d-Serine as the gatekeeper of NMDA receptor activity: implications for the pharmacologic management of anxiety disorders

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.