Lead (Pb²⁺) is a ubiquitous environmental neurotoxicant that continues to threaten public health on a global scale. Epidemiological studies have demonstrated detrimental effects of Pb²⁺ on childhood IQ at very low levels of exposure. However, a mechanistic understanding of how Pb²⁺ affects brain development has remained elusive. The cognitive effects of Pb²⁺ are believed to be mediated through its inhibition of the NMDAR. Studies in animal models of developmental Pb ²⁺ exposure demonstrate altered NMDAR subunit ontogeny and disruption of NMDAR-dependent intracellular signaling. Additional studies have reported that Pb²⁺ exposure affects presynaptic neurotransmission, but a mechanistic link between presynaptic and postsynaptic effects has been missing.

The work presented here used a primary hippocampal culture system to define the synaptic effects of chronic Pb²⁺ exposure in developing neurons. We observed that Pb²⁺ exposure during synaptogenesis results in altered protein expression in both presynaptic and postsynaptic elements. Postsynaptically, chronic Pb²⁺ exposure during synaptogenesis results in a selective decrease in synaptic NR2A-containing NMDARs while increasing NR2B-containing NMDARs. Together, these data suggest that Pb²⁺ exposure during synaptogenesis results in an arrest or delay of the developmental switch from NR2B-containing NMDARs to NR2A-containing receptors, consistent with what has been suggested in rat models of developmental Pb²⁺ exposure.

Presynaptically, we observed that the synaptic vesicle proteins involved in synaptic vesicular release and recycling are reduced after Pb²⁺ exposure, which has significant effects on the vesicular release ability in Pb²⁺-exposed neurons. Neurons exposed to Pb ²⁺ exhibit fewer vesicular release sites, a specific loss of fast-releasing sites, and slower rates of release after Pb²⁺ exposure. These findings closely resemble the effects of the loss of BDNF in animal models and neuronal cultures and suggest that NMDAR activity-dependent retrograde signaling of BDNF is affected during Pb²⁺ exposure. In support of this theory, exogenous addition of BDNF for the final 24 hours of Pb ²⁺ exposure was sufficient to recover both the levels of presynaptic proteins as well as the impairments in vesicular release in Pb²⁺-exposed neurons.

These findings provide the basis for the first working model that accounts for both postsynaptic and presynaptic effects observed in experimental models of Pb²⁺ exposure.