Zhou Xianju, Chen Zhuoyou, Yun Wenwei, Ren Jianhua, Li Chengwei, Wang Hongbing
Department of Neurology, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, China.
Key Laboratory of Translational Neuroscience, Zhoukou Normal University, Zhoukou China.
Neuroscientist. 2015 Aug;21(4):337-44. doi: 10.1177/1073858414548724. Epub 2014 Aug 28.
It is generally accepted that proper activation of N-methyl-d-aspartate receptors (NMDARs) promotes neuronal survival and supports neuroplasticity, and excessive NMDAR activation leads to pathological outcomes and neurodegeneration. As NMDARs are found at both synaptic and extrasynaptic sites, there is significant interest in determining how NMDARs at different subcellular locations differentially regulate physiological as well as pathological functions. Better understanding of this issue may support the development of therapeutic strategies to attenuate neuronal death or promote normal brain function. Although the current prevailing theory emphasizes the major role of extrasynaptic NMDARs in neurodegeneration, there is growing evidence indicating the involvement of synaptic receptors. It is also evident that physiological functions of the brain also involve extrasynaptic NMDARs. Our recent studies demonstrate that the degree of cell death following neuronal insults depends on the magnitude and duration of synaptic and extrasynaptic receptor co-activation. These new results underscore the importance of revisiting the function of extrasynaptic NMDARs in cell fate. Furthermore, the development of antagonists that preferentially inhibit synaptic or extrasynaptic receptors may better clarify the role of NMDARs in neurodegeneration.
一般认为，N-甲基-D-天冬氨酸受体（NMDARs）的适当激活可促进神经元存活并支持神经可塑性，而过度的NMDAR激活会导致病理结果和神经退行性变。由于在突触和突触外部位均发现有NMDARs，因此人们对确定不同亚细胞位置的NMDARs如何差异调节生理和病理功能有着浓厚兴趣。更好地理解这个问题可能有助于开发减轻神经元死亡或促进正常脑功能的治疗策略。尽管当前流行的理论强调突触外NMDARs在神经退行性变中的主要作用，但越来越多的证据表明突触受体也参与其中。同样明显的是，大脑的生理功能也涉及突触外NMDARs。我们最近的研究表明，神经元损伤后的细胞死亡程度取决于突触和突触外受体共同激活的程度和持续时间。这些新结果强调了重新审视突触外NMDARs在细胞命运中的功能的重要性。此外，优先抑制突触或突触外受体的拮抗剂的开发可能会更好地阐明NMDARs在神经退行性变中的作用。
