Lead blocks LTP by an action not at NMDA receptors

Exposure of children to low levels of lead results in a reduction in cognitive ability and a series of behavioral deficits. We have studied the effects of PbCl₂ on longterm potentiation (LTP), the best available electrophysiologic model of learning and memory, in a rat piriform cortex brain slice preparation in order to test the hypothesis that lead neurotoxicity is a result of actions on LTP. With changes in the composition of the Krebs-Ringer solution normally used in brain slices, it is possible to keep the Pb²⁺ in solution at concentrations up to 10 μM. In this concentration range, Pb²⁺ has no effect on the synaptic response elicited in piriform cortex pyramidal neurons upon stimulation of the lateral olfactory tract. We find that Pb²⁺ blocks LTP by about 75% at 5 μM and completely at 10 μM. At these concentrations, Pb²⁺ has no effect on posttetanic potentiation. Since it has been reported that Pb²⁺ blocks N-methyl-D-aspartate (NMDA) responses, and NMDA blockade is known at many sites to block LTP, we studied the effects of Pb²⁺ on NMDA responses. In the concentration range studied there was no effect of Pb²⁺ on NMDA responses. The mechanism whereby Pb²⁺ blocks LTP remains to be determined. While the concentration of Pb²⁺ found to block LTP in these studies is high relative to concentrations of Pb²⁺ in blood that are associated with causing cognitive and behavioral effects in children, the sensitivity to Pb²⁺ may be greater in young animals.