Different distribution of NMDA receptor subunits in cortex contributes to selective vulnerability of motor neurons in amyotrophic lateral sclerosis

To investigate the relationship between different distribution of NMDA receptor subunits and motor neurons selective vulnerability in amyotrophic lateral sclerosis.First we investigated whether administration of THA, a glutamate transport inhibitor, in cultured organotypic brain tissue made different damage of motor cortex and piriform cortex. Then we testified that selective motor cortex injury was related to disparate distribution of NR2A and NR2B by measuring their protein expression with the method of Western blot. In order to make clear different role of NR2A and NR2B in chronic glutamate excitotoxicity of motor neurons injury, we inhibited NR2A and NR2B separately in cultured cortical motor neurons and brain slices to investigate the mortality changes of motor neurons.The mortality rate of neurons in motor cortex was apparently higher than that of piriform cortex (64.50% ± 2.19% and 30.43% ± 4.75%, P<0.01) after cultured brain slices were damaged by THA 100 μmol/L for two weeks. Western blot results showed that protein expression of NR2B/NR2A ratio in motor cortex was prominently higher than that of piriform cortex (0.87 ± 0.09 and 0.47 ± 0.09, P<0.01). In inhibitor protective experiments, NR2B inhibitor showed positive effects. The mortality rates of cultured cortical motor neurons in control, glutamate, glutamate + NR2A inhibitor, glutamate + NR2B inhibitor were 6.85% ± 1.47%,47.48% ± 5.75%, 45.76% ± 8.09%, 18.10% ± 3.11%, respectively. The mortality rates of cultured motor cortex slices in control, THA, THA + NR2A inhibitor, THA + NR2B inhibitor were 12.49% ± 2.09%,100%,110.87% ± 15.76%, 35.13% ± 5.32%, respectively.NR2A and NR2B subunits play different roles in motor neurons chronic glutamate excitotoxicity. Intensive distribution of NR2B subunit in motor cortex makes motor neurons selectively vulnerable to glutamate excitotoxicity in amyotrophic lateral sclerosis.PubMed02228-334