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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES006189-06
Application #
2501308
Study Section
Special Emphasis Panel (ZRG4-ALTX-4 (03))
Project Start
1992-12-01
Project End
2002-11-30
Budget Start
1998-01-01
Budget End
1998-11-30
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
Zhang, Xiao-Lei; McGlothan, Jennifer L; Miry, Omid et al. (2018) From the Cover: 7,8-Dihydroxyflavone Rescues Lead-Induced Impairment of Vesicular Release: A Novel Therapeutic Approach for Lead Intoxicated Children. Toxicol Sci 161:186-195
Wagner, Peter J; Park, Hae-Ryung; Wang, Zhaoxi et al. (2017) In Vitro Effects of Lead on Gene Expression in Neural Stem Cells and Associations between Up-regulated Genes and Cognitive Scores in Children. Environ Health Perspect 125:721-729
Austin, Rachel Narehood; Freeman, Jennifer L; Guilarte, Tomás R (2016) Neurochemistry of lead and manganese. Metallomics 8:561-2
Guariglia, Sara Rose; Stansfield, Kirstie H; McGlothan, Jennifer et al. (2016) Chronic early life lead (Pb2+) exposure alters presynaptic vesicle pools in hippocampal synapses. BMC Pharmacol Toxicol 17:56
Stansfield, K H; Ruby, K N; Soares, B D et al. (2015) Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia. Transl Psychiatry 5:e522
Zhang, Xiao-Lei; Guariglia, Sara R; McGlothan, Jennifer L et al. (2015) Presynaptic mechanisms of lead neurotoxicity: effects on vesicular release, vesicle clustering and mitochondria number. PLoS One 10:e0127461
Abazyan, Bagrat; Dziedzic, Jenifer; Hua, Kegang et al. (2014) Chronic exposure of mutant DISC1 mice to lead produces sex-dependent abnormalities consistent with schizophrenia and related mental disorders: a gene-environment interaction study. Schizophr Bull 40:575-84
Neal, April P; Guilarte, Tomas R (2013) Mechanisms of lead and manganese neurotoxicity. Toxicol Res (Camb) 2:99-114
Kang, N; Peng, H; Yu, Y et al. (2013) Astrocytes release D-serine by a large vesicle. Neuroscience 240:243-57

Showing the most recent 10 out of 45 publications