Selective decrease in NR1 subunit splice variant mRNA in the hippocampus of Pb2+-exposed rats: implications for synaptic targeting and cell surface expression of NMDAR complexes.
We have previously shown that exposure to environmentally relevant levels of Pb(2+) during brain development decreases the expression of N-methyl-D-aspartate receptor (NMDAR) subunit 1 (NR1) and NR2A genes in the hippocampus of young adult rats and was associated with deficits in hippocampal LTP and spatial learning [Neuroscience 99 (2000) 233-242]. In the present study, we demonstrate that the lower levels of NR1 subunit mRNA expressed in the Pb(2+)-exposed hippocampus are principally due to decreased levels of the NR1-4 and NR1-2 splice variants. These changes were present in the absence of changes in GluR1, PSD-95 and alphaCaMKII gene expression. A unique characteristic of these splice variants is that they lack the C1 cassette. Further, these splice variants have been shown to impart the highest cell surface expression, PKC potentiation and calcium kinetics to NMDAR complexes. Our present findings indicate that Pb(2+)-induced changes in NR1 subunit splice variant mRNA expression in the hippocampus may provide a mechanism by which Pb(2+)-exposure can modify NMDAR-mediated calcium signaling and influence the degree of synaptic plasticity.
Molecular Neurotoxicology Laboratory, Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA. tguilart@jhsph.edu
Tomás R
TR
Guilarte
Jennifer L
JL
McGlothan
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D004781:Environmental Exposure; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007854:Lead / Q000633:toxicity*; D020263:Lead Poisoning, Nervous System / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D011956:Receptors, Cell Surface / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics
C409466:NR1 NMDA receptor; D020033:Protein Isoforms; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D007854:Lead; D011493:Protein Kinase C