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

This study was aimed at investigating the effects of the environmental polu tant lead (Pb2+) on the tetrodotoxin (TTX)-insensitive release of neurotran smitters from hippocampal neurons. Evidence is provided that Pb2+ (greater than or equal to 100 nM) increases the frequency of gamma-aminobutyric acid (GABA)- and,glutamate-mediated miniature postsynaptic currents (MPSCs) rec orded by means of the patch-clamp technique from cultured hippocampal neuro ns. 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 p otential-independent release of GABA and glutamate was concentration depend ent and was only partially reversible upon washing of the neurons with nomi nally Pb2+-free external solution. This effect was also Ca2+ independent an d began approximately after 1-2-min exposure of the neurons to Pb2+. The la tency for the onset of the Pb2+ 's effect on the MPSC frequency and the ina bility of the chelator ethylenediamineletraacetic acid (100 mu M) to revers e the effect that remained after washing of the neurons with external solut ion suggested that Pb2+ acted via an intracellular mechanism. Of interest a lso was the finding that Pb2+ simultaneously increased the release of GABA and glutamate, overriding the ability of these neurotransmitters to decreas e the release of one another. Given that synaptic activity is a key mechani sm for the establishment of stable synaptic connections early in the develo pment, it is possible that, by interfering with spontaneous transmitter rel ease, Pb2+ has lasting effects on neuronal maturation and plasticity. (C) 1 999 Elsevier Science B.V. All rights reserved.