Molecular neurobiology of lead (Pb(2+)): effects on synaptic function.
Lead (Pb(2+)) is a ubiquitous environmental neurotoxicant that continues to threaten public health on a global scale. Epidemiological studies have demonstrated detrimental effects of Pb(2+) on childhood IQ at very low levels of exposure. Recently, a mechanistic understanding of how Pb(2+) affects brain development has begun to emerge. The cognitive effects of Pb(2+) exposure are believed to be mediated through its selective inhibition of the N-methyl-D: -aspartate receptor (NMDAR). Studies in animal models of developmental Pb(2+) exposure exhibit altered NMDAR subunit ontogeny and disruption of NMDAR-dependent intracellular signaling. Additional studies have reported that Pb(2+) exposure inhibits presynaptic calcium (Ca(2+)) 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 Pb(2+) exposure are both due to inhibition of the NMDAR by Pb(2+), and that the presynaptic effects of Pb(2+) 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 Pb(2+) exposure on synaptic function. Here, we review the neurotoxic effects of Pb(2+) exposure and discuss the known effects of Pb(2+) exposure in light of these recent findings.
Department of Pharmacology and Toxicology, Michigan State University, B307 Life Sciences Building, East Lansing, MI 48824, USA. Nealap@msu.edu
April P
AP
Neal
Tomás R
TR
Guilarte
D000818:Animals; D001519:Behavior / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003071:Cognition / Q000187:drug effects; D004781:Environmental Exposure; D006801:Humans; D007360:Intelligence / Q000187:drug effects; D007854:Lead / Q000633:toxicity*; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D020258:Neurotoxicity Syndromes / Q000209:etiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000502:physiology*
D016194:Receptors, N-Methyl-D-Aspartate; D007854:Lead