Nanomolar concentrations of lead inhibit glutamatergic and GABAergic transmission in hippocampal neurons

Abstract

To investigate whether lead (Pb 2+) affects the tetrodotoxin (TTX)-sensitive release of neurotransmitters, the whole-cell mode of the patch-clamp technique was applied to cultured hippocampal neurons. Pb 2+ (≥10 nM) reversibly blocked the TTX-sensitive release of glutamate and γ-aminobutyric acid (GABA), as evidenced by the reduction of the amplitude and frequency of glutamate- and GABA-mediated postsynaptic currents (PSCs) evoked by spontaneous neuronal firing. This effect of Pb 2+, which occurred 2–3 s after exposure of the neurons to Pb 2+-containing external solution, was not related to changes in Na +-channel activity, and was quantified by measurements of changes in the amplitude of PSCs evoked when a 50-μs, 5-V stimulus was applied via a bipolar electrode to a neuron synaptically connected to the neuron under study. With an IC 50 of approximately 68 nM, Pb 2+ blocked the evoked release of glutamate and GABA. This effect was most likely mediated by Pb 2+'s actions on extracellular targets, because there was a very short delay (<3 s) for its onset, and it could be completely reversed by the chelator ethylene diaminetetraacetic acid (EDTA). Given that Pb 2+-induced blockade of evoked transmitter release could be reversed by 4-aminopyridine, it is suggested that the effect on release was mediated via the binding of Pb 2+ to voltage-gated Ca 2+ channels. Thus, it is most likely that the neurotoxic effects of Pb 2+ in the mammalian brain involve a decrease of the TTX-sensitive, Ca 2+-dependent release of neurotransmitters.