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.