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Lead and Excitotoxicity

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Handbook of Neurotoxicity

Abstract

Lead (Pb2+) is a known neurotoxicant that impairs learning and memory. However, the mechanism through which it impairs learning and memory is not clearly understood, despite being thoroughly investigated. Of many pathways that are targeted by Pb2+, the most mechanistically relevant is the excitotoxicity caused by modulation of the N-methyl-D-aspartate-type glutamate receptors (NMDAR) in glutamatergic synapses. Pb2+ affects not only the expression of different subunits of the NMDARs but also the ontogenic developmental switch of these NMDAR subunits, which is essential for learning and memory. Overactivation of serine/threonine protein phosphatases (PPs) appears to be involved in these synaptic changes. PPs may affect the functions of NMDAR directly, by modulating the phosphorylation state of its subunits, and indirectly by modulating the phosphorylation state of its downstream effectors like the cyclic AMP response element-binding protein (CREB) and other proteins involved in this process. Overexpression of the neuron-specific metallothionein-3 and the subsequent dysregulation of zinc (Zn2+) homeostasis in the synapse is another proposed mechanism of Pb2+-induced excitotoxicity. Upregulation of the kynurenine pathway of tryptophan metabolism and overproduction of quinolinic acid in the brain by Pb2+ may also result in excitotoxicity. The excitotoxic effects of Pb2+ thus appear to be multifaceted, and Pb2+ is likely to act in coordination with other modulator of excitotoxicity like glutamate, metallothionein-3, quinolinic acid, protein phosphatases, and Zn2+. There is a great need to put these isolated pieces of information together and workout the pathway(s) that are disturbed in Pb2+-induced impairment of learning and memory.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

CaBP:

Calcium-binding protein

CaM:

Calmodulin

CaMKII:

Calcium/calmodulin kinase II

CaMKIV:

Calcium-/calmodulin-dependent protein kinase IV

CREB:

Cyclic AMP response element-binding protein

DG:

Dentate gyrus

EPSP:

Excitatory postsynaptic potential

ERK:

Extracellular signal-regulated kinases

GABA:

γ-aminobutyric acid

GPCRs:

G-protein-coupled receptors

IDO-1:

Indoleamine-2,3-dioxygenase-I

IEG:

Immediate early genes

KP:

Kynurenine pathway

LTD:

Long-term depression

LTM:

Long-term memory

LTP:

Long-term potentiation

mGluR:

Metabotropic glutamate receptors

MT-3:

Metallothionein-3

NCS-1:

Neuronal calcium sensor-1

NMDARs:

N-methyl-D-aspartate-type glutamate receptors

Pb2+:

Lead

PK:

Protein kinases

PKC:

Protein kinase C

PND:

Postnatal day

PP:

Protein phosphatases

QA:

Quinolinic acid

STM:

Short-term memory

VSCC:

Voltage-sensitive calcium channels

References

  • Akinyemi, A. J., Miah, M. R., Ijomone, O. M., Tsatsakis, A., Soares, F. A. A., Tinkov, A. A., Skalny, A. V., Venkataramani, V., & Aschner, M. (2019, August 11). Lead (Pb) exposure induces dopaminergic neurotoxicity in Caenorhabditis elegans: Involvement of the dopamine transporter. Toxicology Reports, 6, 833–840. https://doi.org/10.1016/j.toxrep.2019.08.001

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Alberts, A. S., Montminy, M., Shenolikar, S., & Feramisco, J. R. (1994, July). Expression of a peptide inhibitor of protein phosphatase 1 increases phosphorylation and activity of CREB in NIH 3T3 fibroblasts. Molecular and Cellular Biology, 14(7), 4398–4407. https://doi.org/10.1128/mcb.14.7.4398

    Article  Google Scholar 

  • Al-Saleh, I., Shinwari, N., Nester, M., Mashhour, A., Moncari, L., El Din, M. G., et al. (2008). Longitudinal study of prenatal and postnatal lead exposure and early cognitive development in Al-Kharj, Saudi Arabia: A preliminary results of cord blood lead levels. Journal of Tropical Pediatrics, 54, 300–307.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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 signalling complex. The Journal of Biological Chemistry, 279(30), 31708–31716.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Asano, T., Wang, P. C., & Iwasaki, A. (2010, June). Spectrophotometric detection of labile zinc(II) released from metallothionein: A simple method to evaluate heavy metal toxicity. Journal of Bioscience and Bioengineering, 109(6), 638–644.

    Article  Google Scholar 

  • Aschner, M. (1996). The functional significance of brain metallothioneins. The FASEB Journal, 10, 1129–1136.

    Article  Google Scholar 

  • Atchison, W. D., & Narahashi, T. (1984). Mechanism of action of lead on neuromuscular junction. Neurotoxicology, 5, 267–282.

    Google Scholar 

  • 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.

    Article  Google Scholar 

  • ATSDR. (2017). Agency for toxic substances and disease registry: Case studies in environmental medicine-lead toxicity, course: Wb2832. Available: http://www.atsdr.cdc.gov/csem/csem.html.

  • Attina, T. M., & Trasande, L. (2013, September). Economic costs of childhood lead exposure in low- and middle-income countries. Environmental Health Perspectives, 121(9), 1097–1102.

    Article  Google Scholar 

  • Audesirk, G. (1993). Electrophysiology of lead intoxication: Effects on voltage-sensitive ion channels. Neurotoxicology, 14, 137–147.

    Google Scholar 

  • Baranowska-Bosiacka, I., Gutowska, I., Marchlewicz, M., Marchetti, C., Kurzawski, M., Dziedziejko, V., Kolasa, A., Olszewska, M., Rybicka, M., Safranow, K., Nowacki, P., Wiszniewska, B., & Chlubek, D. (2012). Disrupted pro- and antioxidative balance as a mechanism of neurotoxicity induced by perinatal exposure to lead. Brain Research, 1435, 56–71.

    Article  Google Scholar 

  • Basha, M. R., Wei, W., Brydie, M., Razmiafshari, M., & Zawia, N. H. (2003, February). Lead-induced developmental perturbations in hippocampal Sp1 DNA-binding are prevented by zinc supplementation: In vivo evidence for Pb and Zn competition. International Journal of Developmental Neuroscience, 21(1), 1–12.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Bielarczyk, H., Tian, X., & Suszkiw, J. B. (1996). Cholinergic denervation-like changes in rat hippocampus following developmental lead exposure. Brain Research, 708, 108–115.

    Article  Google Scholar 

  • Bliss, T. V., & Collingridge, G. L. (1993). A synaptic model of memory: Long term potentiation in the hippocampus. Nature, 361, 31–39.

    Article  Google Scholar 

  • Blitzer, R. D., Iyengar, R., & Landau, E. M. (2005). Postsynaptic signalling networks: Cellular cogwheels underlying long-term plasticity. Biological Psychiatry, 57(2), 113–119.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Braidy, N., Alicajic, H., Pow, D., Smith, J., Jugder, B. E., Brew, B. J., Nicolazzo, J. A., & Guillemin, G. J. (2020, September 6). Potential mechanism of cellular uptake of the excitotoxin quinolinic acid in primary human neurons. Molecular Neurobiology. https://doi.org/10.1007/s12035-020-02046-6

  • 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.

    Article  Google Scholar 

  • Bressler, J., Kim, K. A., Chakraborti, T., & Goldstein, G. (1999). Molecular mechanisms of lead neurotoxicity. Neurochemical Research, 24, 595–600.

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • Caito, S., & Aschner, M. (2017). Developmental neurotoxicity of lead. Advances in Neurobiology, 18, 3–12. https://doi.org/10.1007/978-3-319-60189-2_1

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Cammer, W. (2002). Apoptosis of oligodendrocytes in secondary cultures from neonatal rat brains. Neuroscience Letters, 327, 123–127.

    Article  Google Scholar 

  • Carpenter, M. C., Shami, S. A., DeSilva, S., Gleaton, A., Goundie, B., Croteau, M. L., et al. (2016). Thermodynamics of Pb(ii) and Zn(ii) binding to MT-3, a neurologically important metallothionein. Metallomics, 8, 605–617.

    Article  Google Scholar 

  • Centers for Disease Control and Prevention. (2016). Lead (Pb) toxicity: What are the U.S. standards for lead levels? Atsdr.cdc.gov. Retrieved from https://www.atsdr.cdc.gov/csem/csem.asp?csem=7&po=8.

  • Chan, S. F., & Sucher, N. J. (2001). An NMDA receptor signalling complex with protein phosphatase 2A. The Journal of Neuroscience, 21(20), 7985–7992.

    Article  Google Scholar 

  • Chen, Y., Stankovic, R., Cullen, K., Meininger, V., Garner, B., Coggan, S., Grant, R., Brew, B., & Guillemin, G. (2010). The kynurenine pathway and inflammation in amyotrophic lateral sclerosis. Neurotoxicology Research, 18, 132–142.

    Article  Google Scholar 

  • Chen, Y., Brew, B., & Guillemin, G. (2011). Characterization of the kynurenine pathway in NSC-34 cell line: Implications for amyotrophic lateral sclerosis. Journal of Neurochemistry, 118, 816–825.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Clarkson, T. W. (1987). Metal toxicity in the central nervous system. Environmental Health Perspectives, 75, 59–64.

    Article  Google Scholar 

  • Colbran, R. J. (2004). Targeting of calcium/calmodulin-dependent protein kinase II. Biochemical Journal, 378, 1–16.

    Article  Google Scholar 

  • Colín-González, A., Paz-Loyola, A., Serratos, I., Seminotti, B., Ribeiro, C., Leipnitz, G., Souza, D., Wajner, M., & Santamaría, A. (2015). Toxic synergism between quinolinic acid and organic acids accumulating in glutaric acidemia type I and in disorders of propionate metabolism in rat brain synaptosomes: Relevance for metabolic acidemias. Neuroscience, 308, 64–74.

    Article  Google Scholar 

  • Collingridge, G. L., & Bliss, T. V. P. (1987). NMDA receptors – their role in long term potentiation. Trends in Neuropharmacology, 10, 288–293.

    Google Scholar 

  • Collingridge, G. L., & Lester, R. A. (1989). Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacological Reviews, 41, 143–210.

    Google Scholar 

  • 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.

    Article  Google Scholar 

  • Cornell-Bell, A. H., Finkbeiner, S. M., Cooper, M. S., & Smith, S. J. (1990). Glutamate induces calcium waves in cultured astrocytes: Long-range glial signalling. Science, 247, 470–473.

    Article  Google Scholar 

  • Cuajungco, M. P., & Lees, G. J. (1997). Zinc metabolism in the brain: Relevance to human neurodegenerative disorders. Neurobiology of Disease, 4, 137–169.

    Article  Google Scholar 

  • Dai, S., Yin, Z., Yuan, G., Lu, H., Jia, R., Xu, J., et al. (2013). Quantification of metallothionein on the liver and kidney of rats by subchronic lead and cadmium in combination. Environmental Toxicology and Pharmacology, 36, 1207–1216.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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 

  • 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.

    Article  Google Scholar 

  • Dignam, T., Kaufmann, R. B., LeStourgeon, L., & Brown, M. J. (2019). Control of lead sources in the united states, 1970-2017: Public health progress and current challenges to eliminating lead exposure. Journal of Public Health Management and Practice, 25(Suppl 1) Lead Poisoning Prevention, S13–S22.

    Article  Google Scholar 

  • 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 of the United States of America, 84, 7739–7743.

    Article  Google Scholar 

  • 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 of the United States of America, 89, 9359–9363.

    Article  Google Scholar 

  • Ehlers, M. D. (2003). Activity level controls postsynaptic composition and signalling via the ubiquitin-proteasome system. Nature Neuroscience, 6, 231–242.

    Article  Google Scholar 

  • El-Sawi, I., & El-Saied, M. (2013). Umbilical cord-blood lead levels and pregnancy outcome. Journal of Pharmacology and Toxicology, 8, 7.

    Article  Google Scholar 

  • Erickson, J. C., Hollopeter, G., Thomas, S. A., Froelick, G. J., & Palmiter, R. D. (1997). Disruption of the metallothionein-III gene in mice: Analysis of brain zinc, behavior, and neuron vulnerability to metals, aging, and seizures. The Journal of Neuroscience, 17(4), 1271–1281.

    Article  Google Scholar 

  • Ettinger, A. S., Egan, K. B., Homa, D. M., & Brown, M. J. (2020, January). Blood lead levels in U.S. women of childbearing age, 1976–2016. Environmental Health Perspectives, 128(1), 17012. https://doi.org/10.1289/EHP5925

    Article  Google Scholar 

  • Evans, M. L., Busselberg, D., & Carpenter, D. O. (1991). Pb2+ blocks calcium currents of cultured dorsal root ganglion cells. Neuroscience Letters, 129, 103–106.

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Frazzini, V., Rockabrand, E., Mocchegiani, E., & Sensiet, S. L. (2006). Oxidative stress and brain aging: Is zinc the link? Biogerontology, 7, 307–314.

    Article  Google Scholar 

  • Fredrickson, C. J., & Moncrief, D. W. (1994). Zinc-containing neurons. Biological Signals, 3, 127–139.

    Article  Google Scholar 

  • Furtado, J., & Mazurek, M. (1996). Behavioral characterization of quinolinate-induced lesions of the medial striatum: Relevance for Huntington’s disease. Experimental Neurology, 138, 158–168.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Gavazzo, P., Gazzoli, A., Mazzolini, M., & Marchetti, C. (2001). Lead inhibition of NMDA channels in native and recombinant receptors. Neuroreport, 12(14), 3121–3125.

    Article  Google Scholar 

  • Gavazzo, P., Zanardi, I., Baranowska-Bosiacka, I., & Marchetti, C. (2008). Molecular determinants of Pb2+ interaction with NMDA receptor channels. Neurochemistry International, 52, 329–337.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Google Scholar 

  • Gillis, B. S., Arbieva, Z., & Gavin, I. M. (2012). Analysis of lead toxicity in human cells. BMC Genomics, 13, 344. https://doi.org/10.1186/1471-2164-13-344

    Article  Google Scholar 

  • Goering, P. L. (1993). Lead–protein interactions as a basis for lead toxicity. Neurotoxicology, 14, 45–60.

    Google Scholar 

  • Gorkhali, R., Huang, K., Kirberger, M., & Yang, J. J. (2016, June 1). Defining potential roles of Pb(2+) in neurotoxicity from a calciomics approach. Metallomics, 8(6), 563–578. https://doi.org/10.1039/c6mt00038j

    Article  Google Scholar 

  • 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). McGraw-Hill.

    Google Scholar 

  • 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.

    Article  Google Scholar 

  • Guilarte, T. R. (1997). Glutamatergic system and developmental lead neurotoxicity. Neurotoxicology, 18, 665–672.

    Google Scholar 

  • Guilarte, T. R., & McGlothan, J. L. (1998). Hippocampal NMDA receptor mRNA undergoes subunit specific changes during developmental lead exposure. Brain Research, 790, 98–107.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Guilarte, T. R., Miceli, R. C., & Jett, D. A. (1994, Fall). Neurochemical aspects of hippocampal and cortical Pb2+ neurotoxicity. Neurotoxicology, 15(3), 459–466.

    Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Article  Google Scholar 

  • Guillemin, G. (2012). Quinolinic acid, the inescapable neurotoxin. FEBS Journal, 279, 1356–1365.

    Article  Google Scholar 

  • Guillemin, G., Croitoru-Lamoury, J., Dormont, D., Armati, P., & Brew, B. (2003a). Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes. Glia, 41, 371–381.

    Article  Google Scholar 

  • Guillemin, G., Smythe, G., Veas, L., Takikawa, O., & Brew, B. (2003b). A beta 1-42 induces production of quinolinic acid by human macrophages and microglia. Neuroreport, 14, 2311–2315.

    Article  Google Scholar 

  • Guillemin, G., Kerr, S., & Brew, B. (2005a). Involvement of quinolinic acid in AIDS dementia complex. Neurotoxicology Research, 7, 103–123.

    Article  Google Scholar 

  • Guillemin, G., Wang, L., & Brew, B. (2005b). Quinolinic acid selectively induces apoptosis of human astrocytes: Potential role in AIDS dementia complex. Journal of Neuroinflammation, 2, 16.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Hartmann, M., Heumann, R., & Lessmann, V. (2001). Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. The EMBO Journal, 20, 5887–5897.

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • 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). Elsevier Academic Press.

    Google Scholar 

  • 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.

    Article  Google Scholar 

  • Hidalgo, J., Aschner, M., Zatta, M., & Vašák, M. (2001). Roles of the metallothionein family of proteins in the central nervous system. Brain Research Bulletin, 5, 133–145.

    Article  Google Scholar 

  • Hirata, K., Tsuji, N., & Miyamoto, K. (2005). Biosynthetic regulation of phytochelatins, heavy metal-binding peptides. Journal of Bioscience and Bioengineering, 100, 593–599.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Hozumi, I., Suzuki, J. S., Kanazawa, H., Hara, A., Saio, M., Inuzuka, T., et al. (2008). Metallothionein-3 is expressed in the brain and various peripheral organs of the rat. Neuroscience Letters, 438, 54–58.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Ikebuchi, H., Teshima, R., Suzuki, K., Terao, T., & Yamane, Y. (1986, January 15). Simultaneous induction of Pb-metallothionein-like protein and Zn-thionein in the liver of rats given lead acetate. Biochemical Journal, 233(2), 541–546.

    Article  Google Scholar 

  • 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 

  • 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.

    Article  Google Scholar 

  • Izquierdo, I. (1993). Long-term potentiation and the mechanism of memory. Drug Development Research, 30, 1–17.

    Article  Google Scholar 

  • Jiang, X., Tian, F., Mearow, K., Okagaki, P., Lipsky, R. H., & Marini, A. M. (2005). The excitoprotective effect of Nmethyl-d-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. Journal of Neurochemistry, 94, 713–722.

    Article  Google Scholar 

  • Jones, S., Franco, N., Varney, B., Sundaram, G., Brown, D., de Bie, J., Lim, C., Guillemin, G., & Brew, B. (2015). Expression of the kynurenine pathway in human peripheral blood mononuclear cells: Implications for inflammatory and neurodegenerative disease. PLoS One, 10, e0131389.

    Article  Google Scholar 

  • Kandel, E. R. (2001). The molecular biology of memory storage: A dialogue between genes and synapses. Science, 294, 1030–1038.

    Article  Google Scholar 

  • Kasten-Jolly, J., Heo, Y., & Lawrence, D. (2011). Central nervous system cytokine gene expression: Modulation by lead. Journal of Biochemical and Molecular Toxicology, 25, 41–54.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Kelly, W., & Burke, R. (1996). Apoptotic neuron death in rat substantia nigra induced by striatal excitotoxic injury is developmentally dependent. Neuroscience Letters, 220, 85–88.

    Article  Google Scholar 

  • Kerr, S., Armati, P., Guillemin, G., & Brew, B. (1998). Chronic exposure of human neurons to quinolinic acid results in neuronal changes consistent with AIDS dementia complex. AIDS, 12, 355–363.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Kobayashi, T., & Mori, Y. (1998). Ca2+ channel antagonists and neuroprotection from cerebral ischemia. European Journal of Pharmacology, 363, 1–15.

    Article  Google Scholar 

  • Kober, T. E., & Cooper, G. P. (1976). Lead competitively inhibits calcium-dependent synaptic transmission in the bullfrog sympathetic ganglion. Nature, 262, 704–705.

    Article  Google Scholar 

  • Koshibu, K., Graff, J., Beullens, M., Heitz, F. D., Berchtold, D., Russig, H., … Mansuy, I. M. (2009). Protein phosphatase 1 regulates the histone code for long-term memory. Journal of Neuroscience, 29(41), 13079–13089. https://doi.org/10.1523/jneurosci.3610-09.2009

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Kumawat, K., Kaushik, D., Goswami, P., & Basu, A. (2014). Acute exposure to lead acetate activates microglia and induces subsequent bystander neuronal death via caspase-3 activation. Neurotoxicology, 41, 143–153.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Lee, Y. S., & Silva, A. J. (2009). The molecular and cellular biology of enhanced cognition. Nature Reviews. Neuroscience, 10, 126–140.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Lee, M., Ting, K., Adams, S., Brew, B., Chung, R., & Guillemin, G. (2010). Characterisation of the expression of NMDA receptors in human astrocytes. PLoS One, 30(5), e14123.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Lieberman, D. N., & Mody, I. (1994). Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase. Nature, 369, 235–239.

    Article  Google Scholar 

  • Lim, C., Bilgin, A., Lovejoy, D., Tan, V., Bustamante, S., Taylor, B., Bessede, A., Brew, B., & Guillemin, G. (2017a). Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression. Scientific Reports, 7, 41473.

    Article  Google Scholar 

  • Lim, C., Fernández-Gomez, F., Braidy, N., Estrada, C., Costa, C., Costa, S., Bessede, A., Fernandez-Villalba, E., Zinger, A., Herrero, M., & Guillemin, G. (2017b). Involvement of the kynurenine pathway in the pathogenesis of Parkinson’s disease. Progress in Neurobiology, 155, 76–95.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Liu, M., Liu, X., Wang, W., Shen, X., Che, H., Guo, Y., Zhao, M., Chen, J., & Luo, W. (2012). Involvement of microglia activation in the lead induced long term potentiation impairment. PLoS One, 7, e43924.

    Article  Google Scholar 

  • Liu, J., Chen, B., Zhang, J., Kuang, F., & Chen, L. (2015). Lead exposure induced microgliosis and astrogliosis in hippocampus of young mice potentially by triggering TLR4-MyD88-NFκB signalling cascades. Toxicology Letters, 239, 97–107.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Lovelace, M., Varney, B., Sundaram, G., Lennon, M., Lim, C., Jacobs, K., Guillemin, G., & Brew, B. (2017). Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases. Neuropharmacology, 112, 373–388.

    Article  Google Scholar 

  • Ma, O. K., & Sucher, N. J. (2004). Molecular interaction of NMDA receptor subunit NR3A with protein phosphatase 2A. Neuroreport, 15(9), 1447–1450.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Malenka, R. C., & Nicoll, R. A. (1993). NMDA-receptor-dependent synaptic plasticity: Multiple forms and mechanisms. Trends in Neurosciences, 16, 521–527.

    Article  Google Scholar 

  • Malenka, R. C., & Nicoll, R. A. (1999). Long-term potentiation – a decade of progress? Science, 285, 1870–1874.

    Article  Google Scholar 

  • Malinow, R., & Malenka, R. C. (2002). AMPA receptor trafficking and synaptic plasticity. Annual Review of Neuroscience, 25, 103–126.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Marchetti, C. (2003). Molecular targets of lead in brain neurotoxicity. Neurotoxicity Research, 5(3), 221–236.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Mason, L. H., Harp, J. P., & Han, D. Y. (2014). Pb neurotoxicity: Neuropsychological effects of lead toxicity. BioMed Research International, 2014, 840547. https://doi.org/10.1155/2014/840547

    Article  Google Scholar 

  • Massicotte, G., & Baudry, M. (1991). Triggers and substrates of hippocampal synaptic plasticity. Neuroscience and Biobehavioral Reviews, 15, 415–423.

    Article  Google Scholar 

  • Masters, B. A., Quaife, C. J., Erickson, J. C., Kelly, E. J., Froelick, G. J., Zambrowicz, B. P., Brinster, R. L., & Palmiter, R. D. (1994). Metallothionein-III is expressed in neurons that sequester zinc in synaptic vesicles. The Journal of Neuroscience, 14, 5844–5857.

    Article  Google Scholar 

  • Mattiasson, B., Danielsson, B., Hermansson, C., & Mosbach, K. (1978). Enzyme thermistor analysis of heavy metal ions with use of immobilized urease. FEBS Letters, 85, 203–206.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Miles, A. T., Hawksworth, G. M., Beattie, J. H., & Rodilla, V. (2000). Induction, regulation, degradation, and biological significance of mammalian metallothioneins. Critical Reviews in Biochemistry and Molecular Biology, 35, 35–70.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Misztal, M., Frankiewicz, T., Parsons, G., & Danysz, W. (1996a). Learning deficits induced by chronic intraventricular infusion of quinolinic acid–protection by MK-801 and memantine. European Journal of Pharmacology, 296, 1–8.

    Article  Google Scholar 

  • Misztal, M., Skangiel-Kramska, J., Niewiadomska, G., & Danysz, W. (1996b). Subchronic intraventricular infusion of quinolinic acid produces working memory impairment – A model of progressive excitotoxicity. Neuropharmacology, 35, 449–458.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Moody, W. J. (1998). Control of spontaneous activity during development. Journal of Neurobiology, 37, 97–109.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Morris, R. G., Garrud, P., Rawlins, J. N., & O’Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature, 297, 681–683.

    Article  Google Scholar 

  • 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-Daspartate receptor antagonist, AP5. Nature, 319, 774–776.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Muller, F., Song, W., Jang, Y., Liu, Y., Sabia, M., Richardson, A., & Van Remmen, H. (2007). Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 293, R1159–R1168.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Nakao, K., Kibayashi, K., Taki, T., & Koyama, H. (2010). Changes in the brain after intracerebral implantation of a lead pellet in the rat. Journal of Neurotrauma, 27, 1925–1934. https://doi.org/10.1089/neu.2010.1379

    Article  Google Scholar 

  • Nascimento, C. R. B., Risso, W. E., & Bueno dos Reis Martinez, C. (2016). Lead accumulation and metallothionein content in female rats of different ages and generations after daily intake of Pb-contaminated food. Environmental Toxicology and Pharmacology, 48, 272–277.

    Article  Google Scholar 

  • National Institute for Occupational Safety and Health. (2015). Adult blood lead epidemiology and surveillance. Reference blood lead level for adults. https://www.cdc.gov/niosh/topics/ables/description.html. Accessed 1 Nov 2020.

  • Neal, A. P., & Guilarte, T. R. (2010). Molecular neurobiology of lead (Pb2+): Effects on synaptic function. Molecular Neurobiology, 42(3), 151–160.

    Article  Google Scholar 

  • 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 signalling. Toxicological Sciences, 116(1), 249–263.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Niswender, C. M., & Conn, P. J. (2010). Metabotropic glutamate receptors: Physiology, pharmacology, and disease. Annual Review of Pharmacology and Toxicology, 50, 295–322. https://doi.org/10.1146/annurev.pharmtox.011008.145533

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • O’Connor, D., Hou, D., Ye, J., Zhang, Y., Ok, Y. S., Song, Y., Coulon, F., Peng, T., & Tian, L. (2018, December). Lead-based paint remains a major public health concern: A critical review of global production, trade, use, exposure, health risk, and implications. Environment International, 121(Pt 1), 85–101. https://doi.org/10.1016/j.envint.2018.08.052

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • Omelchenko, I., Nelson, C., & Allen, C. (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.

    Google Scholar 

  • Ordemann, J. M., & Austin, R. N. (2016, June 1). Lead neurotoxicity: Exploring the potential impact of lead substitution in zinc-finger proteins on mental health. Metallomics, 8(6), 579–588. https://doi.org/10.1039/c5mt00300h

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Ozawa, S., Kamiya, H., & Tsuzuki, K. (1998). Glutamate receptors in the mammalian central nervous system. Progress in Neurobiology, 54, 581–618.

    Article  Google Scholar 

  • Palmiter, R. D. (1994). Regulation of metallothionein genes by heavy metals appears to be mediated by a zinc-sensitive inhibitor that interacts with a constitutively active transcription factor. MTF-1. Proceedings of the National Academy of Sciences of the United States of America, 91, 1219–1223.

    Article  Google Scholar 

  • Palmiter, R. D. (1995). Constitutive expression of metallothionein-lIl (MT-III), but not MT-I, inhibits growth when cells become zinc deficient. Toxicology and Applied Pharmacology, 135, 139–146.

    Article  Google Scholar 

  • Palmiter, R. D., & Erickson, J. C. (1996). Properties olmetallothionein-IlI (MT-Ill). Toxicologist, 30, 43. (abstr.).

    Google Scholar 

  • Palmiter, R. D., Findley, S. D., Whitmore, T. E., & Durnam, D. M. (1992). MT-Ill, a brain-specific member of the metallothionein family. Proceedings of the National Academy of Sciences of the United States of America, 89, 6333–6337.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Paulson, J. A., & Brown, M. J. (2019, February 28). The CDC blood lead reference value for children: Time for a change. Environmental Health, 18(1), 16. https://doi.org/10.1186/s12940-019-0457-7

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Perez-Otano, I., & Ehlers, M. (2004). Learning from NMDA receptor trafficking: Clues to the development and maturation of glutamatergic synapses. Neurosignals, 13, 175–189.

    Article  Google Scholar 

  • Pérez-Zúñiga, C., Leiva-Presa, À., Austin, R. N., Capdevila, M., & Palacios, Ò. (2018, December 5). Pb(ii) binding to the brain specific mammalian metallothionein isoform MT3 and its isolated αMT3 and βMT3 domains. Metallomics. https://doi.org/10.1039/c8mt00294k

  • Peterson, S. M., Zhang, J., Weber, G., & Freeman, J. L. (2011). Global gene expression analysis reveals dynamic and developmental stage-dependent enrichment of lead-induced neurological gene alterations. Environmental Health Perspectives, 119(5), 615–621. https://doi.org/10.1289/ehp.1002590

  • Pierozan, P., Zamoner, A., Krombauer Soska, Â., Bristot Silvestrin, R., Oliveira Loureiro, S., Heimfarth, L., Mello e Souza, T., Wajner, M., & Pessoa-Pureur, R. (2010). Acute intrastriatal administration of quinolinic acid provokes hyperphosphorylation of cytoskeletal intermediate filament proteins in astrocytes and neurons of rats. Experimental Neurology, 224, 188–196.

    Article  Google Scholar 

  • Pierozan, P., Zamoner, A., Soska, Â., de Lima, B., Reis, K., Zamboni, F., Wajner, M., & Pessoa-Pureur, R. (2012). Signalling mechanisms downstream of quinolinic acid targeting the cytoskeleton of rat striatal neurons and astrocytes. Experimental Neurology, 233, 391–399.

    Article  Google Scholar 

  • Pláteník, J., Stopka, P., Vejrazka, M., & Stípek, S. (2001). Quinolinic acid-iron(ii) complexes: Slow autoxidation, but enhanced hydroxyl radical production in the Fenton reaction. Free Radical Research, 34, 445–459.

    Article  Google Scholar 

  • Pomilio, C., Pavia, P., Gorojod, R. M., Vinuesa, A., Alaimo, A., Galvan, V., Kotler, M., Beauquis, J., & Saravia, F. (2016). Glial alterations from early to late stages in a model of Alzheimer’s disease: Evidence of autophagy involvement in Aβ internalization. Hippocampus, 26, 194–210.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Rahman, A., Ting, K., Cullen, K., Braidy, N., Brew, B., & Guillemin, G. (2009). The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS One, 4, e6344.

    Article  Google Scholar 

  • Rahman, A., Brew, B. J., & Guillemin, G. J. (2011, February). Lead dysregulates serine/threonine protein phosphatases in human neurons. Neurochemical Research, 36(2), 195–204. https://doi.org/10.1007/s11064-010-0300-6

    Article  Google Scholar 

  • Rahman, A., Khan, K., Al-Khaledi, G., Khan, I., & Attur, S. (2012a). Early postnatal lead exposure induces tau phosphorylation in the brain of young rats. Acta Biologica Hungarica, 63, 411–425.

    Article  Google Scholar 

  • Rahman, A., Khan, K. M., Al-Khaledi, G., Khan, I., & Al-Shemary, T. (2012b). 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.

    Article  Google Scholar 

  • Rahman, A., Khan, K. M., & Rao, M. S. (2018a). Exposure to low level of lead during preweaning period increases metallothionein-3 expression and dysregulates divalent cation levels in the brain of young rats. Neurotoxicology, 65, 135–143.

    Article  Google Scholar 

  • Rahman, A., Rao, M. S., & Khan, K. M. (2018b, September 14). Intraventricular infusion of quinolinic acid impairs spatial learning and memory in young rats: A novel mechanism of lead-induced neurotoxicity. Journal of Neuroinflammation, 15(1), 263. https://doi.org/10.1186/s12974-018-1306-2

    Article  Google Scholar 

  • Rahman, A., Al-Qenaie, S., Rao, M. S., Khan, K. M., & Guillemin, G. J. (2019, June 17). Memantine is protective against cytotoxicity caused by lead and quinolinic acid in cultured rat embryonic hippocampal cells. Chemical Research in Toxicology, 32(6), 1134–1143. https://doi.org/10.1021/acs.chemrestox.8b00421

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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 

  • Reddy, G. R., Devi, B. C., & Chetty, C. S. (2007). Developmental lead neurotoxicity: Alterations in brain cholinergic system. Neurotoxicology, 28(2), 402–407.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Roberson, E. D., English, J. D., & Sweatt, J. D. (1996). A biochemist’s view of long-term potentiation. Learning & Memory, 3(1), 1–24.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Roche, K. W., Tingley, W. G., & Huganir, R. L. (1994). Glutamate receptor phosphorylation and synaptic plasticity. Current Opinion in Neurobiology, 4, 383–388.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Sanders, T., Liu, Y., Buchner, V., & Tchounwou, P. B. (2009). Neurotoxic effects and biomarkers of lead exposure: A review. Reviews on Environmental Health, 24(1), 15–45. https://doi.org/10.1515/reveh.2009.24.1.15

    Article  Google Scholar 

  • Sansar, W., Ahboucha, S., & Gamrani, H. (2011). Chronic lead intoxication affects glial and neural systems and induces hypoactivity in adult rat. Acta Histochemica, 113, 601–607.

    Article  Google Scholar 

  • Santa Maria, M. P., Hill, B. D., & Kline, J. (2019, July–September). Lead (Pb) neurotoxicology and cognition. Applied Neuropsychology: Child, 8(3), 272–293. https://doi.org/10.1080/21622965.2018.1428803

    Article  Google Scholar 

  • Santamaría, A., Galván-Arzate, S., Lisý, V., Ali, S., Duhart, H., Osorio-Rico, L., Ríos, C., & Sut’astný, F. (2001). Quinolinic acid induces oxidative stress in rat brain synaptosomes. Neuroreport, 12, 871–874.

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • Savolainen, K. M., Loikkanen, J., Eerikainen, S., & Naarala, J. (1998b). Interactions of excitatory neurotransmitters and xenobiotics inexcitotoxicity and oxidative stress: Glutamate and lead. Toxicology Letters, 102–103, 363–367.

    Article  Google Scholar 

  • Scheetz, A. J., & Constantine-Paton, M. (1994). Modulation of NMDA receptor function: Implications for vertebrate neural development. The FASEB Journal, 8, 745–752.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Sharma, S. K., Goloubinoff, P., & Christen, P. (2008). Heavy metal ions are potent inhibitors of protein folding. Biochemical and Biophysical Research Communications, 372, 341–345.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Silbergeld, E. K. (1992). Mechanisms of lead neurotoxicity, or looking beyond the lamppost. The FASEB Journal, 6(13), 3201–3206.

    Article  Google Scholar 

  • 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 of the United States of America, 99(7), 4221–4226.

    Article  Google Scholar 

  • Simons, T. J. B., & Pocock, G. (1987). Lead enters bovine adrenal medullary cells through calcium channels. Journal of Neurochemistry, 48, 383–389.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Sobin, C., Montoya, M., Parisi, N., Schaub, T., Cervantes, M., & Armijos, R. (2013). Microglial disruption in young mice with early chronic lead exposure. Toxicology Letters, 220, 44–52.

    Article  Google Scholar 

  • Soderling, T. R., & Derkach, V. A. (2000). Postsynaptic protein phosphorylation and LTP. Trends in Neurosciences, 23, 75–80.

    Article  Google Scholar 

  • Steiner, J., Walter, M., Gos, T., Guillemin, G., Bernstein, H., Sarnyai, Z., Mawrin, C., Brisch, R., Bielau, H., Meyer zu Schwabedissen, L., Bogerts, B., & Myint, A. (2011). Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission? Journal of Neuroinflammation, 8, 94.

    Article  Google Scholar 

  • Stillman, M. J. (1995). Metallothioneins. Coordination Chemistry Reviews, 144, 461–511.

    Article  Google Scholar 

  • Struzynska, L. (2009). A glutamatergic component of lead toxicity in adult brain: The role of astrocytic glutamate transporters. Neurochemistry International, 55, 151–156.

    Article  Google Scholar 

  • Struzynska, L., Dabrowska-Bouta, B., Koza, K., & Sulkowski, G. (2007). Inflammation-like glial response in lead-exposed immature rat brain. Toxicological Sciences, 95, 156–162.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • Sundaram, G., Brew, B., Jones, S., Adams, S., Lim, C., & Guillemin, G. (2014). Quinolinic acid toxicity on oligodendroglial cells: Relevance for multiple sclerosis and therapeutic strategies. Journal of Neuroinflammation, 11, 204.

    Article  Google Scholar 

  • Suzuki, K., Sato, M., Morishima, Y., & Nakanishi, S. (2005). Neuronal depolarization controls brain-derived neurotrophic factor-induced upregulation of NR2C NMDA receptor via calcineurin signalling. The Journal of Neuroscience, 25(41), 9535–9543.

    Article  Google Scholar 

  • 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 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Teyler, T. J., & DiScenna, P. (1987). Long-term potentiation. Annual Review of Neuroscience, 10, 131–161.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Tiffany-Castiglioni, E. (1993). Cell culture models for lead toxicity in neuronal and glial cells. Neurotoxicology, 14, 513–536.

    Google Scholar 

  • Tiffany-Castiglioni, E., Zmudzki, J., & Bratton, G. R. (1986). Cellular targets of lead toxicity: In vitro models. Toxicology, 42, 305–315.

    Google Scholar 

  • 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.

    Article  Google Scholar 

  • Tokuda, E., Ono, S., Ishige, K., Naganuma, A., Ito, Y., & Suzuki, T. (2007). Metallothionein proteins expression, copper and zinc concentrations, and lipid peroxidation level in a rodent model for amyotrophic lateral sclerosis. Toxicology, 29, 33–41.

    Article  Google Scholar 

  • Tong, G., Shepherd, D., & Jahr, C. E. (1995). Synaptic desensitization of NMDA receptors by calcineurin. Science, 267(5203), 1510–1512.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Toscano, C. D., & Guilarte, T. R. (2005). Lead neurotoxicity: From exposure to molecular effects. Brain Research Reviews, 49, 529–555.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Uchida, Y., Takio, K., Titani, K., Ihara, Y., & Tomonaga, M. (1991). The growth inhibitory factor that is deficient in Alzheimer’s disease is a 68 amino acid metallothionein-like protein. Neuron, 7, 337–347.

    Article  Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    Article  Google Scholar 

  • Vasak, M., & Meloni, G. (2017). Mammalian metallothionein-3: New functional and structural insights. International Journal of Molecular Sciences, 18(6), E1117. https://doi.org/10.3390/ijms18061117S

    Article  Google Scholar 

  • Vécsei, L., Szalárdy, L., Fülöp, F., & Toldi, J. (2013). Kynurenines in the CNS: Recent advances and new questions. Nature Reviews Drug Discovery, 12, 64–82.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Vorvolakos, T., Arseniou, S., & Samakouri, M. (2016, July–September). There is no safe threshold for lead exposure: Α literature review. Psychiatriki, 27(3), 204–214. https://doi.org/10.22365/jpsych.2016.273.204

    Article  Google Scholar 

  • Vyklicky, V., Korinek, M., Smejkalova, T., Balik, A., Krausova, B., Kaniakova, M., Lichnerova, K., Cerny, J., Krusek, J., Dittert, I., Horak, M., & Vyklicky, L. (2014). Structure, function, and pharmacology of NMDA receptor channels. Physiological Research, 63(Suppl 1), S191–S203. https://doi.org/10.33549/physiolres.932678

  • 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.

    Google Scholar 

  • 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.

    Article  Google Scholar 

  • Wang, J. H., & Kelly, P. T. (1997). Postsynaptic calcineurin activity downregulates synaptic transmission by weakening intracellular Ca2+ signalling mechanisms in hippoccampal CA1 neurons. The Journal of Neuroscience, 17, 4600–4611.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Wang, L., Chen, D., Wang, H., & Liu, Z. (2009). Effects of lead and/or cadmium on the expression of metallothionein in the kidney of rats. Biological Trace Element Research, 129, 190–199.

    Article  Google Scholar 

  • Waters, K. A., & Machaalani, R. (2004, July–August). NMDA receptors in the developing brain and effects of noxious insults. Neurosignals, 13(4), 162–174. https://doi.org/10.1159/000077523

    Article  Google Scholar 

  • Westphal, R. S., Anderson, K. A., Means, A. R., & Wadzinski, B. E. (1998). A signalling complex of Ca2+-calmodulin-dependent protein kinase IV and protein phosphatase 2A. Science, 280(5367), 1258–1261.

    Article  Google Scholar 

  • 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 signalling complex. Science, 285(5424), 93–96.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • WHO. (2010). Childhood Lead Poisoning World Health Organization. [Available from: https://www.who.int/ceh/publications/leadguidance.pdf?ua=1

  • Winder, D. G., & Sweatt, J. D. (2001). Roles of serine/threonine phosphatases in hippocampal synaptic plasticity. Nature Reviews. Neuroscience, 2(7), 461–474.

    Article  Google Scholar 

  • Wong, D. L., Merrifield-MacRae, M. E., & Stillman, M. J. (2017). Lead(II) binding in metallothioneins. Life Sciences, 2017. https://doi.org/10.1515/9783110434330-009

  • 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.

    Article  Google Scholar 

  • Xu, S., & Rajanna, B. (2006). Glutamic acid reverses Pb2+-induced reductions of NMDA receptor subunits in vitro. Neurobehavioral Toxicology, 27, 169–175.

    Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Zalutsky, R. A., & Nicoll, R. A. (1990). Comparison of two forms of long-term potentiation in single hippocampal neurons. Science, 248, 1619–1624.

    Article  Google Scholar 

  • 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 choroid plexus. Toxicology and Applied Pharmacology, 139(2), 445–450.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Zukin, R. S., & Bennett, M. V. (1995). Alternatively spliced isoforms of the NMDARI receptor subunit. Trends in Neurosciences, 18, 306–313.

    Article  Google Scholar 

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Rahman, A., Guillemin, G.J. (2022). Lead and Excitotoxicity. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-031-15080-7_142

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