Clinical studies have shown a correlation between chronic low level lead in the blood of humans, especially children, and various behavioral deficits, including emotional problems, hyperactivity, reduced reaction time, lowered IQ scores, and learning difficulties in school. Although experimental studies of mammalian model systems have found various lead effects, including alteration in regional brain biochemistry and synaptic transmission, the cellular neuronal dysfunctions casued by chronic lead exposure are still not well understood. We will use the large, individually identifiable neurons of the gastropod Lymnaea stagnalis as a model system in which to study the mechanisms whereby lead exposure effects the functioning of nerve cells. The long term objectives of this study are: (1) to understand the effects of lead exposure on the ionic channels which control nerve cell activity; (2) to determine the important differences among neuron types which cause differential sensitivity to lead exposure; (3) to attempt to predict what effects lead exposure will have upon particular neuronal types; (4) to determine the generalizability of our findings to mammalian neurons; and (5) to apply the techniques and information obtained in these experiments to the study of other known or suspected neurotoxins. The specific hypotheses that this project will test are: (1) lead increases resting potassium conductance; (2) lead decreases calcium currents in neurons, leading, in some neuron types with large calcium conductances, to reduced excitability and reduced adaptation currents; (3) lead alters the intracellular calcium concentration, contributing to changes in calcium and potassium conductances and electrical coupling between neurons; and (4) lead alters neurotransmitter concentrations. Animals will be exposed to lead in vivo, and intracellular recording from individually identifiable brain cells will be used to study lead effects. Voltage clamping will be used to investigate changes in membrane ion channels, particularly those selective for potassium and calcium which occur due to lead exposure. The intracellular calciums ion concentration will be measured directly with ion-sensitive microelectrodes. Neurotransmitter concentrations will be measured in individual neurons by radioenzymatic assays. Finally, organ culture of brains will be used to compare the effects of chronic lead exposure in vivo and in vitro.
