Guilarte Tomás R, McGlothan Jennifer L
Molecular Neurotoxicology Laboratory, Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Brain Res Mol Brain Res. 2003 May 12;113(1-2):37-43. doi: 10.1016/s0169-328x(03)00083-4.
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.
我们之前已经表明，在大脑发育过程中暴露于环境相关水平的Pb(2+)会降低成年幼鼠海马体中N-甲基-D-天冬氨酸受体（NMDAR）亚基1（NR1）和NR2A基因的表达，并且与海马体长时程增强（LTP）和空间学习缺陷有关[《神经科学》99（2000）233 - 242]。在本研究中，我们证明在暴露于Pb(2+)的海马体中表达的较低水平的NR1亚基mRNA主要是由于NR1 - 4和NR1 - 2剪接变体水平的降低。这些变化在GluR1、PSD - 95和αCaMKII基因表达没有变化的情况下出现。这些剪接变体的一个独特特征是它们缺乏C1盒。此外，这些剪接变体已被证明能赋予NMDAR复合物最高的细胞表面表达、蛋白激酶C（PKC）增强作用和钙动力学。我们目前的研究结果表明，Pb(2+)诱导的海马体中NR1亚基剪接变体mRNA表达的变化可能提供了一种机制，通过该机制Pb(2+)暴露可以改变NMDAR介导的钙信号传导并影响突触可塑性的程度。
