Chronic developmental lead exposure and hippocampal long-term potentiation: Biphasic dose-response relationship

Developmental exposure to lead (Pb) has long been associated with reduction s in intellectual function in children and behavioral impairments in animal models of learning and memory. We have used long-term potentiation (LTP) i n the dentate gyrus of the Pb-exposed rats to determine the potential of a reduced capacity for synaptic plasticity to contribute to Pb-induced cognit ive dysfunction. Previous work demonstrated that developmental exposure res ulting in moderate blood concentrations of Pb increase the threshold for in duction of long-term potentiation (LTP) in the dentate gyrus in vivo. These findings were also suggestive of reductions in LTP magnitude (Gilbert et a l., 1996). The present study was designed to further examine the effects of Pb on LTP magnitude and to determine ii lower blood Pb levels commonly enc ountered 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 da ys oi age (PN21) to the same solution given their dams and continued on thi s 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 alter de livery 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 i n 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 l evels in reducing LTP magnitude, and did not differ significantly from cont rol values. The mechanisms underlying the reduced efficacy of higher exposu re levels of Pb to impair LTP are not clear. Blood (26-117 mu g/dl) and bra in (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 i n hippocampal glutamate release employing a similar range of exposure level s, i.e., reduction of glutamate release that is absent at higher concentrat ions oi Pb in the drinking water (Lasley et al., 1998). These and previousl y reported data suggest that the ability oi Pb to diminish presynaptic tran smitter release contributes to a reduced capacity for LTP at lower exposure levels. The reversal of the effect of Pb on glutamate release that accompa nies higher exposure levels may serve to compensate for the mechanism under lying the LTP impairment and form the basis for the biphasic dose-response pattern seen with chronic developmental exposure. (C) 1999 Intox Press, Inc .