimental Therapeutics, 279, 1459–1470.Google Scholar
  85. Ivanov, A., Pellegrino, C., Rama, S., Dumalska, I., Salyha, Y., Ben-Ari, Y., & Medina, I. (2006). Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons. The Journal of Physiology, 572(Pt 3), 789–798.PubMedCentralPubMedCrossRefGoogle Scholar
  86. Izquierdo, I. (1993). Long-term potentiation and the mechanism of memory. Drug Development Research, 30, 1–17.CrossRefGoogle Scholar
  87. Jiang, X., Tian, F., Mearow, K., Okagaki, P., Lipsky, R. H., & Marini, A. M. (2005). The excitoprotective effect of N-methyl-d-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. Journal of Neurochemistry, 94, 713–722.PubMedCrossRefGoogle Scholar
  88. Kandel, E. R. (2001). The molecular biology of memory storage: A dialogue between genes and synapses. Science, 294, 1030–1038.PubMedCrossRefGoogle Scholar
  89. Kawamura, Y., Manita, S., Nakamura, T., Inoue, M., Kudo, Y., & Miyakawa, H. (2004). Glutamate release increases during mossy-CA3 LTP but not during Schaffer-CA1 LTP. The European Journal of Neuroscience, 19, 1591–1600.PubMedCrossRefGoogle Scholar
  90. Kim, K. A., 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. Journal of Neuroscience Research, 69, 268–277.PubMedCrossRefGoogle Scholar
  91. Knobloch, M., Farinelli, M., Konietzko, U., Nitsch, R. M., & Mansuy, I. M. (2007). Aβ oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms. The Journal of Neuroscience, 27, 7648–7653.PubMedCrossRefGoogle Scholar
  92. Kobayashi, T., & Mori, Y. (1998). Ca2+ channel antagonists and neuroprotection from cerebral ischemia. European Journal of Pharmacology, 363, 1–15.PubMedCrossRefGoogle Scholar
  93. Kober, T. E., & Cooper, G. P. (1976). Lead competitively inhibits calcium-dependent synaptic transmission in the bullfrog sympathetic ganglion. Nature, 262, 704–705.PubMedCrossRefGoogle Scholar
  94. Koshibu, K., Gräff, J., Beullens, M., Heitz, F. D., Berchtold, D., Russig, H., Farinelli, M., Bollen, M., & Mansuy, I. M. (2009). Protein phosphatase 1 regulates the histone code for long-term memory. The Journal of Neuroscience, 29(41), 13079–13089.PubMedCrossRefGoogle Scholar
  95. Koshibu, K., Gräff, J., & Mansuy, I. M. (2011). Nuclear protein phosphatase-1: An epigenetic regulator of fear memory and amygdala long-term potentiation. Neuroscience, 173, 30–36.PubMedCrossRefGoogle Scholar
  96. Krupp, J. J., Vissel, B., Thomas, C. G., Heinemann, S. F., & Westbrook, G. L. (2002). Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors. Neuropharmacology, 42(5), 593–602.PubMedCrossRefGoogle Scholar
  97. Kuhlmann, A. C., McGlothan, J. L., & Guilarte, T. R. (1997). Developmental lead exposure causes spatial learning deficits in adult rats. Neuroscience Letters, 233, 101–104.PubMedCrossRefGoogle Scholar
  98. Lanphear, B. P., Dietrich, K., Auinger, P., & Cox, C. (2000). Cognitive deficits associated with blood lead concentrations <10 microg/dL in US children and adolescents. Public Health Reports, 115, 521–529.PubMedCentralPubMedCrossRefGoogle Scholar
  99. Lasley, S. M., & Gilbert, M. E. (1996). Presynaptic glutamatergic function in dentate gyrus in vivo is diminished by chronic exposure to inorganic lead. Brain Research, 736, 125–134.PubMedCrossRefGoogle Scholar
  100. Lasley, S. M., & Gilbert, M. E. (1999). Lead inhibits the rat N-methyl-d-aspartate receptor channel by binding to a site distinct from the zinc allosteric site. Toxicology and Applied Pharmacology, 159(3), 224–233.PubMedCrossRefGoogle Scholar
  101. Lasley, S. M., & Gilbert, M. E. (2002). Rat hippocampal glutamate and GABA release exhibit biphasic effects as a function of chronic lead exposure level. Toxicological Sciences, 66(1), 139–147.PubMedCrossRefGoogle Scholar
  102. Lasley, S. M., Green, M. C., & Gilbert, M. E. (2001). Rat hippocampal NMDA receptor binding as a function of chronic lead exposure level. Neurotoxicology and Teratology, 23, 185–189.PubMedCrossRefGoogle Scholar
  103. Lau, W. K., Yeung, C. W., Lui, P. W., Cheung, L. H., Poon, N. T., & Yung, K. K. (2002). Different trends in modulation of NMDAR1 and NMDAR2B gene expression in cultured cortical and hippocampal neurons after lead exposure. Brain Research, 932(1–2), 10–24.PubMedCrossRefGoogle Scholar
  104. Laurie, D. J., & Seeburg, P. H. (1994). Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA. The Journal of Neuroscience, 14, 3180–3194.PubMedGoogle Scholar
  105. Lee, Y. S., & Silva, A. J. (2009). The molecular and cellular biology of enhanced cognition. Nature Reviews. Neuroscience, 10, 126–140.PubMedCentralPubMedCrossRefGoogle Scholar
  106. Lee, H. K., Kameyama, K., Huganir, R. L., & Bear, M. F. (1998). NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron, 21, 1067–1078.CrossRefGoogle Scholar
  107. Lee, H. K., Barbarosie, M., Kameyama, K., Bear, M. F., & Huganir, R. L. (2000). Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature, 405, 955–959.PubMedCrossRefGoogle Scholar
  108. Levitan, I. B. (1999). Modulation of ion channels by protein phosphorylation. How the brain works. Advances in Second Messenger and Phosphoprotein Research, 33, 3–22.PubMedCrossRefGoogle Scholar
  109. Lieberman, D. N., & Mody, I. (1994). Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase. Nature, 369, 235–239.PubMedCrossRefGoogle Scholar
  110. Lindhal, L. S., Bird, L., Legare, M. E., Mikeska, G., Bratton, G. R., & Tiffany-Castiglioni, E. (1999). differential ability of astroglia and neuronal cells to accumulate lead: Dependence on cell type and on degree of differentiation. Toxicological Sciences, 50, 236–243.CrossRefGoogle Scholar
  111. Lindlbauer, R., Mohrmann, R., Hatt, H., & Gottmann, K. (1998). Regulation of kinetic and pharmacological properties of synaptic NMDA receptors depends on presynaptic exocytosis in rat hippocampal neurones. The Journal of Physiology, 508(Pt. 2), 495–502.PubMedCentralPubMedCrossRefGoogle Scholar
  112. Liu, L., Wong, T. P., Pozza, M. F., Lingenhoehl, K., Wang, Y., Sheng, M., Auberson, Y. P., & Wang, Y. T. (2004). Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science, 304(5673), 1021–1024.PubMedCrossRefGoogle Scholar
  113. Liu, F., Grundke-Iqbal, I., Iqbal, K., & Gong, C. X. (2005). Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. The European Journal of Neuroscience, 22(8), 1942–1950.PubMedCrossRefGoogle Scholar
  114. Loikkanen, J., Naarala, J., Vahakangas, K. H., & Savolainen, K. H. (2003). Glutamate increases toxicity of inorganic lead in GT1-7 neurons: Partial protection induced by flunarizine. Archives of Toxicology, 77, 663–671.PubMedCrossRefGoogle Scholar
  115. Ma, O. K., & Sucher, N. J. (2004). Molecular interaction of NMDA receptor subunit NR3A with protein phosphatase 2A. Neuroreport, 15(9), 1447–1450.PubMedCrossRefGoogle Scholar
  116. Ma, L., Zablow, L., Kandel, E. R., & Siegelbaum, S. A. (1999). Cyclic AMP induces functional presynaptic boutons in hippocampal CA3-CA1 neuronal cultures. Nature Neuroscience, 2, 24–30.PubMedCrossRefGoogle Scholar
  117. Madison, D. V., Malenka, R. C., & Nicoll, R. A. (1991). Mechanisms underlying long-term potentiation of synaptic transmission. Annual Review of Neuroscience, 14, 379–397.PubMedCrossRefGoogle Scholar
  118. Malenka, R. C., & Nicoll, R. A. (1993). NMDA-receptor-dependent synaptic plasticity: Multiple forms and mechanisms. Trends in Neurosciences, 16, 521–527.PubMedCrossRefGoogle Scholar
  119. Malenka, R. C., & Nicoll, R. A. (1999). Long-term potentiation – A decade of progress? Science, 285, 1870–1874.PubMedCrossRefGoogle Scholar
  120. Malinow, R., & Malenka, R. C. (2002). AMPA receptor trafficking and synaptic plasticity. Annual Review of Neuroscience, 25, 103–126.PubMedCrossRefGoogle Scholar
  121. Manahan-Vaughan, D., & Braunewell, K. H. (2005). The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity. Cerebral Cortex, 15, 1703–1713.PubMedCrossRefGoogle Scholar
  122. Manahan-Vaughan, D., Ngomba, R. T., Storto, M., Kulla, A., Catania, M. V., Chiechio, S., Rampello, L., Passarelli, F., Capece, A., Reymann, K. G., & Nicoletti, F. (2003). An increased expression of the mGlu5 receptor protein following LTP induction at the perforant path-dentate gyrus synapse in freely moving rats. Neuropharmacology, 44, 17–25.PubMedCrossRefGoogle Scholar
  123. Mansuy, I. M., & Shenolikar, S. (2006). Protein serine/threonine phosphatases in neuronal plasticity and disorders of learning and memory. Trends in Neurosciences, 29(12), 679–686.PubMedCrossRefGoogle Scholar
  124. Marchetti, C. (2003). Molecular targets of lead in brain neurotoxicity. Neurotoxicity Research, 5(3), 221–236.PubMedCrossRefGoogle Scholar
  125. 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. Cellular and Molecular Neurobiology, 23, 165–174.PubMedCrossRefGoogle Scholar
  126. Martin, K. C., Casadio, A., Zhu, H., Yaping, E., Rose, J. C., Chen, M., Bailey, C. H., & Kandel, E. R. (1997). Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: A function for local protein synthesis in memory storage. Cell, 91, 927–938.PubMedCrossRefGoogle Scholar
  127. Massicotte, G., & Baudry, M. (1991). Triggers and substrates of hippocampal synaptic plasticity. Neuroscience and Biobehavioral Reviews, 15, 415–423.PubMedCrossRefGoogle Scholar
  128. Mauna, J. C., Miyamae, T., Pulli, B., & Thiels, E. (2010). Protein phosphatases 1 and 2A are both required for long-term depression and associated dephosphorylation of cAMP response element binding protein in hippocampal area CA1 in vivo. Hippocampus, 21(10), 1093–1104.PubMedCentralPubMedCrossRefGoogle Scholar
  129. Mayadevi, M., Praseeda, M., Kumar, K. S., & Omkumar, R. V. (2002). Sequence determinants on the NR2A and NR2B subunits of NMDA receptor responsible for specificity of phosphorylation by CaMKII. Biochimica et Biophysica Acta, 1598, 40–45.PubMedCrossRefGoogle Scholar
  130. McNamara, R. K., & Skelton, R. W. (1993). The neuropharmacological and neurochemical basis of place learning in the Morris water maze. Brain Research. Brain Research Reviews, 18, 33–49.PubMedCrossRefGoogle Scholar
  131. McNaughton, B. L. (1993). The mechanism of expression of long-term enhancement of hippocampal synapses: Current issues and theoretical implications. Annual Review of Physiology, 55, 375–396.PubMedCrossRefGoogle Scholar
  132. Mike, A., Pereira, E. F., & Albuquerque, E. X. (2000). Ca(2+)-sensitive inhibition by Pb(2+) of alpha7-containing nicotinic acetylcholine receptors in hippocampal neurons. Brain Research, 873(1), 112–123.PubMedCrossRefGoogle Scholar
  133. Miller, C. A., Campbell, S. L., & Sweatt, J. D. (2008). DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. Neurobiology of Learning and Memory, 89(4), 599–603.PubMedCentralPubMedCrossRefGoogle Scholar
  134. Millward, T. A., Zolnierowicz, S., & Hemmings, B. A. (1999). Regulation of protein kinase cascades by protein phosphatase 2A. Trends in Biochemical Sciences, 24, 186–191.PubMedCrossRefGoogle Scholar
  135. Minnema, D. J., Michaelson, I. A., & Cooper, G. P. (1988). Calcium efflux and neurotransmitter release from rat hippocampal synaptosomes exposed to lead. Toxicology and Applied Pharmacology, 92, 351–357.PubMedCrossRefGoogle Scholar
  136. Mizuno, M., Yamada, K., Maekawa, N., Saito, K., Seishima, M., & Nabeshima, T. (2002). CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning. Behavioural Brain Research, 133, 135–141.PubMedCrossRefGoogle Scholar
  137. Monaghan, D. T., Holets, V. R., Toy, D. W., & Cotman, C. W. (1983). Anatomical distributions of four pharmacologically distinct 3H-l-glutamate binding sites. Nature, 306, 176–179.PubMedCrossRefGoogle Scholar
  138. Monyer, H., Sprengel, R., Schoepfer, R., Herb, A., Higuchi, M., Lomeli, H., Burnashev, N., Sakmann, B., & Seeburg, P. H. (1992). Heteromeric NMDA receptors: Molecular and functional distinction of subtypes. Science, 256, 1217–1221.PubMedCrossRefGoogle Scholar
  139. Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B., & Seeburg, P. H. (1994). Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron, 12, 529–540.PubMedCrossRefGoogle Scholar
  140. Moody, W. J. (1998). Control of spontaneous activity during development. Journal of Neurobiology, 37, 97–109.PubMedCrossRefGoogle Scholar
  141. Moriyoshi, K., Masu, M., Ishii, T., Shigemoto, R., Mizuno, N., & Nakanishi, S. (1991). Molecular cloning and characterization of the rat NMDA receptor. Nature, 354, 31–37.PubMedCrossRefGoogle Scholar
  142. Morris, R. G., Garrud, P., Rawlins, J. N., & O’Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature, 297, 681–683.PubMedCrossRefGoogle Scholar
  143. Morris, R. G., Anderson, E., Lynch, G. S., & Baudry, M. (1986). Selective impairment of learning and blockade of long-term potentiation by an N-methyl-d-aspartate receptor antagonist, AP5. Nature, 319, 774–776.PubMedCrossRefGoogle Scholar
  144. Moss, S. J., McDonald, B. J., Rudhard, Y., & Schoepfer, R. (1996). Phosphorylation of the predicted major intracellular domains of the rat and the chick neuronal nicotinic acetylcholine receptor 7 subunit by cAMP-dependent protein kinase. Neuropharmacology, 35, 1023–1028.PubMedCrossRefGoogle Scholar
  145. Mulkey, R. M., Herron, C. E., & Malenka, R. C. (1993). An essential role for protein phosphatases in hippocampal long-term depression. Science, 261, 1051–1055.PubMedCrossRefGoogle Scholar
  146. Mulkey, R. M., Endo, S., Shenolikar, S., & Malenka, R. C. (1994). Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature, 369, 486–488.PubMedCrossRefGoogle Scholar
  147. Naie, K., & Manahan-Vaughan, D. (2004). Regulation by metabotropic glutamate receptor 5 of LTP in the dentate gyrus of freely moving rats: Relevance for learning and memory formation. Cerebral Cortex, 14, 189–198.PubMedCrossRefGoogle Scholar
  148. Neal, A. P., & Guilarte, T. R. (2010). Molecular neurobiology of lead (Pb2+): Effects on synaptic function. Molecular Neurobiology, 42(3), 151–160.PubMedCentralPubMedCrossRefGoogle Scholar
  149. Neal, A. P., Stansfield, K. H., Worley, P. F., Thompson, R. E., & Guilarte, T. R. (2010). Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of NMDA receptor-dependent BDNF signaling. Toxicological Sciences, 116(1), 249–263.PubMedCentralPubMedCrossRefGoogle Scholar
  150. Neal, A. P., Worley, P. F., & Guilarte, T. R. (2011). Lead exposure during synaptogenesis alters NMDA receptor targeting via NMDA receptor inhibition. Neurotoxicology, 32, 281–289.PubMedCentralPubMedCrossRefGoogle Scholar
  151. Needleman, H. L., Gunnoe, C., Leviton, A., Reed, R., Peresie, H., Maher, C., & Barrett, P. (1979). Deficits in psychologic and classroom performance of children with elevated dentine lead levels. The New England Journal of Medicine, 300, 689–695.PubMedCrossRefGoogle Scholar
  152. Nevin, R. (2000). How lead exposure relates to temporal changes in IQ, violent crime, and unwed pregnancy. Environmental Research, 83, 1–22.PubMedCrossRefGoogle Scholar
  153. Neyman, S., & Manahan-Vaughan, D. (2008). Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro. The European Journal of Neuroscience, 27, 1345–1352.PubMedCentralPubMedCrossRefGoogle Scholar
  154. Nihei, M. K., & Guilarte, T. R. (1999). NMDAR-2A subunit protein expression is reduced in the hippocampus of rats exposed to Pb2+ during development. Molecular Brain Research, 66, 42–49.PubMedCrossRefGoogle Scholar
  155. Nihei, M. K., & Guilarte, T. R. (2001). Molecular changes in glutamatergic synapses induced by Pb2+: Association with deficits of LTP and spatial learning. Neurotoxicology, 22, 635–643.PubMedCrossRefGoogle Scholar
  156. Nihei, M. K., Desmond, N. L., McGlothan, J. L., Kuhlmann, A. C., & Guilarte, R. T. (2000). N-methyl-d-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning. Neuroscience, 99, 233–242.PubMedCrossRefGoogle Scholar
  157. Nihei, M. K., McGlothan, J. L., Toscano, C. D., & Guilarte, T. R. (2001). Low level Pb2+ exposure affects hippocampal protein kinase C gamma gene and protein expression in rats. Neuroscience Letters, 298, 212–216.PubMedCrossRefGoogle Scholar
  158. Norman, E. D., Thiels, E., Barrionuevo, G., & Klann, E. (2000). Long-term depression in the hippocampus in vivo is associated with protein phosphatase-dependent alterations in extracellular signal-regulated kinase. Journal of Neurochemistry, 74(1), 192–198.PubMedCrossRefGoogle Scholar
  159. Oberbeck, D. L., McCormack, S., & Houpt, T. A. (2010). Intra-amygdalar okadaic acid enhances conditioned taste aversion learning and CREB phosphorylation in rats. Brain Research, 1348, 84–94.PubMedCentralPubMedCrossRefGoogle Scholar
  160. Omelchenko, I. A., Nelson, C. S., Marino, J. L., & Allen, C. N. (1996). The sensitivity of N-methyl-d-aspartate receptors to lead inhibition is dependent on the receptor subunit composition. The Journal of Pharmacology and Experimental Therapeutics, 278(1), 15–20.PubMedGoogle Scholar
  161. Omelchenko, I. A., Nelson, C. S., & Allen, C. N. (1997). Lead inhibition of N-methyl-d-aspartate receptors containing NR2A NR2C, and NR2D subunits. The Journal of Pharmacology and Experimental Therapeutics, 282, 1458–1464.PubMedGoogle Scholar
  162. Otmakhov, N., Tao-Cheng, J. H., Carpenter, S., Asrican, B., Dosemeci, A., Reese, T. S., & Lisman, J. (2004). Persistent accumulation of calcium/calmodulin-dependent protein kinase II in dendritic spines after induction of NMDA receptor-dependent chemical long-term potentiation. The Journal of Neuroscience, 24(42), 9324–9331.PubMedCrossRefGoogle Scholar
  163. Ozawa, S., Kamiya, H., & Tsuzuki, K. (1998). Glutamate receptors in the mammalian central nervous system. Progress in Neurobiology, 54, 581–618.PubMedCrossRefGoogle Scholar
  164. 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(3), 911–925.PubMedCrossRefGoogle Scholar
  165. Peng, S., Hajela, R. K., & Atchison, W. D. (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. Molecular Pharmacology, 62, 1418–1430.PubMedCrossRefGoogle Scholar
  166. Perez-Otano, I., & Ehlers, M. (2004). Learning from NMDA receptor trafficking: Clues to the development and maturation of glutamatergic synapses. Neuro-Signals, 13, 175–189.PubMedCrossRefGoogle Scholar
  167. Pozzo-Miller, L. D., Gottschalk, W., Zhang, L., McDermott, K., Du, J., Gopalakrishnan, R., Oho, C., Sheng, Z. H., & Lu, B. (1999). Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. The Journal of Neuroscience, 19, 4972–4983.PubMedGoogle Scholar
  168. Prybylowski, K., & Wenthold, R. J. (2004). N-methyl-d-aspartate receptors: Subunit assembly and trafficking to the synapse. The Journal of Biological Chemistry, 279, 9673–9676.PubMedCrossRefGoogle Scholar
  169. Rachline, J., Perin-Dureau, F., Le Goff, A., Neyton, J., & Paoletti, P. (2005). The micromolar zinc-binding domain on the NMDA receptor subunit NR2B. The Journal of Neuroscience, 25(2), 308–317.PubMedCrossRefGoogle Scholar
  170. Rahman, A., Brew, B. J., & Guillemin, G. J. (2010). Lead dysregulates serine/threonine protein phosphatases in human neurons. Neurochemical Research, 36, 195–204.PubMedCentralPubMedCrossRefGoogle Scholar
  171. Rahman, A., Khan, K. M., Al-Khaledi, G., Khan, I., & Al-Shemary, T. (2012). Over activation of hippocampal serine/threonine protein phosphatases PP1 and PP2A is involved in lead-induced deficits in learning and memory in young rats. Neurotoxicology, 33, 370–383 [Epub ahead of print]: DOI:10.1016/j.neuro.2012.02.014.Google Scholar
  172. Rajanna, B., Rajanna, S., Hall, E., & Yallapragada, P. R. (1997). In vitro metal inhibition of N-methyl-d-aspartate specific glutamate receptor binding in neonatal and adult rat brain. Drug and Chemical Toxicology, 20(1–2), 21–29.PubMedCrossRefGoogle Scholar
  173. Raymond, L. A., Tingley, W. G., Blackstone, C. D., Roche, K. W., & Huganir, R. L. (1994). Glutamate receptor modulation by protein phosphorylation. The Journal of Physiology, 88, 181–192.Google Scholar
  174. Reddy, G. R., Devi, B. C., & Chetty, C. S. (2007). Developmental lead neurotoxicity: Alterations in brain cholinergic system. Neurotoxicology, 28(2), 402–407.PubMedCrossRefGoogle Scholar
  175. Ricciarelli, R., & Azzi, A. (1998). Regulation of recombinant PKC alpha activity by protein phosphatase 1 and protein phosphatase 2A. Archives of Biochemistry and Biophysics, 355, 197–200.PubMedCrossRefGoogle Scholar
  176. Roberson, E. D., English, J. D., & Sweatt, J. D. (1996). A biochemist’s view of long-term potentiation. Learning & Memory, 3(1), 1–24.CrossRefGoogle Scholar
  177. Robinson, G. B., & Reed, G. D. (1992). Effect of MK-801 on the induction and subsequent decay of long-term potentiation in the unanesthetized rabbit hippocampal dentate gyrus. Brain Research, 569, 78–85.PubMedCrossRefGoogle Scholar
  178. Roche, K. W., Tingley, W. G., & Huganir, R. L. (1994). Glutamate receptor phosphorylation and synaptic plasticity. Current Opinion in Neurobiology, 4, 383–388.PubMedCrossRefGoogle Scholar
  179. Rogan, W. J., Dietrich, K. N., Ware, J. H., Dockery, D. W., Salganik, M., Radcliffe, J., Jones, R. L., Ragan, N. B., Chisolm, J. J., & Rhoads, G. G. (2001). The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. The New England Journal of Medicine, 344, 1421–1426.PubMedCrossRefGoogle Scholar
  180. Savolainen, K. M., Loikkanen, J., Eerikainen, S., & Naarala, J. (1998a). Glutamate-stimulated ROS production in neuronal cultures: Interactions with lead and the cholinergic system. Neurotoxicology, 19, 669–674.PubMedGoogle Scholar
  181. Savolainen, K. M., Loikkanen, J., Eerikainen, S., & Naarala, J. (1998b). Interactions of excitatory neurotransmitters and xenobiotics in excitotoxicity and oxidative stress: Glutamate and lead. Toxicology Letters, 102–103, 363–367.PubMedCrossRefGoogle Scholar
  182. Scheetz, A. J., & Constantine-Paton, M. (1994). Modulation of NMDA receptor function: Implications for vertebrate neural development. The FASEB Journal, 8, 745–752.Google Scholar
  183. Schultz, S., Siemer, H., Krug, M., & Hollt, V. (1999). Direct evidence for biphasic cAMP responsive element-binding protein phosphorylation during long-term potentiation in the rat dentate gyrus in vivo. The Journal of Neuroscience, 19, 5683–5692.Google Scholar
  184. Seguela, P., Wadiche, J., Dineley-Miller, K., Dani, J. A., & Patrick, J. W. (1993). Molecular cloning, functional properties and distribution of rat brain alpha 7: A nicotinic cation channel highly permeable to calcium. The Journal of Neuroscience, 13, 596–604.PubMedGoogle Scholar
  185. Selevan, S. G., Rice, D. C., Hogan, K. A., Euling, S. Y., Pfahles- Hutchens, A., & Bethel, J. (2003). Blood lead concentration and delayed puberty in girls. The New England Journal of Medicine, 348, 1527–1536.PubMedCrossRefGoogle Scholar
  186. Sharifi, A. M., Baniasadi, S., Jorjani, M., Rahimi, F., & Bakhshayesh, M. (2002). Investigation of acute lead poisoning on apoptosis in rat hippocampus in vivo. Neuroscience Letters, 329, 45–48.PubMedCrossRefGoogle Scholar
  187. Shields, S. M., Ingebritsen, T. S., & Kelly, P. T. (1985). Identification of protein phosphatase 1 in synaptic junctions: Dephosphorylation of endogenous calmodulin-dependent kinase II and synapse-enriched phosphoproteins. The Journal of Neuroscience, 5(12), 3414–3422.PubMedGoogle Scholar
  188. Shimizu, E., Tang, Y. P., Rampon, C., & Tsien, J. Z. (2000). NMDA receptor-dependent synaptic reinforcement as a process for memory consolidation. Science, 290, 1170–1174.PubMedCrossRefGoogle Scholar
  189. Silbergeld, E. K. (1992). Mechanisms of lead neurotoxicity, or looking beyond the lamppost. The FASEB Journal, 6(13), 3201–3206.Google Scholar
  190. Silverstein, A. M., Barrow, C. A., Davis, A. J., & Mumby, M. C. (2002). Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits. Proceedings of the National Academy of Sciences, 99(7), 4221–4226.CrossRefGoogle Scholar
  191. Simons, T. J. B. (1993). Lead-calcium interactions in cellular lead toxicity. Neurotoxicology, 14, 77–85.PubMedGoogle Scholar
  192. Simons, T. J. B., & Pocock, G. (1987). Lead enters bovine adrenal medullary cells through calcium channels. Journal of Neurochemistry, 48, 383–389.PubMedCrossRefGoogle Scholar
  193. Small, D. L., Murray, C. L., Mealing, G. A., Poulter, M. O., Buchan, A. M., & Morley, P. (1998). Brain derived neurotrophic factor induction of N-methyl-d-aspartate receptor subunit NR2A expression in cultured rat cortical neurons. Neuroscience Letters, 252, 211–214.PubMedCrossRefGoogle Scholar
  194. Soderling, T. R., & Derkach, V. A. (2000). Postsynaptic protein phosphorylation and LTP. Trends in Neurosciences, 23, 75–80.PubMedCrossRefGoogle Scholar
  195. Struzynska, L. (2009). A glutamatergic component of lead toxicity in adult brain: The role of astrocytic glutamate transporters. Neurochemistry International, 55, 151–156.PubMedCrossRefGoogle Scholar
  196. Sui, L., Ge, S. Y., Ruan, D. Y., Chen, J. T., Xu, Y. Z., & Wang, M. (2000). Age-related impairment of long-term depression in area CA1 and dentate gyrus of rat hippocampus following developmental lead exposure in vitro. Neurotoxicology and Teratology, 22, 381–387.PubMedCrossRefGoogle Scholar
  197. Sun, L., Zhao, Z. Y., Hu, J., & Zhou, X. L. (2005). Potential association of lead exposure during early development of mice with alteration of hippocampus nitric oxide levels and learning memory. Biomedical and Environmental Sciences, 18, 375–378.PubMedGoogle Scholar
  198. Suszkiw, J. B. (2004). Presynaptic disruption of transmitter release by lead. Neurotoxicology, 25, 599–604.PubMedCrossRefGoogle Scholar
  199. Suzuki, K., Sato, M., Morishima, Y., & Nakanishi, S. (2005). Neuronal depolarization controls brain-derived neurotrophic factor-induced upregulation of NR2C NMDA receptor via calcineurin signaling. The Journal of Neuroscience, 25(41), 9535–9543.PubMedCrossRefGoogle Scholar
  200. Swanson, K. L., Marchioro, M., Ishihara, K., Alkondon, M., Pereira, E. F. R., & Albuquerque, E. X. (1997). Neuronal targets of lead in the hippocampus: Relationship to low-level lead intoxication. Comprehensive Toxicology, 11, 470–491.Google Scholar
  201. Swope, S. L., Moss, S. J., Raymond, L. A., & Huganir, R. L. (1999). Regulation of ligand-gated ion channels by protein phosphorylation. Advances in Second Messenger and Phosphoprotein Research, 33, 49–78.PubMedCrossRefGoogle Scholar
  202. Tartaglia, N., Du, J., Tyler, W. J., Neale, E., Pozzo-Miller, L., & Lu, B. (2001). Protein synthesis-dependent and -independent regulation of hippocampal synapses by brain-derived neurotrophic factor. The Journal of Biological Chemistry, 276, 37585–37593.PubMedCrossRefGoogle Scholar
  203. Teyler, T. J., & DiScenna, P. (1987). Long-term potentiation. Annual Review of Neuroscience, 10, 131–161.PubMedCrossRefGoogle Scholar
  204. Thiels, E., Norman, E. D., Barrionuevo, G., & Klann, E. (1998). Transient and persistent increases in protein phosphatase activity during long-term depression in the adult hippocampus in vivo. Neuroscience, 86(4), 1023–1029.PubMedCrossRefGoogle Scholar
  205. Thiels, E., Kanterewicz, B. I., Norman, E. D., Trzaskos, J. M., & Klann, E. (2002). Long-term depression in the adult hippocampus in vivo involves activation of extracellular signal-regulated kinase and phosphorylation of Elk-1. The Journal of Neuroscience, 22(6), 2054–2062.PubMedGoogle Scholar
  206. Tiffany-Castiglioni, E. (1993). Cell culture models for lead toxicity in neuronal and glial cells. Neurotoxicology, 14, 513–536.PubMedGoogle Scholar
  207. Tiffany-Castiglioni, E., Zmudzki, J., & Bratton, G. R. (1986). Cellular targets of lead toxicity: In vitro models. Toxicology, 42, 305–315.Google Scholar
  208. Tingley, W. G., Ehlers, M. D., Kameyama, K., Doherty, C., Ptak, J. B., Riley, C. T., & Huganir, R. L. (1997). Characterization of protein kinase A and protein kinase C phosphorylation of the N-methyl-d-aspartate receptor NR1 subunit using phosphorylation site-specific antibodies. The Journal of Biological Chemistry, 272, 5157–5166.PubMedCrossRefGoogle Scholar
  209. Tong, G., Shepherd, D., & Jahr, C. E. (1995). Synaptic desensitization of NMDA receptors by calcineurin. Science, 267(5203), 1510–1512.PubMedCrossRefGoogle Scholar
  210. Toni, N., Buchs, P. A., Nikonenko, I., Bron, C. R., & Muller, D. (1999). LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature, 402, 421–425.PubMedCrossRefGoogle Scholar
  211. Topolnik, L., Azzi, M., Morin, F., Kougioumoutzakis, A., & Lacaille, J. C. (2006). MGluR1/5 subtype-specific calcium signalling and induction of long-term potentiation in rat hippocampal oriens/alveus interneurones. The Journal of Physiology, 575, 115–131.PubMedCentralPubMedCrossRefGoogle Scholar
  212. Toscano, C. D., & Guilarte, T. R. (2005). Lead neurotoxicity: From exposure to molecular effects. Brain Research Reviews, 49, 529–555.PubMedCrossRefGoogle Scholar
  213. Toscano, C. D., Hashemzadeh-Gargari, H., McGlothan, J. L., & Guilarte, T. R. (2002). Developmental Pb2+ exposure alters NMDAR subtypes and reduces CREB phosphorylation in the rat brain. Developmental Brain Research, 139, 217–226.PubMedCrossRefGoogle Scholar
  214. Toscano, C. D., McGlothan, J. L., & Guilarte, T. R. (2003). Lead exposure alters cyclic-AMP response element binding protein phosphorylation and binding activity in the developing rat brain. Developmental Brain Research, 145, 219–228.PubMedCrossRefGoogle Scholar
  215. Toscano, C. D., O’Callaghan, J. P., & Guilarte, T. R. (2005). Calcium/calmodulin-dependent protein kinase II activity and expression are altered in the hippocampus of Pb2+-exposed rats. Brain Research, 1044, 51–58.PubMedCrossRefGoogle Scholar
  216. Ujihara, H., & Albuquerque, E. X. (1992). Developmental change of the inhibition by lead of NMDA activated currents in cultured hippocampal neurons. The Journal of Pharmacology and Experimental Therapeutics, 263, 868–875.PubMedGoogle Scholar
  217. United States Centers for Disease Control and Prevention. Atlanta: CDC; (2002). Managing elevated blood lead levels among young children: Recommendations from the advisory committee on childhood lead poisoning prevention. CDC, Atlanta, GA, United States.Google Scholar
  218. Vanhoutte, P., & Bading, H. (2003). Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signalling and BDNF gene regulation. Current Opinion in Neurobiology, 13(3), 366–371.PubMedCrossRefGoogle Scholar
  219. Viola, H., Furman, M., Izquierdo, L. A., Alonso, M., Barros, D. M., de Souza, M. M., Izquierdo, I., & Medina, J. H. (2000). Phosphorylated cAMP response element-binding protein as a molecular marker of memory processing in rat hippocampus: Effect of novelty. The Journal of Neuroscience, 20(23), RC112.PubMedGoogle Scholar
  220. Wadzinski, B. E., Wheat, W. H., Jaspers, S., Peruski, L. F., Jr., Lickteig, R. L., Johnson, G. L., & Klemm, D. J. (1993). Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. Molecular and Cellular Biology, 13(5), 2822–2834.PubMedCentralPubMedGoogle Scholar
  221. Walz, C., Jungling, K. L., & Gottmann, K. (2006). Presynaptic plasticity in an immature neocortical network requires NMDA receptor activation and BDNF release. Journal of Neurophysiology, 96, 3512–3516.PubMedCrossRefGoogle Scholar
  222. Wang, J. H., & Kelly, P. T. (1997). Postsynaptic calcineurin activity downregulates synaptic transmission by weakening intracellular Ca2+ signaling mechanisms in hippocampal CA1 neurons. The Journal of Neuroscience, 17, 4600–4611.PubMedGoogle Scholar
  223. Wang, L. Y., Orser, B. A., Brautigan, D. L., & MacDonald, J. F. (1994). Regulation of NMDA receptors in cultured hippocampal neurons by protein phosphatases 1 and 2A. Nature, 369, 230–232.PubMedCrossRefGoogle Scholar
  224. Wang, L., Luo, L., Luo, Y. Y., Gu, Y., & Ruan, D. Y. (2007). Effects of Pb2+ on muscarinic modulation of glutamatergic synaptic transmission in rat hippocampal CA1 area. Neurotoxicology, 28(3), 499–507.PubMedCrossRefGoogle Scholar
  225. Waters, K.A. & Machaalani, R. (2004). NMDA receptors in the developing brain and effects of noxious insults. Neurosignals 13,162–174.PubMedCrossRefGoogle Scholar
  226. Westphal, R. S., Anderson, K. A., Means, A. R., & Wadzinski, B. E. (1998). A signaling complex of Ca2+-calmodulin-dependent protein kinase IV and protein phosphatase 2A. Science, 280(5367), 1258–1261.PubMedCrossRefGoogle Scholar
  227. Westphal, R. S., Tavalin, S. J., Lin, J. W., Alto, N. M., Fraser, I. D., Langeberg, L. K., Sheng, M., & Scott, J. D. (1999). Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Science, 285(5424), 93–96.PubMedCrossRefGoogle Scholar
  228. White, L. D., Cory-Slechta, D. A., Gilbert, M. E., Tiffany-Castiglioni, E., Zawia, N. H., Virgolini, M., Rossi-George, A., Lasley, S. M., Qian, Y. C., & Basha, M. R. (2007). New and evolving concepts in the neurotoxicology of lead. Toxicology and Applied Pharmacology, 225(1), 1–27.PubMedCrossRefGoogle Scholar
  229. Winder, D. G., & Sweatt, J. D. (2001). Roles of serine/threonine phosphatases in hippocampal synaptic plasticity. Nature Reviews. Neuroscience, 2(7), 461–474.PubMedCrossRefGoogle Scholar
  230. Xiao, C., Gu, Y., Zhou, C. Y., Wang, L., Zhang, M. M., & Ruan, D. Y. (2006). Pb2+ impairs GABAergic synaptic transmission in rat hippocampal slices: A possible involvement of presynaptic calcium channels. Brain Research, 1088, 93–100.PubMedCrossRefGoogle Scholar
  231. Xu, S., & Rajanna, B. (2006). Glutamic acid reverses Pb2+-induced reductions of NMDA receptor subunits in vitro. Neurotoxicology, 27, 169–175.PubMedCrossRefGoogle Scholar
  232. Xu, S. Z., Bullock, L., Shan, C. J., Cornelius, K., & Rajanna, B. (2005). PKC isoforms were reduced by lead in the developing rat brain. International Journal of Developmental Neuroscience, 23(1), 53–64.PubMedCrossRefGoogle Scholar
  233. Xu, J., Yan, C. H., Yang, B., Xie, H. F., Zou, X. Y., Zhong, L., Gao, Y., Tian, Y., & Shen, X. M. (2009a). The role of metabotropic glutamate receptor 5 in developmental lead neurotoxicity. Toxicology Letters, 191(2–3), 223–230.PubMedCrossRefGoogle Scholar
  234. Xu, J., Zhu, Y., Contractor, A., & Heinemann, S. F. (2009b). mGluR5 has a critical role in inhibitory learning. The Journal of Neuroscience, 29, 3676–3684.PubMedCentralPubMedCrossRefGoogle Scholar
  235. Xy, Z., Liu, A. P., Ruan, D. Y., & 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. Neurotoxicology and Teratology, 24, 149–160.CrossRefGoogle Scholar
  236. Yamashita, T., Inui, S., Maeda, K., Hua, D. R., Takagi, K., Fukunaga, K., & Sskaguchi, N. (2006). Regulation of CamKII by alpha4/PP2Ac contributes to learning and memory. Brain Research, 1082(1), 1–10.PubMedCrossRefGoogle Scholar
  237. Zalutsky, R. A., & Nicoll, R. A. (1990). Comparison of two forms of long-term potentiation in single hippocampal neurons. Science, 248, 1619–1624.PubMedCrossRefGoogle Scholar
  238. Zhang, W., Shen, H., Blaner, W. S., Zhao, Q., Ren, X., & Graziano, J. H. (1996). Chronic lead exposure alters transthyretin concentration in rat cerebrospinal fluid: The role of the choroid plexus. Toxicology and Applied Pharmacology, 139(2), 445–450.CrossRefGoogle Scholar
  239. Zhang, X. Y., Liu, A. P., Ruan, D. Y., & 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. Neurotoxicology and Teratology, 24(2), 149–160.PubMedCrossRefGoogle Scholar
  240. Zukin, R. S., & Bennett, M. V. (1995). Alternatively spliced isoforms of the NMDARI receptor subunit. Trends in Neurosciences, 18, 306–313.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Food Science and Nutrition, College for WomenKuwait UniversitySafatKuwait

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