Lead toxicity is a major human public health problem because of widespread pollution and the great sensitivity of the human organism to lead. Only a few humans are exposed to fatal levels of lead. However chronic, low level exposure to lead at concentrations recently considered to be safe is now known to cause delayed cognitive development and reduced IQ scores in children. The mechanisms underlying these effects of lead are poorly understood. The experiments proposed are designed to test the hypothesis that lead is toxic through actions at one or more types of ion channel and/or through interference with long term potentiation (LTP). LTP is a calcium-dependent change in synaptic efficacy which is one of the best available models of learning and memory. The proposed experiments will utilize both invertebrate (Aplysia) and mammalian (rat hippocampal and piriform cortex) neurons and will examine effects of both inorganic and organic lead. The effects of lead on three types of calcium channels in Aplysia neurons will be determined: the voltage-dependent calcium channel; the presynaptic calcium channel, as monitored by measuring transmitter release; and the serotonin-activated calcium channel. Using acutely dissociated hippocampal neurons we will record calcium currents and determine sensitivity of the isolated mammalian neurons to lead. In experiments performed on brain slices of hippocampus and piriform cortex we will a) determine sensitivity of response to iontophoretic application of three """"""""specific"""""""" excitatory amino acid agonists (NMDA, kainate and quisqualate) to lead, and b) determine sensitivity to lead of the monosynaptic excitation of piriform cortex neurons upon stimulation of the lateral olfactory tract, and c) determine sensitivity of two pharmacologically distinct forms of LTP (sensitive and not sensitive to NMDA antagonists) to lead. We will pretreat rats with a representative organolead and determine 2 to 5 days later whether brain slices show similar or different toxic effects. If the above studies demonstrate a sensitivity of LTP to lead we will examine the age dependence of LTP and its sensitivity to inorganic and organic lead.
