NMDA receptor-mediated signaling in the lead exposed rat brain

Lead is a ubiquitous environmental toxicant, which causes cognitive deficits in children. A detailed molecular explanation of how lead exerts its neurotoxicity has yet to be proposed. The purpose of this work is to advance the understanding of molecular mechanisms of lead neurotoxicity by exploring lead's effects on NMDA receptor (NMDAR)-activated calcium signaling pathways necessary for synaptic plasticity.; The effect of developmental lead exposure on the composition of functional NMDAR in rat hippocampus and cortex was determined by using ifenprodil, an antagonist of NR2B containing NMDARs. A higher number of binding sites ( Bmax) with no change in binding affinity (K d) was observed in Pb2+-exposed animals in the absence of changes in [3H]-glutamate binding. These results suggest a greater proportion of extrasynaptic NR1/NR2B receptors are expressed in the Pb2+-exposed rat brain.; The changes in NMDAR composition in lead-exposed rat brain may alter phosphorylation of proteins such as CREB that reside at the terminus of NMDAR-activated calcium signaling pathways. CREB is a nuclear transcription factor that integrates NMDAR-dependent calcium signaling pathways and is necessary for transcription of genes needed for learning, memory and synaptic plasticity. We demonstrate that phosphorylation and binding activity of CREB is altered by lead exposure. Alteration of pCREB expression and binding activity suggest that calcium signaling pathway activity, which integrates at CREB, is altered in the lead-exposed rat brain.; Two NMDAR-activated calcium signaling pathways, the mitogen activated protein kinase (MAPK) and calcium/calmodulin dependent protein kinase II (CAMKII) pathways were examined in the hippocampus of lead exposed rats at a time point where we have previously demonstrated a lead-induced deficit in synaptic plasticity and learning. An increase in MAPK phosphorylation and an alteration in the kinetics of CAMKII were observed. The lead-dependent increase in MAPK phosphorylation is not well understood but we show that the alteration of CAMKII kinetics could be partially explained by direct interaction of lead with CAMKII.; This data advances the understanding of the molecular effects of lead associated with cognitive and synaptic plasticity deficits. It is clear from our observations that the NMDAR-dependent signaling pathways in the brain are altered after developmental lead exposure.