Despite significant efforts during the last three decades to reduce lead contamination of the environment, a significant number of children continue to be exposed to this potent and ubiquitous neurotoxicant. A recent report by the Surgeon General of the United States (Satcher, 2000) indicates that """"""""lead poisoning poses one of the greatest environmental threats to children in America"""""""". It further states that the latest data show that in the United States, 1 in 20 children under the age of 6 have blood lead levels exceeding those considered to produce lasting deficits in cognitive function. Unfortunately, this problem is not going to disappear in the near future and we must devise new strategies to ameliorate or modify the devastating effects of lead on the central nervous system. The goal of the work proposed is to continue to elucidate the molecular mechanisms of lead-induced neurotoxicity. Our work has demonstrated that the N-methyI-D-Aspartate (NMDA)-type of glutamate excitatory amino acid receptors is a target for lead in the central nervous system. This is important because NMDA receptor function is essential for a number of physiological processes in the developing and mature brain. One of these processes is the acquisition and consolidation of learning and memory. We have shown that exposure to lead during development produces lasting changes in learning and memory in a rodent model of lead neurotoxicity. Further, the impairment in learning is associated with deficits in long-term potentiation in the hippocampus and alterations in NMDA receptor subunit genes and protein expression. Based on this new knowledge, we tested the hypothesis that environmental enrichment may alter the cognitive and molecular deficits induced by lead. Our studies show that environmental enrichment is able to reverse the cognitive and NMDA receptor deficits induced by developmental exposure to lead. This is an extremely important finding because it demonstrates that some of the lead-induced cognitive and molecular deficits are reversible. Further, environmental enrichment is an intervention that is applicable to children. The goal of our proposed studies is to further our understanding of the neurobiological substrates associated with lead-induced neurotoxicity and its reversibility by environmental enrichment. It is important to determine whether environmental enrichment is an intervention strategy that benefits children of any age and if the benefits are long lasting.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Kirshner, Annette G
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Johns Hopkins University
Public Health & Prev Medicine
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Pittman-Polletta, Benjamin; Hu, Kun; Kocsis, Bernat (2018) Subunit-specific NMDAR antagonism dissociates schizophrenia subtype-relevant oscillopathies associated with frontal hypofunction and hippocampal hyperfunction. Sci Rep 8:11588
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