Presynaptic Mechanisms of Lead Neurotoxicity: Effects on Vesicular Release, Vesicle Clustering and Mitochondria Number

Childhood lead (Pb(2+)) intoxication is a global public health problem and accounts for 0.6% of the global burden of disease associated with intellectual disabilities. Despite the recognition that childhood Pb(2+) intoxication contributes significantly to intellectual disabilities, there is a fundamental lack of knowledge on presynaptic mechanisms by which Pb(2+) disrupts synaptic function. In this study, using a well-characterized rodent model of developmental Pb(2+) neurotoxicity, we show that Pb(2+) exposure markedly inhibits presynaptic vesicular release in hippocampal Schaffer collateral-CA1 synapses in young adult rats. This effect was associated with ultrastructural changes which revealed a reduction in vesicle number in the readily releasable/docked vesicle pool, disperse vesicle clusters in the resting pool, and a reduced number of presynaptic terminals with multiple mitochondria with no change in presynaptic calcium influx. These studies provide fundamental knowledge on mechanisms by which Pb(2+) produces profound inhibition of presynaptic vesicular release that contribute to deficits in synaptic plasticity and intellectual development.