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Neuroscientist. 2015 Aug;21(4):337-44. doi: 10.1177/1073858414548724. Epub 2014 Aug 28.

Extrasynaptic NMDA Receptor in Excitotoxicity: Function Revisited.

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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.
College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou China.
Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, MI, USA


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.


calcium; excitotoxicity; extrasynaptic NMDAR; neurodegeneration; synaptic NMDAR

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