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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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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