N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels widely expressed in the central nervous system that play key role in brain development and plasticity. On the downside, NMDAR dysfunction, be it hyperactivity or hypofunction, is harmful to neuronal function and has emerged as a common theme in various neuropsychiatric disorders including autism spectrum disorders, epilepsy, intellectual disability, and schizophrenia. Not surprisingly, NMDAR signaling is under a complex set of regulatory mechanisms that maintain NMDAR-mediated transmission in check. These include an unusual large number of endogenous agents that directly bind NMDARs and tune their activity in a subunit-dependent manner. Here, we review current knowledge on the regulation of NMDAR signaling. We focus on the regulation of the receptor by its microenvironment as well as by external (i.e. pharmacological) factors and their underlying molecular and cellular mechanisms. Recent developments showing how NMDAR dysregulation participate to disease mechanisms are also highlighted.

N-甲基-D-天冬氨酸受体 (NMDAR) 是在中枢神经系统中广泛表达的谷氨酸门控离子通道 ，在大脑发育和可塑性中发挥着关键作用。不利的一面是，NMDAR 功能障碍，无论是过度活跃还是功能减退，都会对神经元功能有害，并且已成为各种神经精神疾病的共同主题，包括自闭症谱系障碍、癫痫、智力障碍和精神分裂症。毫不奇怪，NMDAR 信号传导受到一组复杂的调节机制的控制，这些机制可维持 NMDAR 介导的传输受到控制。其中包括异常大量的内源性物质，它们直接结合 NMDAR 并以亚基依赖性方式调节其活性。在这里，我们回顾了有关 NMDAR 信号传导调控的最新知识。我们专注于受体的微环境以及外部（即药理学）因素及其潜在的分子和细胞机制的调节。最近的进展也强调了 NMDAR 失调如何参与疾病机制。