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.
Pathological fear and anxiety disorders, including post-traumatic stress disorder (PTSD), which are associated with exaggerated reactions to fearful stimuli and an inability to extinguish learned fear, underlie some of the most common and debilitating psychiatric disorders1. The understanding of the neural circuitry and genetics underlying PTSD has rapidly progressed over recent years, and there is great interest in developing novel pharmacologic treatments based on these findings. Human neuroimaging and rodent models have implicated numerous cortical, subcortical, and midbrain regions in producing the symptoms observed in patients with PTSD (Fig. 1a). This disorder is frequently conceptualized as a memory disorder with dysregulated fear learning at the core of many of its signs and symptoms2. Three of the most well studied and interconnected brain regions linked to PTSD symptoms are the amygdala, medial prefrontal cortex (mPFC), and hippocampus (HP). In PTSD, there is a failure of top-down cortical inhibition, leading to the reactivation of memories associated with trauma-related thoughts and feelings. Failure of top-down inhibition impairs the ability to extinguish fear3, which is the active learning of a new non-threatening association. Thus, previously dangerous stimuli are no longer considered fearful. PTSD patients exhibit deficits in recall of extinction memory and display diminished activation of the mPFC and HP, which correlates with symptom severity and disrupted prefrontal-amygdala functional connectivity3,4. In addition, recent evidence suggests that the neurobiological underpinnings related to altered cognition and mood are due to dysfunctions in the hippocampus and amygdala and their ability to regulate PFC top-down control5.