Glutamatergic components underlying lead-induced impairments in hippocampal synaptic plasticity

Epidemiological investigations have established the relationship between ch ronic developmental lead (Pb) exposure and cognitive impairments in young c hildren, defining Pb neurotoxicity as a significant pediatric health proble m. Exposed animals have proven to be effective models of this condition, ex hibiting similar sensitivity to the actions of Pb and replicating abnormal learning behaviors in exposed children. Research has extended these observa tions in animals to identifing the processes underlying the cognitive dysfu nction, utilizing the long-term potentiation (LTP) paradigm as a correlate of learning ability. Results from these studies have been in widespread agr eement in reporting impairments in synaptic plasticity. Exposure-related ch anges consist of increases in LTP induction threshold, decreases in magnitu de of potentiation, and shortened LTP duration. Furthermore, while LTP may be more readily affected by Pb during early development, exposure initiated after weaning also potently affects synaptic plasticity. Biphasic dose-eff ect relationships also appear in which impaired LTP is observed at intermed iate exposure levels (27-62 mug/100 mi), hut not at higher exposures. Inves tigation of the synaptic processes underlying LTP has provided additional i nsight into the bases of the impaired potentiation and diminished cognitive ability Biochemical and neurophysiological approaches have found stimulate d glutamate release to be diminished in hippocampus at blood Pb values wher e deficits in LTP have been observed. Multiple actions of Ph may be involve d at this exposure level since animals exposed postweaning exhibited simila r decrements in evoked glutamate release to those exposed continuously from conception, similar to the observations in measures of LTP. A biphasic dos e-effect relationship was also found in which stimulated glutamate release in hippocampus was decreased at intermediate exposures, but not at higher l evels. A direct inhibitory effect of Pb+2 on NMDA receptor function does no t appear to occur at environmentally relevant exposure levels, but both exp osure-induced increases and decreases in receptor density have been reporte d by different workers. Evidence from behavioral and neurophysiological inv estigations can be explained by increased NMDA receptor density on the base s of increased sensitivity to agonists and decreased sensitivity to antagon ists. From this body of findings it is apparent that decreases in stimulate d glutamate release are a significant contributing factor to the exposure-r elated changes seen in LTP Furthermore, despite general agreement on the ac tions of Pb on synaptic plasticity, reports of exposure effects on NMDA rec eptor function have been relatively variable, suggesting either that the na ture of the receptor changes are dependent on exposure conditions or that t he receptors are secondarily affected by Ph actions produced at signal tran sduction or cellular loci. (C) 2000 Inter Press, Inc.