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

To investigate whether lead (Pb²⁺) affects the tetrodotoxin (TTX)- sensitive release of neurotransmitters, the whole-cell mode of the patch- clamp technique was applied to cultured hippocampal neurons. Pb²⁺ (≥ 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 Pb²⁺, which occurred 2-3 s after exposure of the neurons to Pb²⁺-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 IC₅₀ of approximately 68 nM, Pb²⁺ blocked the evoked release of glutamate and GABA. This effect was most likely mediated by Pb²⁺'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 Pb²⁺-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 Pb²⁺ to voltage-gated Ca²⁺ channels. Thus, it is most likely that the neurotoxic effects of Pb²⁺ in the mammalian brain involve a decrease of the TTX-sensitive, Ca²⁺-dependent release of neurotransmitters.