title: Chronic developmental lead exposure and hippocampal long-term potentiation: biphasic dose-response relationship.
abstract: Developmental exposure to lead (Pb) has long been associated with reductions in intellectual function in children and behavioral impairments in animal models of learning and memory. We have used long-term potentiation (LTP) in the dentate gyrus of the Pb-exposed rats to determine the potential of a reduced capacity for synaptic plasticity to contribute to Pb-induced cognitive dysfunction. Previous work demonstrated that developmental exposure resulting in moderate blood concentrations of Pb increase the threshold for induction of long-term potentiation (LTP) in the dentate gyrus in vivo. These findings were also suggestive of reductions in LTP magnitude (Gilbert et al., 1996). The present study was designed to further examine the effects of Pb on LTP magnitude and to determine if lower blood Pb levels commonly encountered in children are also effective in impairing synaptic plasticity in this rodent model. Pregnant dams were exposed to control tap water or 0.1, 0.2, 0.5 or 1.0% Pb-acetate in the drinking water beginning just prior to parturition (gestational day 16, GD16). Male offspring were weaned at 21 days of age (PN21) to the same solution given their dams and continued on this regimen until testing. As adults, animals were anesthetized with urethane and stimulating and recording electrodes placed in the perforant path and dentate gyrus, respectively. Post-train I/O functions taken 1 hour after delivery of a series of six high frequency (400Hz) trains revealed a reduced capacity for LTP of the PS amplitude and EPSP slope in Pb-exposed animals in all but the 1.0% group, indicative of a biphasic dose-effect relationship. The 1.0% Pb exposure was clearly less effective than the lower exposure levels in reducing LTP magnitude, and did not differ significantly from control values. The mechanisms underlying the reduced efficacy of higher exposure levels of Pb to impair LTP are not clear. Blood (26-117 microg/dl) and brain (220-1812 ng/g tissue) concentrations of Pb were elevated as a function of increasing exposure (0.1%-1.0%) and cannot readily account for the lack of an effect in the 1.0% group on LTP. We have observed a similar profile in hippocampal glutamate release employing a similar range of exposure levels, i.e., reduction of glutamate release that is absent at higher concentrations of Pb in the drinking water (Lasley et al., 1998). These and previously reported data suggest that the ability of Pb to diminish presynaptic transmitter release contributes to a reduced capacity for LTP at lower exposure levels. The reversal of the effect of Pb on glutamate release that accompanies higher exposure levels may serve to compensate for the mechanism underlying the LTP impairment and form the basis for the biphasic dose-response pattern seen with chronic developmental exposure.
authors: National Research Council and Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. gilbert.mary@epamail.epa.gov
authors: M E
authors: ME
authors: Gilbert
authors: C M
authors: CM
authors: Mack
authors: S M
authors: SM
authors: Lasley
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018728:Entorhinal Cortex / Q000166:cytology / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000502:physiology*; D007854:Lead / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D019580:Perforant Pathway / Q000166:cytology / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D007854:Lead