Disruption of developing synapses by lead is mediated by inhibition of the NMDAR and downstream signaling

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.