Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

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.

Fig. 1: D-serine circuits, sympotom clusters, and the ‘serine shuttle'.

a Diagram illustrating the human and rodent forebrain regions expressing high levels of serine racemase that are implicated in the major post-traumatic stress disorder symptom clusters. b Schematic representation of the serine shuttle in astrocytes and neurons. Glucose is transported from the blood into astrocytes by glucose transporter-1. Most brain l-serine is synthesized de novo from the glycolytic intermediate 3-phosphoglycerate, with phosphoglycerate 3-dehydrogenase being the committed step in astrocytic l-serine biosynthesis. l-serine is released from astrocytes by the alanine/serine/cysteine/threonine transporter-1 and is then taken up into neurons via currently unidentified transporter(s), where it is converted to d-serine by the enzyme serine racemase. Serine racemase is strongly inhibited by glycine, which competes for binding with l-serine. Serine racemase and d-serine are concentrated in dendrites and dendritic spines of glutamatergic and GABAergic neurons. d-serine is released from neurons, in part, by the alanine-serine-cysteine-1 transporter, where it binds to the glycine modulatory site on synaptic N-methyl-d-aspartate receptors. Glycine also regulates d-serine metabolism by affecting the efficiency of d-serine transport, as it is a high-affinity substrate of the alanine-serine-cysteine-1 transporter and can enhance the release of d-serine by amino acid hetero-exchange. d-serine can be eliminated from the synaptic space by either reuptake into astrocytes where it is catabolized by d-amino acid oxidase or via neuronal serine racemase. Asc-1 alanine-serine-cysteine-1, Slc7a10 solute carrier family 7 member 10, ASCT-1 alanine/serine/cysteine/threonine transporter-1 (Slc1a4; solute carrier Family 1 member 4), DAO d-amino acid oxidase, GLUT1 glucose transporter-1, GlyT-1 glycine transporter-1, mPFC medial prefrontal cortex, NMDAR N-methyl-d-aspartate receptor, PHGDH phosphoglycerate 3-dehydrogenase, PSD postsynaptic density, SHMT serine hydroxymethyltransferase, SR serine racemase, Some clipart in this figure were downloaded from

Pavlovian fear conditioning is one of the most widely used models for studying emotional memory and associative learning in rodents6. The amygdala is a central hub in the emotional learning circuit, integrating sensory information from both cortical and subcortical brain regions related to the conditioning and extinction experience7. Although multiple neurotransmitter systems can regulate extinction learning, many studies demonstrate the importance of NMDAR function in extinction learning using antagonists given either systemically or intracranially. In particular, NMDARs within the amygdala, mPFC, and hippocampus are essential for the acquisition and the extinction of fear memories and their associated physiologic symptoms8. NMDARs require the binding of a co-agonist, d-serine or glycine, at the glycine modulator site (GMS) to function. d-serine is functionally a more potent activator of synaptic NMDARs than glycine9, and mounting evidence suggests that it serves as the major NMDAR co-agonist in limbic brain regions implicated in neuropsychiatric disorders10. Finally, clinical evidence suggests that D-cycloserine (DCS), a partial agonist at the NMDAR GMS, is modestly effective at treating patients with anxiety disorders, including PTSD, in conjunction with cognitive behavioral therapy11,12. In the following sections, we discuss how the systems that regulate 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.

PTSD symptom domains and brain circuits

Intrusion symptoms in PTSD as defined in the DSM-5, are those in which the traumatic event is persistently re-experienced and can include recurring involuntary intrusive memories and physiological reactivity13. Individuals with PTSD often display increased amygdala activity and decreased medial prefrontal cortex (mPFC) activity during symptom provocation studies when compared with controls14,15,16,17. This suggests that the reactivation of trauma-related memories in PTSD is associated with a failure of top-down cortical inhibition (e.g., from the mPFC) of the reactivation of trauma-related memories18. Failure of top-down cortical inhibition might also underlie fear extinction impairments in PTSD3.

In classical conditioning, fear conditioning occurs when a neutral cue (a tone or an image) is paired with an intrinsically aversive stimulus, such as electric shock, whereby subsequent presentations of the neutral cue induce a fear response. Fear extinction refers to the gradual reduction of the fear response to a conditioned stimulus when it fails to be reinforced19. There is strong evidence that fear extinction involves the formation of a competing new memory that inhibits the fear response rather than an erasure of the original memory19,20. However, fear memories may also weaken during recall through a process called reconsolidation21. Although individuals with PTSD can encode new fear extinction memories, they do not retain them as well3,22,23, suggesting a deficit in fear extinction retention that underlies PTSD symptoms. In PTSD subjects, the size and activity of the ventromedial PFC (vmPFC) is associated with the extent of fear extinction24 and the changes to the functional connectivity between the vmPFC and the amygdala25. These circuit changes could offer a mechanistic basis for the extinction retention impairments observed in PTSD subjects, since vmPFC-mediated inhibition of the amygdala is thought to be necessary for fear extinction26.

Effortful avoidance of distressing trauma-related stimuli is another DSM-5 PTSD symptom domain13. Imaging studies suggest that avoidance symptoms and fear circuit activation are closely linked, implicating the anterior cingulate and inferior frontal cortices, as well as hippocampus and amygdala. They also suggest that avoidance is integral to the observed PTSD fear extinction deficits5. Since a cue or context that is avoided cannot be extinguished, behavioral therapy approaches for PTSD focus on decreasing avoidance behaviors.

Negative alterations in cognition and mood that begin or worsen after a traumatic event are another criterion in the DSM-5 PTSD diagnosis and include memory deficits and anhedonia symptomatology13. Many of these alterations highly overlap with the symptoms of depression. Although preliminary, evidence points towards aberrations in limbic brain regions, particularly the hippocampus and amygdala, and their relationship with top-down PFC control. As the hippocampus is crucial for learning and memory processes, particularly declarative memory27, hippocampal dysfunction has been proposed to account for PTSD memory deficits28. The hippocampus is involved in the initial storage and integration of aspects of memory during retrieval. A substantial literature, including the largest brain imaging study of PTSD to date, demonstrates reduced hippocampal volume in PTSD patients29,30. Individuals with PTSD also exhibit decreased hippocampal activity while taking part in a declarative memory task when compared with trauma-exposed controls without PTSD31, as well as decreased hippocampal activity and a failure to recall extinction learning when taking part in a fear conditioning paradigm3. Finally, extensive research also shows that individuals with PTSD have deficits in a number of executive function tasks32.

d-Serine mediated nmdar activation and behavior

As described above, the neural circuit abnormalities that contribute to the pathophysiology of PTSD are becoming more well defined. This section will focus on several interconnected limbic brain regions, including the amygdala, hippocampus, and mPFC, for which NMDAR-dependent activation is well-established in mediating behaviors in animal models that are relevant for the symptoms observed in PTSD patients (Table 1). Specifically, we highlight what is known about d-serine dependent NMDAR activation, as both serine racemase (SR) and d-serine are enriched in excitatory and inhibitory neurons of these cortico-limbic brain regions33,34,35.

Table 1 Findings supporting the role of d-serine in fear conditioning and anxiety disorders.

NMDARs are unique compared to other ionotropic glutamate receptors because of their slow deactivation kinetics, high permeability to calcium, and their role as molecular coincidence detectors. Calcium influx through the NMDAR in neurons triggers a cascade of intracellular events that mediate local, acute functional synaptic plasticity and changes in gene expression that further influence synaptic plasticity36. In addition to the binding of its agonist glutamate to the GluN2 subunit, NMDAR activation requires postsynaptic depolarization, which relieves the Mg2+ blockade of the channel, and the binding of either glycine or d-serine at the GMS on the GluN1 subunit37,38. Although the co-agonists glycine and d-serine are present in the extracellular space37, the GMS is not saturated in vivo39. Importantly, d-serine is functionally more effective than glycine in activating NMDARs and is essential for NMDAR-dependent long-term potentiation (LTP) in numerous adult forebrain regions, including the hippocampus, amygdala, mPFC, and striatum9,10,40,41,42,43,44. It should be noted that glycine does serve a role in maintaining NMDAR-dependent plasticity in some adult synapses, such as in the thalamo-lateral amygdala10 and medial perforant path-dentate gyrus synapses9.

Individuals with PTSD display impairments in the extinction of traumatic memories. Although multiple neurotransmitter systems can regulate fear extinction learning, there is a very extensive literature demonstrating the importance of NMDAR function in extinction learning using antagonists given either systemically or intracranially. In particular, NMDARs within the amygdala and mPFC are essential for the acquisition and the extinction of fear memories and their associated physiologic symptoms8. NMDAR function in the basolateral amygdala (BLA) is also critical for extinguishing conditioned fear responses, as many studies have shown that NMDAR antagonists delivered into the BLA impair extinction retrieval, while the infusion of DCS or d-serine into the BLA enhances extinction retrieval11. The extinction of conditioned fear memory also depends on the mPFC, and in particular the infralimbic (IL) division, which sends very strong projections to the BLA8,45,46,47,48. Extinction training induces NMDAR-dependent plasticity and increases burst firing in IL neurons, which stabilizes fear extinction memory49. Ligands of the NMDAR GMS, such as d-serine, are required for extinction learning. We have shown that SR levels are dynamically up-regulated in the hippocampus, amygdala, and mPFC after fear memory extinction33. Mice that lack SR and have 90% lower d-serine, display impaired post-retrieval extinction of contextual fear memory that can be restored by d-serine administration, implicating a role for d-serine in the reconsolidation process50. Exogenous d-serine or DCS administration facilitates the acquisition and retention of fear extinction11,33,51, while d-serine also facilitates the extinction of drug seeking behavior52. Clinical evidence also suggests that DCS is modestly effective at treating patients with anxiety disorders, including PTSD, in conjunction with cognitive behavioral therapy11,12. In addition, a recent placebo-controlled, double-blind, three-day fear conditioning and delayed extinction fMRI study in healthy participants, found that DCS enhanced extinction consolidation, as reflected by reduced arousal ratings and activation of brain regions that mediate defensive reactions53. Interestingly, findings in mice suggest that DCS may also serve as a precursor to d-serine in the brain54. Finally, there is genetic evidence linking d-serine with PTSD. A single nucleotide polymorphism (SNP; rs4523957) within the human serine racemase (SRR) gene previously associated with other disorders55,56,57, is a functional eQTL at the level of regulating SR mRNA expression in post-mortem human brain and is associated with PTSD33 in a highly traumatized civilian population58,59.

While extinction of classical fear conditioning (e.g., inhibitory and safety learning) relies on lower limbic implicit memory systems and processing of negative valence as a function of threat expectancy60, fear extinction of hippocampus-dependent learning requires more complex, higher order associative learning processes61. As such, episodic and semantic memory systems are predominantly prefrontal cortical and hippocampal/temporal, and thus likely engage different memory systems than those used for processing implicit, subcortical memory associations62. Since NMDAR antagonism can produce discrete impairments in episodic and semantic memory63, it is possible that increasing endogenous d-serine levels to increase NMDAR activity could facilitate the extinction of fear memories that engage higher-order processing.

Emerging literature describes the brain circuits engaged in mediating passive (freezing) and active avoidance strategies (e.g., escaping to a safe chamber) when an animals are presented with threat-associated stimuli64. Rodent lesion studies indicate that passive freezing is mediated by signals transmitted from the lateral amygdala to the central amygdala and then to the periaqueductal gray65. d-serine administration enhances memory extinction in an inhibitory avoidance task66,67, potentially through increasing GluA2-containing AMPA receptor endocytosis67.

Individuals with PTSD exhibit negative alterations in cognition and mood, such as anxiety and social withdrawal, that rely on proper NMDAR function and begin or worsen after a traumatic event. Numerous studies have demonstrated the importance of endogenous d-serine in mediating NMDAR activation for contextual and working memory in rodents41,42,50,68,69,70. Furthermore, endogenous d-serine is important for maintaining proper dendritic spine density and dendritic arborization of excitatory neurons and promotes the proliferation and survival of adult-born hippocampal neurons41,71,72,73,74,75,76. Preclinical studies indicate that d-serine or DCS administration can normalize behaviors used as models for anxiety and depression, as well as social memory and social interaction deficits, in genetic and pharmacologic rodent models77,78,79,80. It should be noted that small clinical studies suggest that NMDAR antagonism either with ketamine81,82 or Ifenprodil (GluN2B-specififc)83,84 had beneficial effects in treating depressive symptoms in PTSD patients and flashbacks of adolescent female PTSD patients with a history of abuse, respectively, through undefined mechanisms. Furthermore, the role of d-serine in neuroplasticity would presumably be beneficial to PTSD patients given that in rodents, stress, a key environmental risk factor for PTSD, reduces hippocampal volume, adult neurogenesis, dendritic complexity, and spine density85. These findings in rodents comport with neuroimaging studies demonstrating that patients with PTSD have reduced volumes of the hippocampal and prefrontal brain regions30,86,87. Finally, clinical studies demonstrate that GMS agonists, including d-serine, can improve cognition in healthy participants and patients with neuropsychiatric disorders88,89,90,91. It should be noted that the majority of these clinical studies had small sample sizes and included subjects primarily with schizophrenia, PTSD, or dementia. However, these proof-of-concept clinical trials do provide evidence supporting the use of NMDAR GMS agonists to improve mood and cognition.

d-Serine metabolism, uptake, and release

d-Serine production and localization

d-Serine synthesis is carried out by SR, which catalyzes the racemization of l-serine into d-serine92. A distinctive feature of SR is the catalysis of a parallel reaction consisting of the α, β-elimination of water from l-serine and production of pyruvate and ammonia, suggesting that SR also has a catabolic function93. d-Serine and SR were initially thought to be exclusively present in astrocytes, leading to a series of studies that investigated the effects of “glial” d-serine40,94,95. However, as recently reviewed in detail96,97, studies purporting d-serine as a “gliotransmitter” lack the proper controls to ensure that the effects observed in NMDAR physiology are due to glial d-serine, such as the use of cell-selective SR-KO mice. The generation of more selective antibodies to SR and better techniques to detect d-serine98, along with the use of SR-KO mice as controls for immunostaining35,99,100 demonstrated that SR is preferentially expressed in neurons and d-serine having a neuronal origin. Cell-selective deletion of SR indicates that glutamatergic neurons are the primary site of d-serine synthesis99,101, whereas the deletion of SR from astroglia had little effect on brain d-serine99. NMDAR-dependent hippocampal plasticity is impaired in vitro and in vivo by the elimination of SR from glutamatergic neurons, while the deletion of astrocytic SR had no effect, indicating that astrocytic d-serine does not play a role in synaptic plasticity under normal conditions99,102.

The serine shuttle

A constant supply of l-serine is critical for d-serine synthesis, as the intracellular levels of l-serine (~1 mM) are one order of magnitude below the apparent affinity of SR to l-serine93. Although l-serine is a non-essential amino acid, most brain l-serine is synthesized from the glycolytic intermediate 3-phosphoglycerate by the sequential actions of three astrocyte-specific enzymes, phosphoglycerate dehydrogenase (Phgdh), phosphoserine aminotransferase 1 (Psat-1), and phosphoserine phosphatase (Psph)103. Mutations in Phgdh, the committed step in astrocytic l-serine biosynthesis, cause microcephaly and severe neurodevelopmental deficits in humans attributable to deficits in brain l-serine104,105. In agreement with human genetic studies, the astrocytic knockout of Phgdh decreases brain l-serine and d-serine in mice106. This is associated with a decrease in the neuronal staining of d-serine100, suggesting the existence of a “serine shuttle”, whereby astrocytic l-serine shuttles to neurons to sustain neuronal synthesis of d-serine (Fig. 1b). Pharmacological inhibition of Phgdh in acute brain slices impairs NMDAR-dependent hippocampal functional plasticity, without changing basal neurotransmission101, supporting the notion that the serine shuttle is essential for NMDAR activation107.

The ASCT1 (Slc1a4) transporter mediates the export of l-serine and other neutral amino acids from astrocytes69,108. Mice with targeted deletion of ASCT1 have lower brain d-serine, associated with a reduction in hippocampal volume, impairments in spatial memory, and motor dysfunction69. Similar to patients with mutations in Phgdh, children with loss-of-function mutations in ASCT1 display microcephaly and severe neurodevelopmental deficits109,110,111, highlighting the role of astrocytic l-serine in neurodevelopment.

Hitherto unidentified transporters mediate the uptake of astrocyte-derived l-serine in neurons. Possible candidates include the Asc-1 (Slc7a10) neutral amino acid antiporter112, system A (Slc38 family) transporters113, or system L (Slc7 family) antiporters with broad specificity to zwitterionic amino acids114. Once synthesized by SR, neuronal d-serine is released, at least in part, through Asc-1, which mediates d-serine efflux by exchange with extracellular neutral amino acids and/or facilitated diffusion115,116. Targeted deletion or pharmacological inhibition of Asc-1 decreases the extracellular levels of d-serine117 and impairs NMDAR-dependent synaptic plasticity in hippocampal Schaffer collaterals-CA1 synapses116. Conversely, activation of the Asc-1 antiporter by increasing the levels of extracellular Asc-1 substrates enhances the d-serine release and promotes NMDAR synaptic activation115. Asc-1 also uses glycine as substrate. Asc-1-KO mice display lower brain glycine and hyperekplexia due to the impairment of glycinergic inhibitory transmission that is preventable by administering glycine to the mice112. These observations indicate that increasing the hetero-exchange activity of Asc-1 by selective substrates provides a strategy to increase the availability of NMDAR co-agonists.

Regulation of d-serine production at the postsynaptic site

Different from classical transmitters, d-serine appears to be mainly produced at postsynaptic sites. Subcellular fractionation demonstrated co-purification of SR with detergent-resistant postsynaptic density membranes118. SR is localized to neurons34,35, where it is enriched at dendritic spines74. Furthermore, SR contains a PDZ binding region at its C-terminus and associates with several postsynaptic-enriched proteins, such as glutamate receptor interacting protein 1 (Grip-1)119, discs large MAGUK scaffold protein 3 (SAP-102)120, stargazin120, discs large MAGUK scaffold protein 4 (PSD-95)74,120, Disrupted in schizophrenia 1 (DISC1)121, and protein interacting with PRKCA 1 (PICK1)122. The proximity of SR to the postsynaptic sites provides a mechanism for local activation of synaptic NMDARs. Partial saturation of synaptic NMDARs by tonic d-serine release would allow immediate activation of NMDARs upon glutamate binding.

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) stimulation has indirect effects on SR activity. In vitro evidence suggests that SR forms a quaternary complex with PSD-95, stargazin, and AMPARs, which partially inhibits the synthesis of d-serine. AMPAR activation leads to the dissociation of SR from stargazin and increases SR activity, providing a crosstalk between AMPAR and NMDAR activities that may play a role in synaptic homeostasis120.

NMDAR activation leads to a cascade of events that inhibits SR activity by different mechanisms, providing a feedback regulation of NMDAR activity. NMDAR activation triggers the production of nitric oxide (NO) by nitric oxide synthase, leading to the S-nitrosylation of SR and inhibition of d-serine synthesis123. NMDAR stimulation also elicits the translocation of SR from the cytosol to membranes and the cell nucleus, where the enzyme is mostly inactive118,124. Feedback inhibition of SR likely serves to prevent NMDAR neurotoxicity under situations of increased neuronal activity. Conversely, blockade of NMDARs by chronic MK-801 administration increases SR expression in the brain125, providing another connection between NMDAR activity and d-serine production.

SR levels are also regulated by the proteasomal system126. DISC1 binds to and stabilizes SR by decreasing its degradation through the proteasome121. DISC1 truncation segregates with schizophrenia and other psychiatric conditions in a Scottish family127. Mice expressing mutant DISC1 exhibit lower SR and d-serine levels that are associated with behavioral alterations121. In addition to feedback regulation, SR is strongly inhibited by glycine, which competes with l-serine for binding to SR128,129. Injection of glycine leads to a decrease in the extracellular levels of d-serine in vivo, indicating their metabolism is connected101. Inhibition of SR by glycine ensures that little d-serine will be produced in the brainstem and spinal cord, where glycine is the major inhibitory neurotransmitter130. Glycine also regulates d-serine metabolism by affecting the efficiency of d-serine transport. Like d-serine, glycine is a high-affinity substrate of the Asc-1 transporter, and it enhances the release of d-serine via Asc-1 by amino acid hetero-exchange101. The dual role of glycine in regulating d-serine metabolism is puzzling, and their regional variation and distinct half-lives provide a plethora of mechanisms to fine-tune NMDAR activity.

d-Serine catabolism

In the forebrain, d-serine has a half-life of 16.9 h131, indicating slow metabolism. In comparison, metabolic labeling indicates that GABA and glutamate half-lives are around 30 min132. Although d-serine can be degraded by d-amino acid oxidase (DAO) in peroxisomes, this enzyme is mostly restricted to the cerebellum, brainstem, and spinal cord133. Mice expressing a catalytically-inactive DAO enzyme display no changes in cortical d-serine, indicating that DAO does not play a significant metabolic role in the adult forebrain134. Human DAO expression is more widespread in forebrain regions, but the very low affinity for its cofactor FAD suggests this enzyme does not efficiently degrade d-serine in humans135. Another possible catabolic route for d-serine is the SR enzyme itself, which can degrade d-serine into pyruvate and ammonia by the α,β-elimination reaction93. However, although this pathway can play a role in limiting the build-up of d-serine in forebrain regions, the rate of conversion of l-serine into d-serine is faster than the α,β-elimination with d-serine136, indicating that the d-serine synthesis is the preferential reaction of SR.

Transport mechanisms to remove d-serine from the synapse are not as efficient as with classical transmitters. d-serine reuptake systems are not stereoselective and display only moderate to low-affinity for the d-enantiomer137. Therefore, we predict that d-serine will remain at the synapse for prolonged periods of time and will be functionally more effective than glycine, as powerful glycine transporters (e.g., glycine transporter-1; GlyT1), limit glycine access to synaptic NMDARs39,138. In contrast to classical transmitters, neuronal depolarization has only modest effects on d-serine release139. In this framework, we propose that d-serine works as an NMDAR gatekeeper that is tonically released at postsynaptic sites. The selective action of d-serine at NMDARs and its role in regulating behavior provides an opportunity to develop drugs that will gently affect NMDAR function by affecting the basal occupancy of the receptor.

Conclusions and future directions

d-serine is a dynamic gatekeeper of NMDAR function in forebrain regions that are implicated in the pathophysiology of fear and anxiety-related disorders. We highlight the potential utility of d-serine or molecules that augment d-serine availability as a means to enhance extinction learning, as well as improving cognition and mood. The latter strategy could be accomplished by increasing release or blocking reuptake via the aforementioned transporters or inhibiting the breakdown of d-serine by DAO (Table 2). While most of the properties of d-serine metabolism were characterized in the hippocampus and neocortex, it is likely that they are also conserved in the amygdala, as the expression of SR and other components of the serine shuttle are widespread throughout the brain. It will also be useful to test pharmacologic tools that augment d-serine mediated NMDAR-activation using rodent models of impaired extinction, which aim to recapitulate the aberrant extinction learning observed in PTSD patients140. In addition, we propose the novel idea that d-serine is not a pre-synaptically released co-agonist, but a postsynaptically released “autocrine” molecule. Thus, the receptive neuron, not the glutamatergic input, determines NMDAR functionality. We hope this review helps to spur new lines of investigation into the mechanisms that regulate d-serine availability across brain regions and the relative contribution of GMS agonists at NMDARs on excitatory versus inhibitory neurons. We and others have shown strong d-serine immunoreactivity in several classes of GABAergic interneurons in the hippocampus, amygdala, cortex, and striatum33,34,35,74. Little is known about the regulation of SR in inhibitory neurons, but the postsynaptic localization of SR suggests that d-serine could also play an “autocrine” role in activating NMDARs on GABAergic neurons. Such findings could potentially help identify novel therapeutic targets to enhance d-serine mediated NMDAR function. A need for a deeper understanding of d-serine mediated NMDAR activation is highlighted by the modest success of DCS, a partial agonist at the GMS site, in augmenting exposure therapy outcomes in patients with anxiety disorders and PTSD12,141.

Table 2 Putative novel pharmacologic strategies to increase d-serine mediated NMDA receptor transmission as a means to treat anxiety-related disorders.


  1. 1.

    Kessler, R. C. et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593–602 (2005).

    Google Scholar 

  2. 2.

    Jovanovic, T. & Ressler, K. J. How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Am. J. Psychiatry 167, 648–62. (2010).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Milad, M. R. et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol. Psychiatry 66, 1075–82. (2009).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Sheynin, J. & Liberzon, I. Circuit dysregulation and circuit-based treatments in posttraumatic stress disorder. Neurosci. Lett. 649, 133–138 (2017).

    CAS  PubMed  Google Scholar 

  5. 5.

    Fenster, R. J. et al. Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man. Nat. Rev. Neurosci. 19, 535–551 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

    CAS  PubMed  Google Scholar 

  7. 7.

    Janak, P. H. & Tye, K. M. From circuits to behaviour in the amygdala. Nature 517, 284–292 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Tovote, P., Fadok, J. P. & Luthi, A. Neuronal circuits for fear and anxiety. Nat. Rev. Neurosci. 16, 317–31. (2015).

    CAS  PubMed  Google Scholar 

  9. 9.

    Le Bail, M. et al. Identity of the NMDA receptor coagonist is synapse specific and developmentally regulated in the hippocampus. Proc. Natl Acad. Sci. USA 112, E204–E213 (2015).

    PubMed  Google Scholar 

  10. 10.

    Li, Y. et al. Identity of endogenous NMDAR glycine site agonist in amygdala is determined by synaptic activity level. Nat. Commun. 4, 1760 (2013).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Singewald, N. et al. Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharm. Ther. 149, 150–190 (2015).

    CAS  Google Scholar 

  12. 12.

    Mataix-Cols, D. et al. D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant Data. JAMA Psychiatry 74, 501–510 (2017).

    Article  Google Scholar 

  13. 13.

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (ed American Psychiatric Association) (APA Publishing, 2013).

  14. 14.

    Bremner, J. D. et al. Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am. J. Psychiatry 156, 1787–1795 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Lanius, R. A. et al. Neural correlates of traumatic memories in posttraumatic stress disorder: a functional MRI investigation. Am. J. Psychiatry 158, 1920–1922 (2001).

    CAS  PubMed  Google Scholar 

  16. 16.

    Rauch, S. L. et al. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch. Gen. Psychiatry 53, 380–387 (1996).

    CAS  PubMed  Google Scholar 

  17. 17.

    Shin, L. M. et al. Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch. Gen. Psychiatry 61, 168–176 (2004).

    PubMed  Google Scholar 

  18. 18.

    Lanius, R. A. et al. Emotion modulation in PTSD: Clinical and neurobiological evidence for a dissociative subtype. Am. J. Psychiatry 167, 640–647 (2010).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Milad, M. R. & Quirk, G. J. Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev. Psychol. 63, 129–151 (2012).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Rescorla, R. A. & Heth, C. D. Reinstatement of fear to an extinguished conditioned stimulus. J. Exp. Psychol. Anim. Behav. Process 1, 88–96 (1975).

    CAS  PubMed  Google Scholar 

  21. 21.

    Kroes, M. C. et al. Translational approaches targeting reconsolidation. Curr. Top. Behav. Neurosci. 28, 197–230 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Garfinkel, S. N. et al. Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal. J. Neurosci. 34, 13435–43. (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Norrholm, S. D. et al. Fear extinction in traumatized civilians with posttraumatic stress disorder: relation to symptom severity. Biol. Psychiatry 69, 556–563 (2011).

    PubMed  Google Scholar 

  24. 24.

    Rauch, S. L. et al. Selectively reduced regional cortical volumes in post-traumatic stress disorder. Neuroreport 14, 913–916 (2003).

    PubMed  Google Scholar 

  25. 25.

    Stevens, J. S. et al. Disrupted amygdala-prefrontal functional connectivity in civilian women with posttraumatic stress disorder. J. Psychiatr. Res. 47, 1469–1478 (2013).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Phelps, E. A. et al. Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43, 897–905 (2004).

    CAS  PubMed  Google Scholar 

  27. 27.

    Squire, L. R. & Zola-Morgan, S. The medial temporal lobe memory system. Science 253, 1380–1386 (1991).

    CAS  PubMed  Google Scholar 

  28. 28.

    Elzinga, B. M. & Bremner, J. D. Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)? J. Affect Disord. 70, 1–17 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Logue, M. W. et al. Smaller hippocampal volume in posttraumatic stress disorder: a multisite enigma-pgc study: subcortical volumetry results from posttraumatic stress disorder consortia. Biol. Psychiatry 83, 244–253 (2018).

    Google Scholar 

  30. 30.

    Pitman, R. K. et al. Biological studies of post-traumatic stress disorder. Nat. Rev. Neurosci. 13, 769–787 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Bremner, J. D. et al. MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am. J. Psychiatry 160, 924–932 (2003).

    PubMed  Google Scholar 

  32. 32.

    Polak, A. R. et al. The role of executive function in posttraumatic stress disorder: a systematic review. J. Affect Disord. 141, 11–21 (2012).

    PubMed  Google Scholar 

  33. 33.

    Balu, D. T. et al. Serine Racemase and D-serine in the amygdala are dynamically involved in fear learning. Biol. Psychiatry 83, 273–283 (2018).

    CAS  PubMed  Google Scholar 

  34. 34.

    Balu, D. T. et al. D-serine and serine racemase are localized to neurons in the adult mouse and human forebrain. Cell Mol. Neurobiol. 34, 419–435 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Miya, K. et al. Serine racemase is predominantly localized in neurons in mouse brain. J. Comp. Neurol. 510, 641–654 (2008).

    CAS  PubMed  Google Scholar 

  36. 36.

    Greer, P. L. & Greenberg, M. E. From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron 59, 846–860 (2008).

    CAS  PubMed  Google Scholar 

  37. 37.

    Johnson, J. W. & Ascher, P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325, 529–31. (1987).

    CAS  PubMed  Google Scholar 

  38. 38.

    Kleckner, N. W. & Dingledine, R. Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science 241, 835–837 (1988).

    CAS  PubMed  Google Scholar 

  39. 39.

    Bergeron, R. et al. Modulation of N-methyl-D-aspartate receptor function by glycine transport. Proc. Natl Acad. Sci. U.S.A. 95, 15730–15734 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Papouin, T. et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 150, 633–646 (2012).

    CAS  PubMed  Google Scholar 

  41. 41.

    Balu, D. T. et al. Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc. Natl Acad. Sci. U.S.A. 110, E2400–E2409 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Basu, A. C. et al. Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior. Mol. Psychiatry 14, 719–727 (2009).

    CAS  PubMed  Google Scholar 

  43. 43.

    Curcio, L. et al. Reduced D-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity. Brain 136(Pt 4), 1216–30. (2013).

    PubMed  Google Scholar 

  44. 44.

    Fossat, P. et al. Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex. Cereb. cortex 22, 595–606 (2012).

    PubMed  Google Scholar 

  45. 45.

    Amano, T., Unal, C. T. & Pare, D. Synaptic correlates of fear extinction in the amygdala. Nat. Neurosci. 13, 489–494 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Milad, M. R. & Quirk, G. J. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002).

    CAS  PubMed  Google Scholar 

  47. 47.

    Senn, V. et al. Long-range connectivity defines behavioral specificity of amygdala neurons. Neuron 81, 428–437 (2014).

    CAS  Google Scholar 

  48. 48.

    Quirk, G. J. et al. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J. Neurosci. 20, 6225–6231 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Burgos-Robles, A. et al. Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex. Neuron 53, 871–880 (2007).

    CAS  PubMed  Google Scholar 

  50. 50.

    Inoue, R. et al. Dissociated Role of D-Serine in Extinction During Consolidation vs. Reconsolidation of Context Conditioned Fear. Front Mol. Neurosci. 11, 161 (2018).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Matsuda, S. et al. d-serine enhances extinction of auditory cued fear conditioning via ERK1/2 phosphorylation in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 895–902 (2010).

    CAS  PubMed  Google Scholar 

  52. 52.

    Hammond, S. et al. D-Serine facilitates the effectiveness of extinction to reduce drug-primed reinstatement of cocaine-induced conditioned place preference. Neuropharmacology 64, 464–471 (2013).

    CAS  PubMed  Google Scholar 

  53. 53.

    Ebrahimi, C. et al. Augmenting extinction learning with D-cycloserine reduces return of fear: a randomized, placebo-controlled fMRI study. Neuropsychopharmacology 45, 499–506 (2019).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Horio, M., Mori, H. & Hashimoto, K. Is D-cycloserine a prodrug for D-serine in the brain? Biol. Psychiatry 73, e33–e34 (2013).

    CAS  PubMed  Google Scholar 

  55. 55.

    Shimasaki, A. et al. A genetic variant in 12q13, a possible risk factor for bipolar disorder, is associated with depressive state, accounting for stressful life events. PLoS One 9, e115135 (2014).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Van der Auwera, S. et al. The inverse link between genetic risk for schizophrenia and migraine through NMDA (N-methyl-D-aspartate) receptor activation via D-serine. Eur. Neuropsychopharmacol. 26, 1507–1515 (2016).

    PubMed  Google Scholar 

  57. 57.

    Zhang, S. et al. Association of serine racemase gene variants with type 2 diabetes in the Chinese Han population. J. Diabetes Investig. 5, 286–289 (2014).

    CAS  PubMed  Google Scholar 

  58. 58.

    Andero, R. et al. Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. Sci. Transl. Med. 5, 188ra73 (2013).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Gillespie, C. F. et al. Trauma exposure and stress-related disorders in inner city primary care patients. Gen. Hosp. Psychiatry 31, 505–14. (2009).

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Craske, M. G., Hermans, D. & Vervliet, B. State-of-the-art and future directions for extinction as a translational model for fear and anxiety. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 373, 20170025 (2018).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Otto, M. W. et al. Enhancement of psychosocial treatment with d-cycloserine: models, moderators, and future directions. Biol. Psychiatry 80, 274–283 (2016).

    CAS  Google Scholar 

  62. 62.

    Radulovic, J., Ren, L. Y. & Gao, C. N-Methyl D-aspartate receptor subunit signaling in fear extinction. Psychopharmacology 236, 239–250 (2019).

    CAS  PubMed  Google Scholar 

  63. 63.

    Morgan, C. J. & Curran, H. V. Acute and chronic effects of ketamine upon human memory: a review. Psychopharmacology 188, 408–424 (2006).

    CAS  PubMed  Google Scholar 

  64. 64.

    LeDoux, J. E. et al. The birth, death and resurrection of avoidance: a reconceptualization of a troubled paradigm. Mol. Psychiatry 22, 24–36 (2017).

    CAS  Google Scholar 

  65. 65.

    Choi, J. S., Cain, C. K. & LeDoux, J. E. The role of amygdala nuclei in the expression of auditory signaled two-way active avoidance in rats. Learn Mem. 17, 139–147 (2010).

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Fiorenza, N. G. et al. Modulation of the extinction of two different fear-motivated tasks in three distinct brain areas. Behav. Brain Res. 232, 210–216 (2012).

    CAS  PubMed  Google Scholar 

  67. 67.

    Bai, Y. et al. D-serine enhances fear extinction by increasing GluA2-containing AMPA receptor endocytosis. Behav. Brain Res. 270, 223–227 (2014).

    CAS  PubMed  Google Scholar 

  68. 68.

    DeVito, L. M. et al. Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology. Genes Brain Behav. 10, 210–22. (2011).

    CAS  PubMed  Google Scholar 

  69. 69.

    Kaplan, E. et al. ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d-serine and neurodevelopment. Proc. Natl Acad. Sci. U.S.A. 115, 9628–9633 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Balu, D. T. et al. An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia. Neuropsychopharmacology 41, 2052–2061 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Balu, D. T. et al. The NMDA receptor co-agonists, d-serine and glycine, regulate neuronal dendritic architecture in the somatosensory cortex. Neurobiol. Dis. 45, 671–682 (2012).

    CAS  PubMed  Google Scholar 

  72. 72.

    Balu, D. T. & Coyle, J. T. Neuronal d-serine regulates dendritic architecture in the somatosensory cortex. Neurosci. Lett. 517, 77–81 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Balu, D. T. & Coyle, J. T. Chronic D-serine reverses arc expression and partially rescues dendritic abnormalities in a mouse model of NMDA receptor hypofunction. Neurochem. Int. 75C, 76–78 (2014).

    Google Scholar 

  74. 74.

    Lin, H. et al. D-Serine and Serine Racemase Are Associated with PSD-95 and Glutamatergic Synapse Stability. Front. Cell Neurosci. 10, 34 (2016).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Sultan, S. et al. D-serine increases adult hippocampal neurogenesis. Front. Neurosci. 7, 155 (2013).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Sultan, S. et al. Synaptic integration of adult-born hippocampal neurons is locally controlled by astrocytes. Neuron 88, 957–972 (2015).

    CAS  PubMed  Google Scholar 

  77. 77.

    Terrillion, C. E. et al. DISC1 in astrocytes influences adult neurogenesis and hippocampus-dependent behaviors in mice. Neuropsychopharmacology 42, 2242–2251 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Zoicas, I. & Kornhuber, J. The role of the N-methyl-D-aspartate receptors in social behavior in rodents. Int. J. Mol. Sci. 20, 22 (2019).

    Google Scholar 

  79. 79.

    Malkesman, O. et al. Acute D-serine treatment produces antidepressant-like effects in rodents. Int. J. Neuropsychopharmacol. 15, 1135–1148 (2012).

    CAS  PubMed  Google Scholar 

  80. 80.

    Wang, J. et al. Epigenetic activation of ASCT2 in the hippocampus contributes to depression-like behavior by regulating D-serine in mice. Front. Mol. Neurosci. 10, 139 (2017).

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Feder, A. et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry 71, 681–688 (2014).

    CAS  PubMed  Google Scholar 

  82. 82.

    Hartberg, J., Garrett-Walcott, S. & De Gioannis, A. Impact of oral ketamine augmentation on hospital admissions in treatment-resistant depression and PTSD: a retrospective study. Psychopharmacology 235, 393–398 (2018).

    CAS  PubMed  Google Scholar 

  83. 83.

    Kishimoto, A. et al. Ifenprodil for the treatment of flashbacks in female posttraumatic stress disorder patients with a history of childhood sexual abuse. Biol. Psychiatry 71, e7–e8 (2012).

    PubMed  Google Scholar 

  84. 84.

    Sasaki, T. et al. Ifenprodil for the treatment of flashbacks in adolescent female posttraumatic stress disorder patients with a history of abuse. Psychother. Psychosom. 82, 344–345 (2013).

    PubMed  Google Scholar 

  85. 85.

    McEwen, B. S., Nasca, C. & Gray, J. D. Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 41, 3–23 (2016).

    CAS  PubMed  Google Scholar 

  86. 86.

    Kremen, W. S. et al. Twin studies of posttraumatic stress disorder: differentiating vulnerability factors from sequelae. Neuropharmacology 62, 647–653 (2012).

    CAS  PubMed  Google Scholar 

  87. 87.

    Woon, F. L., Sood, S. & Hedges, D. W. Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 1181–1188 (2010).

    PubMed  Google Scholar 

  88. 88.

    Peyrovian, B. et al. The glycine site of NMDA receptors: A target for cognitive enhancement in psychiatric disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 92, 387–404 (2019).

    CAS  PubMed  Google Scholar 

  89. 89.

    Heresco-Levy, U. et al. Pilot controlled trial of D-serine for the treatment of post-traumatic stress disorder. Int J. Neuropsychopharmacol. 12, 1275–1282 (2009).

    CAS  PubMed  Google Scholar 

  90. 90.

    Hashimoto, K. Genomic triplication of the glycine decarboxylase gene and N-methyl-d-aspartate receptor hypofunction: improvement by glycine and D-cycloserine. Biol. Psychiatry 86, 497–498 (2019).

    CAS  PubMed  Google Scholar 

  91. 91.

    Bodkin, J. A. et al. Targeted treatment of individuals with psychosis carrying a copy number variant containing a genomic triplication of the glycine decarboxylase gene. Biol. Psychiatry 86, 523–535 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Wolosker, H. et al. Purification of serine racemase: biosynthesis of the neuromodulator D- serine. Proc. Natl Acad. Sci. U.S.A. 96, 721–725 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Foltyn, V. N. et al. Serine racemase modulates intracellular D-serine levels through an alpha,beta-elimination activity. J. Biol. Chem. 280, 1754–1763 (2005).

    CAS  PubMed  Google Scholar 

  94. 94.

    Panatier, A. et al. Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 125, 775–784 (2006).

    CAS  PubMed  Google Scholar 

  95. 95.

    Henneberger, C. et al. Long-term potentiation depends on release of D-serine from astrocytes. Nature 463, 232–236 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Wolosker, H., Balu, D. T. & Coyle, J. T. The rise and fall of the D-serine-mediated gliotransmission hypothesis. Trends Neurosci. 39, 712–721 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Wolosker, H., Balu, D. T. & Coyle, J. T. Astroglial versus neuronal d-serine: check your controls! Trends Neurosci. 40, 520–522 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Kartvelishvily, E. et al. Neuron-derived D-serine release provides a novel means to activate N-methyl-D-aspartate receptors. J. Biol. Chem. 281, 14151–62. (2006).

    CAS  PubMed  Google Scholar 

  99. 99.

    Benneyworth, M. A. et al. Cell selective conditional null mutations of serine racemase demonstrate a predominate localization in cortical glutamatergic neurons. Cell Mol. Neurobiol. 32, 613–624 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Ehmsen, J. T. et al. D-serine in glia and neurons derives from 3-phosphoglycerate dehydrogenase. J. Neurosci.: Off. J. Soc. Neurosci. 33, 12464–12469 (2013).

    CAS  Google Scholar 

  101. 101.

    Neame, S. et al. The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. Proc. Natl Acad. Sci. U.S.A. 116, 20736–20742 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Perez, E. J. et al. Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury. J. Clin. Investig. 127, 3114–3125 (2017).

    PubMed  Google Scholar 

  103. 103.

    Yamasaki, M. et al. 3-Phosphoglycerate dehydrogenase, a key enzyme for l-serine biosynthesis, is preferentially expressed in the radial glia/astrocyte lineage and olfactory ensheathing glia in the mouse brain. J. Neurosci. 21, 7691–7704 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    de Koning, T. J. et al. Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency. Lancet 364, 2221–2222 (2004).

    PubMed  Google Scholar 

  105. 105.

    Tabatabaie, L. et al. L-serine synthesis in the central nervous system: a review on serine deficiency disorders. Mol. Genet. Metab. 99, 256–262 (2010).

    CAS  PubMed  Google Scholar 

  106. 106.

    Yang, J. H. et al. Brain-specific Phgdh deletion reveals a pivotal role for L-serine biosynthesis in controlling the level of D-serine, an N-methyl-D-aspartate receptor co-agonist, in adult brain. J. Biol. Chem. 285, 41380–90. (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Wolosker, H. & Radzishevsky, I. The serine shuttle between glia and neurons: Implications for neurotransmission and neurodegeneration. Biochem. Soc. Trans. 41, 1546–1550 (2013).

    CAS  PubMed  Google Scholar 

  108. 108.

    Sakai, K. et al. Neutral amino acid transporter ASCT1 is preferentially expressed in L-Ser-synthetic/storing glial cells in the mouse brain with transient expression in developing capillaries. The. J. Neurosci.: Off. J. Soc. Neurosci. 23, 550–560 (2003).

    CAS  Google Scholar 

  109. 109.

    Heimer, G. et al. SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum. Clin. Genet. 88, 327–35. (2015).

    CAS  PubMed  Google Scholar 

  110. 110.

    Srour, M. et al. A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly. Clin. Genet. 88, e1–e4 (2015).

    CAS  PubMed  Google Scholar 

  111. 111.

    Damseh, N. et al. Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination. J. Med. Genet. 52, 541–547 (2015).

    CAS  PubMed  Google Scholar 

  112. 112.

    Safory, H. et al. The alanine-serine-cysteine-1 (Asc-1) transporter controls glycine levels in the brain and is required for glycinergic inhibitory transmission. EMBO Rep. 16, 590–598 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Broer, S. The SLC38 family of sodium-amino acid co-transporters. Pflug. Arch. Eur. J. Physiol. 466, 155–172 (2014).

    CAS  Google Scholar 

  114. 114.

    Pineda, M. et al. Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J. Biol. Chem. 274, 19738–44. (1999).

    CAS  PubMed  Google Scholar 

  115. 115.

    Rosenberg, D. et al. Neuronal D-serine and glycine release via the Asc-1 transporter regulates NMDA receptor-dependent synaptic activity. The. J. Neurosci. 33, 3533–44. (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Sason, H. et al. Asc-1 transporter regulation of synaptic activity via the tonic release of d-serine in the forebrain. Cereb. Cortex 27, 1573–1587 (2017).

    PubMed  Google Scholar 

  117. 117.

    Sakimura, K. et al. A novel Na(+) -Independent alanine-serine-cysteine transporter 1 inhibitor inhibits both influx and efflux of D-Serine. J. Neurosci. Res. 94, 888–895 (2016).

    CAS  PubMed  Google Scholar 

  118. 118.

    Balan, L. et al. Feedback inactivation of D-serine synthesis by NMDA receptor-elicited translocation of serine racemase to the membrane. Proc. Natl Acad. Sci. U.S.A. 106, 7589–7594 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Kim, P. M. et al. Serine racemase: activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration. Proc. Natl Acad. Sci. U.S.A. 102, 2105–2110 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Ma, T. M. et al. Serine racemase regulated by binding to stargazin and PSD-95: potential N-methyl-D-aspartate-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (NMDA-AMPA) glutamate neurotransmission cross-talk. The. J. Biol. Chem. 289, 29631–29641 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Ma, T. M. et al. Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion. Mol. Psychiatry 18, 557–567 (2012).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Hikida, T. et al. Modulation of d-Serine Levels in Brains of Mice Lacking PICK1. Biol. Psychiatry 63, 997–1000 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Mustafa, A. K. et al. Nitric oxide S-nitrosylates serine racemase, mediating feedback inhibition of D-serine formation. Proc. Natl Acad. Sci. U.S.A. 104, 2950–2955 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Kolodney, G. et al. Nuclear compartmentalization of serine racemase regulates d-serine production: IMPLICATIONS FOR N-METHYL-d-ASPARTATE (NMDA) RECEPTOR ACTIVATION. The. J. Biol. Chem. 290, 31037–31050 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Hashimoto, A. et al. Effects of MK-801 on the expression of serine racemase and d-amino acid oxidase mRNAs and on the D-serine levels in rat brain. Eur. J. Pharm. 555, 17–22 (2007).

    CAS  Google Scholar 

  126. 126.

    Dumin, E. et al. Modulation of D-serine levels via ubiquitin-dependent proteasomal degradation of serine racemase. J. Biol. Chem. 281, 20291–20302 (2006).

    CAS  PubMed  Google Scholar 

  127. 127.

    Millar, J. K. et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 9, 1415–1423 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Dunlop, D. S. & Neidle, A. Regulation of serine racemase activity by amino acids. Brain Res. Mol. Brain Res. 133, 208–14. (2005).

    CAS  PubMed  Google Scholar 

  129. 129.

    Marchetti, M. et al. ATP binding to human serine racemase is cooperative and modulated by glycine. FEBS J. 280, 5853–5863 (2013).

    CAS  PubMed  Google Scholar 

  130. 130.

    Betz, H. et al. Structure and functions of inhibitory and excitatory glycine receptors. Ann. N. Y Acad. Sci. 868, 667–76. (1999).

    CAS  PubMed  Google Scholar 

  131. 131.

    Dunlop, D. S. & Neidle, A. The origin and turnover of D-serine in brain. Biochem. Biophys. Res. Commun. 235, 26–30 (1997).

    CAS  PubMed  Google Scholar 

  132. 132.

    Patel, A. B. et al. Comparison of Glutamate Turnover in Nerve Terminals and Brain Tissue During [1,6-(13)C2] Glucose Metabolism in Anesthetized Rats. Neurochem. Res. 42, 173–190 (2017).

    PubMed  Google Scholar 

  133. 133.

    Horiike, K. et al. D-amino-acid oxidase is confined to the lower brain stem and cerebellum in rat brain: regional differentiation of astrocytes. Brain Res. 652, 297–303 (1994).

    CAS  PubMed  Google Scholar 

  134. 134.

    Hashimoto, A. et al. Free D-serine, D-aspartate and D-alanine in central nervous system and serum in mutant mice lacking D-amino acid oxidase. Neurosci. Lett. 152, 33–36 (1993).

    CAS  PubMed  Google Scholar 

  135. 135.

    Sacchi, S. et al. Structure-function relationships in human D-amino acid oxidase. Amino Acids 43, 1833–1850 (2012).

    CAS  PubMed  Google Scholar 

  136. 136.

    Strisovsky, K. et al. Dual substrate and reaction specificity in mouse serine racemase: identification of high-affinity dicarboxylate substrate and inhibitors and analysis of the beta-eliminase activity. Biochemistry 44, 13091–100. (2005).

    CAS  PubMed  Google Scholar 

  137. 137.

    Wolosker, H. The Neurobiology of d-Serine Signaling. Adv. Pharm. 82, 325–348 (2018).

    CAS  Google Scholar 

  138. 138.

    Berger, A. J., Dieudonne, S. & Ascher, P. Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J. Neurophysiol. 80, 3336–3340 (1998).

    CAS  PubMed  Google Scholar 

  139. 139.

    Rosenberg, D. et al. Neuronal release of D-serine: a physiological pathway controlling extracellular D-serine concentration. Faseb J. 24, 2951–61. (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Singewald, N. & Holmes, A. Rodent models of impaired fear extinction. Psychopharmacology 236, 21–32 (2019).

    CAS  Google Scholar 

  141. 141.

    Rosenfield, D. et al. Changes in dosing and dose timing of d-cycloserine explain its apparent declining efficacy for augmenting exposure therapy for anxiety-related disorders: an individual participant-data meta-analysis. J. Anxiety Disord. 68, 102149 (2019).

    PubMed  Google Scholar 

  142. 142.

    Miserendino, M. J. et al. Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature 345, 716–718 (1990).

    CAS  Google Scholar 

  143. 143.

    Wolosker, H., Blackshaw, S. & Snyder, S. H. Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc. Natl Acad. Sci. U.S.A. 96, 13409–13414 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Rodrigues, S. M., Schafe, G. E. & LeDoux, J. E. Intra-amygdala blockade of the NR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning. J. Neurosci. 21, 6889–96. (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Walker, D. L. et al. Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J. Neurosci. 22, 2343–2351 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Ressler, K. J. et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch. Gen. Psychiatry 61, 1136–1144 (2004).

    PubMed  Google Scholar 

  147. 147.

    Rosenberg, D. et al. Neuronal D-serine and glycine release via the Asc-1 transporter regulates NMDA receptor-dependent synaptic activity. J. Neurosci. 33, 3533–44. (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Lane, H. Y. et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry 70, 1267–1275 (2013).

    CAS  PubMed  Google Scholar 

  149. 149.

    Lin, C. H. et al. Sodium benzoate, a D-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: a randomized, double-blind, placebo-controlled Trial. Biol. Psychiatry 84, 422–432 (2018).

    CAS  PubMed  Google Scholar 

  150. 150.

    Szilagyi, B. et al. Discovery of isatin and 1H-indazol-3-ol derivatives as d-amino acid oxidase (DAAO) inhibitors. Bioorg. Med. Chem. 26, 1579–1587 (2018).

    CAS  PubMed  Google Scholar 

  151. 151.

    Graham, D. L. et al. Human serine racemase: key residues/active site motifs and their relation to enzyme function. Front. Mol. Biosci. 6, 8 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


This work was supported by the Whitehall Foundation (#2018-05-107), BrightFocus Foundation (A2019034S), 1R03AG063201-01 (NIA), and a subcontract of R01NS098740-02 to DTB, as well a grant from Israel Science Foundation (337/19) and the Allen and Jewell Prince Center for Neurodegenerative Diseases to H.W. We thank Joseph T. Coyle M.D. for critical reading and helpful comments on topics discussed in this manuscript.

Author information



Corresponding author

Correspondence to Darrick T. Balu.

Ethics declarations

Conflict of interest

D.T.B. served as a consultant for LifeSci Capital and received research support from Takeda Pharmaceuticals. H.W. reports no biomedical financial interests or potential conflicts of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wolosker, H., Balu, D.T. d-Serine as the gatekeeper of NMDA receptor activity: implications for the pharmacologic management of anxiety disorders. Transl Psychiatry 10, 184 (2020).

Download citation

Further reading


Quick links