N-甲基-D-天冬氨酸受体介导的学习记忆及神经毒性的研究进展

Research progress of learning and memory and neurotoxicity mediated by NMDA receptor

N-甲基-D-天冬氨酸受体(N-methyl-D-aspartic acid receptor,NMDAR)是一种谷氨酸能兴奋性神经受体,由多种亚基组成强制性异四聚体。NMDAR的兴奋性谷氨酸能神经传递对于神经元的突触可塑性和神经细胞的存活至关重要。海马体和纹状体的突触可塑性与学习记忆的关系密切,其中,海绵体的突触可塑性的原型形式长时程增强(long-term potentiation,LTP)参与学习记忆的维持和巩固,而纹状体的突触可塑性是构成学习和记忆的细胞基础。生理状态下的NMDAR的各个亚基可对学习记忆的产生起促进作用。然而,NMDAR亚基的过度激活,则会引起学习记忆障碍及诱导兴奋性神经毒性并促进神经细胞死亡。此外,突触内NMDAR的正常激活启动突触可塑性并刺激细胞存活。相反,突触外NMDAR的过度激活可诱导Ca2+超载,介导兴奋性神经毒性并促进神经细胞死亡;但是,目前越来越多的研究表明,突触内NMDAR在促进神经元存活的同时,同样可以介导兴奋性神经毒性从而引起神经细胞死亡。主流观点认为兴奋性神经毒性主要由Ca2+超载介导,部分观点则认为NMDAR还可以通过Ca2+超载与非离子通道同时介导兴奋性神经毒性。本文主要就NMDAR对学习记忆促进及抑制作用及其诱导的兴奋性神经毒性的研究进展进行综述。

N-methyl-D-aspartic acid receptor(NMDAR) is a glutamatergic excitatory neuroreceptor, which is transformed into a mandatory heterotetramer by a variety of subgroups. Excitatory glutamatergic neurotransmission of NMDAR is essential for synaptic plasticity and survival of neurons. Synaptic plasticity in hippocampus and striatum is closely related to learning and memory. Long-term potentiation(long-term potentiation, LTP), the prototype form of synaptic plasticity in cavernous body, is involved in the maintenance and consolidation of learning and memory, while synaptic plasticity in striatum is the cellular basis of learning and memory. The subunits of NMDAR in physiological state can promote the production of learning and memory. However, excessive activation of NMDAR subunit can cause learning and memory impairment, induce excitatory neurotoxicity and promote nerve cell death. In addition, the normal activation of NMDAR in synapses initiates synaptic plasticity and stimulates cell survival. On the contrary, the overactivation of extracellular NMDAR can induce Ca2+ overload, mediate excitatory neurotoxicity and promote neuronal death. However, more and more studies have shown that NMDAR in synapses can also induce excitatory neurotoxicity and cause neuronal death while promoting neuronal survival. The mainstream view is that excitatory neurotoxicity is mainly mediated by Ca2+ overload, while some think that NMDAR can also mediate excitatory neurotoxicity through Ca2+ overload and Nonionic channels at the same time. This paper mainly reviews the research progress of the promoting and inhibitory effect of NMDAR on learning and memory and its excitatory neurotoxicity.