Lead exposure during synaptogenesis alters NMDA receptor targeting via NMDA receptor inhibition

Abstract

N-methyl-D-aspartate receptor (NMDAR) ontogeny and subunit expression are altered during developmental lead (Pb 2+ ) exposure. However, it is unknown whether these changes occur at the synaptic or cellular level. Synaptic and extra-synaptic NMDARs have distinct cellular roles, thus, the effects of Pb 2+ on NMDAR synaptic targeting may affect neuronal function. In this communication, we show that Pb 2+ exposure during synaptogenesis in hippocampal neurons altered synaptic NMDAR composition, resulting in a decrease in NR2A-containing NMDARs at established synapses. Conversely, we observed increased targeting of the obligatory NR1 subunit of the NMDAR to the postsynaptic density (PSD) based on the increased colocalization with the postsynaptic protein PSD-95. This finding together with increased binding of the NR2B-subunit specific ligand [ 3 H]-ifenprodil, suggests increased targeting of NR2B-NMDARs to dendritic spines as a result of Pb 2+ exposure. During brain development, there is a shift of NR2B-to NR2A-containing NMDARs. Our findings suggest that Pb 2+ exposure impairs or delays this developmental switch at the level of the synapse. Finally, we show that alter expression of NMDAR complexes in the dendritic spine is most likely due to NMDAR inhibition, as exposure to the NMDAR antagonist aminophosphonovaleric acid (APV) had similar effects as Pb 2+ exposure. These data suggest that NMDAR inhibition by Pb 2+ during synaptogensis alters NMDAR synapse development, which may have lasting consequences on downstream signaling.

Lead Exposure Impairs Hippocampus Related Learning and Memory by Altering Synaptic Plasticity and Morphology During Juvenile Period

“…On the protein level, a recent study showed that Pb exposure resulted in the decrease in NR2A-containing NMDARs at synaptogenesis in a cell culture system [25]. Thus, it is not surprising that the NR2A expression both in protein and mRNA level were decreased significantly in adult hippocampus during juvenile Pb exposure.…”

Pb(II) Disruption of Synaptic Activity Through Ca(II)- and Zn(II)-binding Proteins

“…Exposure to Pb 2+ appears to inhibit both excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs), resulting in reduced neurotransmission in the glutamatergic and GABAergic systems associated with hippocampal neurons [131] . Moreover, expression levels of presynaptic proteins synaptophysin (Syn) and synaptobrevin (Syb) were both reduced, accompanied by reduction in the release of vesicular neurotransmitters associated with glutamatergic and GABAergic synapses, in the presence of Pb 2+ [132] . Further studies have reported that adverse effects of Pb 2+ on the GABAergic system during CNS development is dependent on the level of exposure, and the stage of development [21] , where low concentrations of Pb 2+ (50 ppb) reduced expression of GABA genes at 48 hours post-fertilization (hpf), but subsequently increased gene expression at 60 hpf, at the same concentration.…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…Moreover, the hippocampus appears to be particularly vulnerable as in this brain structure NMDA receptors undergo subunit specific changes during developmental Pb2+ exposure . Exposure to Pb2+ during synaptogenesis causes decreased expression of hippocampal NR2A-subunit of NMDARs at synapses and increased targeting of NR2B-NMDARs to dendritic spines (without increased NR2B-NMDARs expression) (Nihei and Guilarte, 1999;Neal et al, 2011;Zhang et al, 2002).…”