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Molecular Neurobiology of Lead (Pb2+): Effects on Synaptic Function

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Abstract

Lead (Pb2+) is a ubiquitous environmental neurotoxicant that continues to threaten public health on a global scale. Epidemiological studies have demonstrated detrimental effects of Pb2+ on childhood IQ at very low levels of exposure. Recently, a mechanistic understanding of how Pb2+ affects brain development has begun to emerge. The cognitive effects of Pb2+ exposure are believed to be mediated through its selective inhibition of the N-methyl-d -aspartate receptor (NMDAR). Studies in animal models of developmental Pb2+ exposure exhibit altered NMDAR subunit ontogeny and disruption of NMDAR-dependent intracellular signaling. Additional studies have reported that Pb2+ exposure inhibits presynaptic calcium (Ca2+) channels and affects presynaptic neurotransmission, but a mechanistic link between presynaptic and postsynaptic effects has been missing. Recent work has suggested that the presynaptic and postsynaptic effects of Pb2+ exposure are both due to inhibition of the NMDAR by Pb2+, and that the presynaptic effects of Pb2+ may be mediated by disruption of NMDAR activity-dependent signaling of brain-derived neurotrophic factor (BDNF). These findings provide the basis for the first working model to describe the effects of Pb2+ exposure on synaptic function. Here, we review the neurotoxic effects of Pb2+ exposure and discuss the known effects of Pb2+ exposure in light of these recent findings.

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Acknowledgements

Work performed in the laboratory of TRG is funded by NIEHS grant ES006189. APN is currently funded by R01-ES03299.

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Correspondence to Tomás R. Guilarte.

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Neal, A.P., Guilarte, T.R. Molecular Neurobiology of Lead (Pb2+): Effects on Synaptic Function. Mol Neurobiol 42, 151–160 (2010). https://doi.org/10.1007/s12035-010-8146-0

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  • DOI: https://doi.org/10.1007/s12035-010-8146-0

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