Fear, anxiety, and trauma-related disorders, including post-traumatic stress disorder (PTSD), are quite common and debilitating, with an estimated lifetime prevalence of ~28% in Western populations. They are associated with excessive fear reactions, often including an inability to extinguish learned fear, increased avoidance behavior, as well as altered cognition and mood. There is an extensive literature demonstrating the importance of N-methyl-d-aspartate receptor (NMDAR) function in regulating these behaviors. NMDARs require the binding of a co-agonist, d-serine or glycine, at the glycine modulatory site (GMS) to function. d-serine is now garnering attention as the primary NMDAR co-agonist in limbic brain regions implicated in neuropsychiatric disorders. l-serine is synthesized by astrocytes, which is then transported to neurons for conversion to d-serine by serine racemase (SR), a model we term the ‘serine shuttle.’ The neuronally-released d-serine is what regulates NMDAR activity. Our review discusses how the systems that regulate the synaptic availability of d-serine, a critical gatekeeper of NMDAR-dependent activation, could be targeted to improve the pharmacologic management of anxiety-related disorders where the desired outcomes are the facilitation of fear extinction, as well as mood and cognitive enhancement.

恐惧，焦虑和与创伤有关的疾病，包括创伤后应激障碍（PTSD），非常普遍且令人衰弱，据估计，西方人群的终生患病率约为28％。它们与过度的恐惧反应相关，通常包括无法消除已习得的恐惧，增加的回避行为以及改变的认知和情绪。有大量文献证明的重要性N-甲基d在调节这些行为天冬氨酸受体（NMDAR）的功能。NMDAR需要在甘氨酸调节位点（GMS）上结合辅助激动剂d-丝氨酸或甘氨酸来发挥功能。d-丝氨酸作为涉及神经精神疾病的边缘脑区域中的主要NMDAR协同激动剂，现在受到关注。星形胶质细胞合成1-丝氨酸，然后通过丝氨酸消旋酶（SR）（我们称为“丝氨酸穿梭”模型）将其转运至神经元，以转化为d-丝氨酸。神经元释放的d-丝氨酸调节NMDAR活性。我们的综述讨论了调节d-丝氨酸突触可用性的系统，该系统是NMDAR依赖性激活的关键关守，可如何改善焦虑相关疾病的药理学管理，其中所需的结果是消除恐惧，如以及情绪和认知增强。