Exposure to environmental lead (Pb) continues to be a major hazard to the well being of millions of children in the United States and throughout the industrialized world. The developing central nervous system (CNS) appears to be particularly vulnerable to the toxic effects of Pb and recent evidence suggest an apparent lack of a threshold for inducing cognitive dysfunction. The long term goal of the research is to understand the mechanism(s) underlying the cognitive deficits observed in children exposed to low levels of Pb. The working hypothesis is that developmental Pb exposure inhibits the activation of the excitatory amino acid receptor subtype N-Methyl-D-Aspartate (NMDA), disrupting the wiring of defined neuronal networks, altering neuronal function and resulting in the permanent cognitive deficits.
The specific aims are designed to determine the effects of Pb exposure on cellular processes mediated by NMDA receptors which are associated with learning and memory in the mammalian brain.
These aims will be accomplished using an integrated approach of neurochemical, electrophysiological, and behavioral methods which can correlate Pb-induced changes in NMDA receptor function and cellular processes associated with learning and memory. The investigator's previous work and the preliminary studies presented in this proposal are beginning to elucidate mechanism(s) by which Pb alters brain development and provide causal relationships between NMDA receptor changes, impaired cellular function, and cognitive deficits. The effects measured in the animal model of Pb neurotoxicity are present at blood Pb levels in the 20-30 ug/dl range. Thus, their work is relevant to the greatest percentage of affected children. The investigator's work indicates that developmental Pb exposure causes impairment in cognitive function through NMDA receptor mediated changes in synaptic plasticity within the hippocampus, a brain structure associated with learning and memory. Emerging evidence also indicates that the age and regional brain susceptibility to Pb neurotoxicity may be imparted by the differential expression of NMDA receptor populations with different subunit composition. The proposed studies will provide new information on the mechanism(s) by which Pb: (1) interacts with the NMDA receptor, (2) alters cellular processes such as long-term potentiation, and (3) impairs a spatial learning task. The investigator's findings will also help elucidate preventative and/or therapeutic strategies for the treatment of Pb neurotoxicity.
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