Lead neurotoxicity: From exposure to molecular effects

The effects of lead (Ph2+) on human health have been recognized since antiquity. However, it was not until the 1970s that seminal epidemiological studies provided evidence on the effects of Ph2+ intoxication on cognitive function in children. During the last two decades, advances in behavioral, cellular and molecular neuroscience have provided the necessary experimental tools to begin deciphering the many and complex effects of Ph2+ on neuronal processes and cell types that are essential for synaptic plasticity and learning and memory in the mammalian brain. In this review, we concentrate our efforts on the effects of Pb2+ on glutamatergic synapses and specifically on the accumulating evidence that the N-methyl-D-aspartate type of excitatory amino acid receptor (NMDAR) is a direct target for Pb2+ effects in the brain. Our working hypothesis is that disruption of the ontogenetically defined pattern of NMDAR subunit expression and NMDAR-mediated calcium signaling in glutamatergic synapses is a principal mechanism for Ph2+-induced deficits in synaptic plasticity and in learning and memory documented in animal models of Pb2+ neurotoxicity. We provide an introductory overview of the magnitude of the problem of Pb2+ exposure to bring forth the reality that childhood Pb2+ intoxication remains a major public health problem not only in the United States but worldwide. Finally, the latest research offers some hope that the devastating effects of childhood Pb2+ intoxication in a child's ability to learn may be reversible if the appropriate stimulatory environment is provided. (c) 2005 Elsevier B.V. All rights reserved.