肌萎缩侧索硬化（ALS)是一种致死性的运动神经元变性疾病，谷氨酸兴奋毒性损伤是ALS最重要的发病原因。谷氨酸损伤后通过激活NMDA受体（一种亲离子型谷氨酸受体）使细胞内钙超载造成神经元变性死亡，但临床上NMDA受体抑制剂并未产生神经保护作用。进一步研究表明NMDA受体由不同亚单位构成，其中NR2AR和NR2BR在分布和功能上有很大差异，但二者发挥作用的机制至今未明。我们的研究旨在明确NR2AR和NR2BR在ALS发病机制中的作用，包括慢性谷氨酸损伤后NR2AR和NR2BR的活动情况，激活后能否引起ALS的典型病理改变，对神经元生存/死亡状态的影响，以及引起改变的细胞内信号传导通路。我们前期的研究发现慢性谷氨酸损伤早期NR2AR/PTEN/TDP-43信号通路激活具有神经保护作用，下一步将明确NR2BR在谷氨酸损伤中的作用。我们的研究结果将为ALS发病机制及治疗提供新思路和新途径。

Amyotrophic lateral sclerosis (ALS) is a serious lethal motor neurons degenerative disease. Glutamate excitotoxicity is the major cause of ALS. Activation of N-methyl-D-aspartate (NMDA) receptors, an ionotropic glutamate receptor, brings about intracellular calcium overload, which induces a great deal oxidative enzymes and leads to neurons degeneration after glutamate injury. The course shows that NMDA receptors activation plays a key role in glutamate injury. However, NMDA receptor inhibitors do not show neuroprotective effects. Previous studies showed that NMDA receptors were made up of different subunits, of which NR2AR (NR2A-containing NMDA receptors) and NR2BR (NR2B-containing receptors) differed widely on the distribution and function, but what roles they played in pathogenesis of ALS were still not clear. Our study is designed to make clear the role of NR2AR and NR2BR activation in pathogenesis of ALS, including the activities of NR2AR and NR2BR during different course of chronic glutamate injury, whether inducing the typical pathological changes of ALS, and the impact of neuronal survival/death state, as well as the intracellular signaling pathways inducing neuronal degeneration. Our previous study found that NR2AR/PTEN/TDP-43 signaling pathway activation had a neuroprotective effect in the early stage of chronic glutamate injury.The result has been accepted by Journal of Cell Science (IF 6.290). Next, we will focuse on the effect of NR2BR in ALS pathogenesis. We expect that NR2AR and NR2BR activation occurs in different phases of chronic glutamate injury, NR2AR activities in early stage has neuroprotective effects, on the contrary NR2BR activities in late stage induces neuronal degeneration. Activation of NR2BR in the late stage of chronic glutamate injury will induce pathological change of ALS, including motor neurons apoptosis, abnormal TDP-43 cytoplasmic inclusions, and most obviously TDP-43 sequestrated from nuclear. NR2BR activation induces neuodegeneration through PTEN upregulation/ CREB downregulation/ TDP-43 downregulation signaling pathway. Our results will provide new ideas for the pathogenesis research of ALS, and provide new drug targets for ALS treatment.