Neurochemical aspects of hippocampal and cortical Pb2+ neurotoxicity.
The amino acid glutamate is the neurotransmitter used by most excitatory synapses in the mammalian brain. Glutamatergic synapses in the hippocampus and cerebral cortex play an important role in synaptic plasticity. In the developing brain, the interaction of neurotoxins with presynaptic and/or postsynaptic sites on glutamatergic neurons could alter synaptic plasticity. Recent studies have shown that chronic lead (Pb2+) exposure may impair neuronal process underlying synaptic plasticity via a direct interaction with the N-Methyl-D-Aspartate (NMDA) glutamate receptor subtype. The NMDA receptor-ion channel complex regulates calcium influx and is involved in the initiation of changes in synaptic plasticity. In vitro and in vivo neurochemical studies have found that Pb2+ has a marked inhibitory effect on the activation of the NMDA receptor-ion channel complex. Evidence indicates that the inhibitory effect of Pb2+ on the NMDA receptor complex may be mediated by its interaction with a zinc regulatory site on the receptor complex. The ability of Pb2+ to inhibit NMDA receptor-ion channel function was shown to be age-dependent and brain region-specific. The age-dependent effects of Pb2+ on the NMDA receptor complex may help explain the selective toxicity of this heavy metal in the developing brain.
Department of Environmental Health Sciences, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland.
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Guilarte
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Miceli
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Jett
D000367:Age Factors; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D007854:Lead / Q000633:toxicity*; D008297:Male; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology
D016194:Receptors, N-Methyl-D-Aspartate; D007854:Lead; D016291:Dizocilpine Maleate; D015032:Zinc