Presynaptic malfunction: the neurotoxic effects of cadmium and lead on the proton gradient of synaptic vesicles and glutamate transport.

Exposure to Cd(2+) and Pb(2+) has neurotoxic consequences for human health and may cause neurodegeneration. The study focused on the analysis of the presynaptic mechanisms underlying the neurotoxic effects of non-essential heavy metals Cd(2+) and Pb(2+). It was shown that the preincubation of rat brain nerve terminals with Cd(2+) (200 µM) or Pb(2+) (200 µM) resulted in the attenuation of synaptic vesicles acidification, which was assessed by the steady state level of the fluorescence of pH-sensitive dye acridine orange. A decrease in L-[(14)C]glutamate accumulation in digitonin-permeabilized synaptosomes after the addition of the metals, which reflected lowered L-[(14)C]glutamate accumulation by synaptic vesicles inside of synaptosomes, may be considered in the support of the above data. Using isolated rat brain synaptic vesicles, it was found that 50 µM Cd(2+) or Pb(2+) caused dissipation of their proton gradient, whereas the application of essential heavy metal Mn(2+) did not do it within the range of the concentration of 50-500 µM. Thus, synaptic malfunction associated with the influence of Cd(2+) and Pb(2+) may result from partial dissipation of the synaptic vesicle proton gradient that leads to: (1) a decrease in stimulated exocytosis, which is associated not only with the blockage of voltage-gated Ca(2+) channels, but also with incomplete filling of synaptic vesicles; (2) an attenuation of Na(+)-dependent glutamate uptake.