Lead increases tetrodotoxin-insensitive spontaneous release of glutamate and GABA from hippocampal neurons

This study was aimed at investigating the effects of the environmental pollutant lead (Pb²⁺) on the tetrodotoxin (TTX)-insensitive release of neurotransmitters from hippocampal neurons. Evidence is provided that Pb²⁺ (≥ 100 nM) increases the frequency of γ-aminobutyric acid (GABA)- and glutamate-mediated miniature postsynaptic currents (MPSCs) recorded by means of the patch-clamp technique from cultured hippocampal neurons. Because Pb²⁺ changed neither the amplitude nor the decay-time constant of the MPSCs, Pb²⁺-induced changes in MPSC frequency are exclusively due to a presynaptic action of this heavy metal. Increase by Pb²⁺ of the action potential-independent release of GABA and glutamate was concentration dependent and was only partially reversible upon washing of the neurons with nominally Pb²⁺-free external solution. This effect was also Ca²⁺ independent and began approximately after 1-2-min exposure of the neurons to Pb²⁺. The latency for the onset of the Pb²⁺'s effect on the MPSC frequency and the inability of the chelator ethylenediaminetetraacetic acid (100 μM) to reverse the effect that remained after washing of the neurons with external solution suggested that Pb²⁺ acted via an intracellular mechanism. Of interest also was the finding that Pb²⁺ simultaneously increased the release of GABA and glutamate, overriding the ability of these neurotransmitters to decrease the release of one another. Given that synaptic activity is a key mechanism for the establishment of stable synaptic connections early in the development, it is possible that, by interfering with spontaneous transmitter release, Pb²⁺ has lasting effects on neuronal maturation and plasticity.