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Lead and Excitotoxicity

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Handbook of Neurotoxicity

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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

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Authors and Affiliations

  1. Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait City, Kuwait

    Abdur Rahman

  2. Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW, Australia

    Gilles J. Guillemin

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  1. Abdur Rahman
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  2. Gilles J. Guillemin
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  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Rahman, A., Guillemin, G.J. (2021). Lead and Excitotoxicity. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_142-1

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