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

Abstract

Exposure to Cd2+ and Pb2+ 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 Cd2+ and Pb2+. It was shown that the preincubation of rat brain nerve terminals with Cd2+ (200μM) or Pb2+ (200μM) 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-[14C]glutamate accumulation in digitonin-permeabilized synaptosomes after the addition of the metals, which reflected lowered l-[14C]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 50μM Cd2+ or Pb2+ caused dissipation of their proton gradient, whereas the application of essential heavy metal Mn2+ did not do it within the range of the concentration of 50–500μM. Thus, synaptic malfunction associated with the influence of Cd2+ and Pb2+ 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 Ca2+ channels, but also with incomplete filling of synaptic vesicles; (2) an attenuation of Na+-dependent glutamate uptake.