title: Hippocampal expression of N-methyl-D-aspartate receptor (NMDAR1) subunit splice variant mRNA is altered by developmental exposure to Pb(2+).
abstract: N-methyl-D-aspartate receptors (NMDAR) play an important role in synaptic plasticity and brain development. We have previously shown that NR1-pan mRNA is significantly increased in the hippocampus of rats chronically exposed to low levels of lead (Pb(2+)) during development [T.R. Guilarte, J.L. McGlothan, Hippocampal NMDA receptor mRNA undergoes subunit specific changes during developmental lead exposure, Brain Res., 790 (1998) 98-107]. It is not known whether this Pb(2+)-induced increase in NR1-pan mRNA is associated with changes in specific splice isoforms. To study this effect, we used in situ hybridization of oligonucleotides to probe for the NR1-a, NR1-b, NR1-1, NR1-2, and NR1-4 isoforms which are most abundantly expressed in the rat hippocampus. Developmental exposure to increasing levels of Pb(2+) resulted in significant increases in NR1-a mRNA throughout the pyramidal and granule cell layers of the rat hippocampus at postnatal day 14 (PN14). NR1-b mRNA was increased in the pyramidal cell layer of Pb(2+)-exposed rats at PN21. Splicing of the C-terminus cassettes was also regulated by developmental exposure to Pb(2+). NR1-2 mRNA was increased in CA4 pyramidal cells and in dentate granule cells of PN21 Pb(2+)-exposed rats. Notably, expression of NR1-4 mRNA in CA3 pyramidal cells was increased in Pb(2+)-exposed rats at PN14 and decreased at PN21. No significant Pb(2+) effect was measured for NR1-1 mRNA expression. These data indicate that alternative splicing of the NR1 gene shows selective anatomical and temporal regulation by Pb(2+) in the developing rat hippocampus. This study provides further support to the hypothesis that NMDARs are important targets for Pb(2+)-induced neurotoxicity.
authors.affiliation: Department of Environmental Health Sciences, The Johns Hopkins University, School of Hygiene and Public Health, 615 North Wolfe Street, Room 2001, Baltimore, MD 21205, USA. tguilart@jhsph.edu
authors.forename: T R
authors.initials: TR
authors.lastname: Guilarte
authors.forename: J L
authors.initials: JL
authors.lastname: McGlothan
authors.forename: M K
authors.initials: MK
authors.lastname: Nihei
mesh_terms: D000375:Aging / Q000378:metabolism*; D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D014644:Genetic Variation; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism*; D007854:Lead / Q000097:blood / Q000633:toxicity; D007855:Lead Poisoning / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*
chemical_list: D007854:Lead; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate