Revisiting the function of extrasynaptic NMDA receptor in excitotoxicity Running title: NMDA receptor and excitotoxicity

• Published in: The Neuroscientist (Baltimore, Md.) Md.), 2014-08, Vol.21 (4), p.337-344
• Main Authors: Zhou, Xianju, Chen, Zhuoyou, Yun, Wenwei, Ren, Jianhua, Li, Chenwei, Wang, Hongbing
• Format: Article
• Language: English
• ISSN: 1073-8584; 1089-4098
• DOI: 10.1177/1073858414548724

It is generally accepted that proper activation of NMDA 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 to determine how NMDARs at different subcellular locations differentially regulate physiological as well as pathological functions. Better understanding on this issue may aid the development of therapeutic strategies to attenuate neuronal death or promote brain functions including cognition and mental health. 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 study demonstrates that the degree of cell death following neuronal insults depends on the magnitude and duration of synaptic and extrasynaptic receptor co-activation. This re-kindles the interest to revisit 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.