Advances in PsychiatryVolume 2014 (2014), Article ID 859735, 16 pageshttp://dx.doi.org/10.1155/2014/859735

Review Article

D-Serine in Neuropsychiatric Disorders: New Advances

Andrea R. Durrant¹ and Uriel Heresco-Levy1,2

¹Research and Psychiatry Departments, Ezrath Nashim-Herzog Memorial Hospital, P.O. Box 3900, 91035 Jerusalem, Israel²Hadassah Medical School, Hebrew University, Jerusalem, Israel

Received 2 February 2014; Accepted 17 April 2014; Published 19 June 2014

Academic Editor: Raphael J. Braga

Copyright © 2014 Andrea R. Durrant and Uriel Heresco-Levy. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

D-Serine (DSR) is an endogenous amino acid involved in glia-synapse interactions that has unique neurotransmitter characteristics. DSR acts as obligatory coagonist at the glycine site associated with the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) and has a cardinal modulatory role in major NMDAR-dependent processes including NMDAR-mediated neurotransmission, neurotoxicity, synaptic plasticity, and cell migration. Since either over- or underfunction of NMDARs may be involved in the pathophysiology of neuropsychiatric disorders; the pharmacological manipulation of DSR signaling represents a major drug development target. A first generation of proof-of-concept animal and clinical studies suggest beneficial DSR effects in treatment-refractory schizophrenia, movement, depression, and anxiety disorders and for the improvement of cognitive performance. A related developing pharmacological strategy is the indirect modification of DSR synaptic levels by use of compounds that alter the function of main enzymes responsible for DSR production and degradation. Accumulating data indicate that, during the next decade, we will witness important advances in the understanding of DSR role that will further contribute to elucidating the causes of neuropsychiatric disorders and will be instrumental in the development of innovative treatments.

1. Introduction

Although the enzyme D-amino-acid oxidase (DAAO) has been identified in higher organisms in 1935 [1], historically, D-amino acids were thought to be absent in mammalian tissue. This dogma was revolutionized at the beginning of 1990’s when it was found that abundant quantities of free D-serine (DSR) occur in the mammalian brain, at concentrations comparable with those of classical neurotransmitters and higher than those of most essential amino acids [2, 3]. Presently, DSR is considered the most biologically active D-amino acid described in mammalian systems [4]. Phylogenetically, its concentrations appear to be extremely low in the brains of fish, amphibians, and birds, suggesting that endogenous DSR is specifically maintained at high levels in the mammalian brain among vertebrates [5].

In the late 1990s, it was demonstrated that DSR is an obligatory endogenous coagonist of the N-methyl-D-aspartate receptor (NMDAR), functioning in vivo as a specific and potent full agonist at the NMDAR-associated glycine (GLY) modulatory site (GMS). The NMDAR subtype of glutamate (GLU) receptors is widely expressed in the central nervous system (CNS) and has a cardinal role in activity-dependent changes in synaptic strength and connectivity underlying higher brain functions such as memory and learning [6, 7]. Unlike other neurotransmitter receptors, which are activated by individual neurotransmitters, NMDARs activation requires, in addition to the agonist GLU, the binding of a coagonist which was originally thought to be GLY [8, 9]. However, research over the last decade indicates that significant amounts of DSR are produced in the CNS [10–12], where DSR is converted from L-serine by serine racemase (SR) and is degraded by DAAO [11–13]. Furthermore, functional studies demonstrate that DSR represents the physiological ligand for the GMS in different brain areas including cortex and hippocampus [14–18], hypothalamus [19], and the retina [20, 21].

DSR has a cardinal modulatory role in major NMDAR-dependent processes, including NMDAR neurotransmission [22], neurotoxicity [23, 24], synaptic plasticity, [21] and cell migration [25]. Either over- or underfunction of NMDAR neurotransmission may elicit neurotoxicity, leading to behavioral and cognitive dysfunction. NMDAR hyperactivity can cause cell death mediated by excitotoxic calcium overload [26, 27] in stroke and neurodegenerative disorders such as Alzheimer’s disease (AD) [28, 29]. By contrast, synaptic NMDAR hypoactivity leads to apoptosis [30, 31] and may contribute to the generation of psychotic symptoms and cognitive deficits. The long standing paradox that NMDARs can both promote neuronal health and kill neurons [32] highlights the importance of a strictly regulated optimal NMDAR function. Within this context, DSR modulation appears to play a critical role in the achievement of balanced NMDAR activity. Furthermore, compelling evidence suggests that dysfunctional DSR signaling may be involved in the pathophysiology of neuropsychiatry disorders.

2. D-Serine Neurobiology: An Overview

Despite notable progress in the 20 years since DSR was first identified, many aspects of DSR neurobiology remain enigmatic and are presently the focus of intense research. In contrast to classic neurotransmitters, DSR was originally shown to be exclusively produced and released from astrocytes via a vesicular release mechanism [33–35]. However, although glial DSR is prominent, DSR presence was subsequently identified in neurons as well [23]. Some studies have found DSR in most or in a subset of neurons in the cerebral cortex [36], whereas others observed DSR mainly in hindbrain neurons [37, 38]. Recent data indicate that DSR is predominantly expressed in glutamatergic neurons further challenging the notion that DSR is exclusively released from astrocytes [23, 39–41]. Furthermore, it was reported that neurons robustly release endogenous DSR [42] and that neuronal DSR release via the amino acid transporter Asc-1 enhances NMDAR potentials and long term potentiation (LTP), a cellular mechanism that underlies learning and memory [43]. The presence of DSR in neurons led to an updated DSR signaling model (rev. in [34, 44]) which incorporates the release and uptake of DSR from both neurons and astrocytes (see Figure 1). This model emphasizes DSR role in the neuron-glia cross-talk relevant to NMDAR function modulation and allows for conceivably distinct roles of glial and neuronal DSR in both physiological and disturbed NMDAR function.

Figure 1: Schematic diagram of D-serine signaling at a glutamatergic synapse. NMDARsyn and NMDARexsyn = synaptic and extrasynaptic N-methyl-D-aspartate receptor; GMS = Glycine modulatory site; GLU = L-glutamate binding site; SR = serine racemase; ASC 1 and ASCT 2 = neutral amino acid transporters; DAAO = D-amino-acid oxidase; αKa = alpha-Keto acid; NH₃ = ammonia; H₂O₂ = hydrogen peroxide.

NMDAR is a tetramer composed of two NR1 subunits and two NR2 subunits or less commonly two NR3 subunits. NMDAR activation requires the binding of either GLY or DSR at the GMS on the NR1 subunit [45, 46]. DSR is enriched in corticolimbic regions of the brain where its localization closely parallels that of NMDARs [46] and is thought to be the primary forebrain NMDAR coagonist. SR is considered the primary endogenous source of DSR (using L-serine as a substrate), while DAAO is generally regarded as its primary mechanism of degradation. This view is however confounded by the fact that SR also degrades both DSR and L-serine irreversibly to pyruvate and ammonia, appearing thus to provide a bidirectional regulation of free serine levels in vivo [4]. Synaptic DSR is taken up into glia and neurons differentially via Asc-1 and ASCT-2 transporters and is broken down mainly by peroxisomal DAAO forming the alpha-keto acid (AKA), ammonia, and hydrogen peroxide (Figure 1).

As a physiological coagonist of NMDARs, DSR may play a role in NMDAR-dependent neurodegeneration and can mediate neurotoxicity in primary cultures and hippocampal slices [23, 24]. Selective DSR degradation by DAAO markedly reduces NMDAR neurotransmission in cortical and hippocampal preparations [22, 47]. Moreover, DSR depletion in the medial prefrontal cerebral cortex diminishes NMDAR synaptic potentials and prevents LTP inhibition [48]. Recent data suggests that DSR release from astrocytes controls NMDAR-dependent plasticity and LTP in many thousands of excitatory synapses nearby [49], while in adulthood, neuronally-derived DSR regulates neuronal dendritic architecture in the somatosensory cortex [39].

Although they are both endogenous NMDAR coagonists, GLY and DSR seem to act at distinct receptor populations, with DSR present at synaptic NMDARs and GLY at their extrasynaptic counterparts [47], which may constitute a functionally distinct pool of receptors (rev. in [32, 47]). Synaptic NMDARs are responsible for inducing the most common forms of synaptic plasticity found in the brain, namely, LTP and long-term depression (LTD). Whether specific subsets of synaptic NMDARs mediate LTP or LTD [50–54] and whether extrasynaptic receptors also play a role in these processes [55] are controversial. Extrasynaptic NMDARs contribute to neuronal synchronization [56, 57] but have mostly been implicated in neurodegenerative disorders, including stroke, AD, and Huntington’s disease [58–60]. Recent evidence suggests that synaptic NMDARs are neuroprotective, whereas extrasynaptic receptors may promote cell death [32].

Overall, the complexities involved in the neurobiology of DSR-based signaling in the human brain are expected to further unravel during the coming decade and contribute to the understanding of a novel and complex neurotransmitter system and to the development of innovative pharmacotherapy for neuropsychiatric disorders.

3. D-Serine Therapeutic Potential

NMDARs crucial role in both physiological and pathophysiological processes has generated massive clinical interest in the development of novel pharmacological interventions aiming at NMDAR-related therapeutic targets. Since direct stimulation of NMDAR with GLU or aspartate, agonists of the primary GLU receptor site, is associated with neurotoxicity [68], most of the efforts to date have focused on the GMS. The main compounds directly acting at this site that have been so far assessed in clinical trials include GLY, DSR, and D-cycloserine (DCS), a tuberculostatic antibiotic having also complex agonist/antagonist action at the GMS [69]. In this context, a number of advantages are associated with DSR use, including better blood-brain-barrier penetration and stronger affinity at the GMS versus GLY [70] and, in contrast to DCS, specific and potent full agonist action at this site. Accordingly, during the last two decades, the first proof-of-concept animal and clinical studies have been performed with DSR in the context of neuropsychiatric disorders including schizophrenia, Parkinson’s disease, depression, and anxiety disorders.

3.1. Schizophrenia

Over the last 20 years, glutamatergic models of schizophrenia have become increasingly accepted as etiopathological models of this disorder, mainly based on the observation that the cyclohexylamine “dissociative anesthetics” phencyclidine (PCP) and ketamine induce schizophrenia-like positive and negative symptoms and cognitive deficits by blocking NMDAR neurotransmission (rev. in [66, 71]). The PCP/NMDAR model implies that treatments which aimed at potentiating NMDAR function should be therapeutically beneficial. Furthermore, pharmacological manipulation of DSR signaling represents a particularly attractive candidate strategy since convergent lines of evidence suggest an involvement of dysfunctional DSR transmission in schizophrenia [72–75]. Single polymorphisms for SR and DAAO have been linked to schizophrenia [76–78], in rodents genetic loss of DAAO activity reverses schizophrenia-like phenotypes [79, 80] and reduced DSR serum and cerebrospinal fluid (CSF) levels were documented in chronic schizophrenia patients [81–85]. Moreover, supporting the hypo-NMDAR hypothesis of schizophrenia, DSR selectively blocks PCP-induced hyperactivity and stereotypic behavior [86, 87].

A number of clinical studies [62, 65, 88–90] have demonstrated that adjuvant DSR (30–120 mg/kg/day) added to ongoing treatment with non-clozapine antipsychotics results in significant symptom improvements in chronic schizophrenia patients. The most significant changes were registered in the negative symptom cluster (Figure 2). Nevertheless, two recent meta-analytic reviews indicate that additional dysfunction domains may be affected by DSR. S. P. Singh and V. Singh [91] reported medium effect sizes of DSR for negative symptoms (standardized mean difference (SMD), −0.53) and total symptomatology (SMD, −0.40). Tsai and Lin [92] found DSR effective for negative symptoms (effect size (ES), 0.48), cognitive symptoms (ES, 0.42), and total psychopathology (ES, 0.40).

Figure 2: D-serine effects on negative symptoms in controlled add-on clinical trials with chronic schizophrenia patients. versus placebo; versus placebo; versus baseline.

Two schizophrenia treatment issues stemming from these findings are the potential use of DSR for improving cognition and as stand-alone pharmacotherapy in this disorder. In a preliminary four week open-label study [65], it was shown that high dose DSR (≥60 mg/kg/day) improves neurocognitive functions as measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. An additional controlled pilot investigation [93] compared the effectiveness of DSR (3 g/day) versus high-dose olanzapine (30 mg/day) as antipsychotic monotherapy in 18 treatment-resistant schizophrenia patients. The primary LOCF analysis indicated a lack of efficacy of DSR as compared to high-dose olanzapine (Figure 3). However, DSR was not inferior to the prestudy antipsychotic drug treatment. Furthermore, among the patients who completed the nine study weeks, high dose olanzapine and DSR did not differ in their effectiveness, suggesting that a subgroup of patients may be successfully maintained on DSR.

Figure 3: Positive and Negative Syndrome Scale (PANSS) symptom clusters score changes during monotherapy with high dose olanzapine and D-serine (, d.f. = 1.16, ).

In all clinical trials performed to date with DSR in schizophrenia, no significant adverse events have been observed at doses of ≤4 g/day. A potential concern with DSR use is nephrotoxicity [94, 95] which has been reported in one patient receiving 120 mg/kg/day and resolved following DSR discontinuation [65]. This apparent paucity of side effects seems remarkable in view of the fact that both acute [65, 96] and chronic [62, 88, 93] administration of 1-2 g DSR results in ≥100 times increases in DSR serum levels. Nevertheless, orally administered DSR is substantially metabolized by DAAO diminishing its bioavailability and necessitating the administration of gram level doses. In view of these limitations, the ideal dosage and mode of administration of DSR remain to be determined.

3.2. Parkinsonism, Drug-Induced Dyskinesia, and Parkinson’s Disease

Idiopathic Parkinson’s disease (PD) is an age-dependent neurodegenerative disorder characterized by intertwined motor and behavioral and cognitive dysfunctions. Current pharmacological approaches to PD predominantly target the dopamine system. Although dopaminergic medications are effective, a significant number of patients show continued motor symptoms, drug-induced dyskinesia, and “on/off” phenomena, even during treatment. Furthermore, the treatment of nonmotor symptoms represents an additional major therapeutic challenge in PD. Among these manifestations, apathy and cognitive impairment respond poorly to presently available medications, pose increased management difficulties, and contribute significantly to caregiver burden. An innovative pharmacological approach for PD presently under investigation is the modulation of NMDAR-mediated glutamatergic neurotransmission (rev. in [97]).

We have hypothesized that direct or indirect augmentation of synaptic GLY or DSR levels may represent a novel type of treatment for PD [63]. This line of thought stems mainly from the clinical data obtained in schizophrenia research, indicating GLY and DSR efficacy against negative symptoms (rev. in [91, 92]). To the extent that negative symptoms of schizophrenia overlap with components of the apathy syndrome characteristic of PD (e.g., reduced motivation/initiative/volition and anhedonia) and have similar underlying etiology, that is, prefrontal dopaminergic deficit [98], the beneficial effect of DSR on negative symptoms would predict potential beneficial effects against apathy in PD. Moreover, therapeutic effects of NMDAR agonists are not confined to behavioral symptoms of schizophrenia but extend to motor symptoms as well. Some GLY and DSR schizophrenia clinical trials have included subjects that had significant antipsychotic drugs-induced parkinsonian [62, 64] and tardive dyskinesia [61, 62, 64, 65] symptoms. In these studies, highly significant, large effect size improvements were registered in these symptom domains (Figures 4 and 5). Thus, since GMS agonists affect motor and nonmotor clinical domains that overlap significantly with PD phenomenology, it is hypothesized that NMDAR neurotransmission modulation specifically via DSR administration may represent an innovative treatment approach in PD.

(a)

(b)

Figure 4: Effect of NMDAR-glycine site agonists on extrapyramidal symptoms as reflected in Simpson Angus Scale for Extrapyramidal Symptoms (SAS) change scores. Data are from glycine [61] and D-serine [62] studies. versus placebo. (Reproduced from [63]).

(a)

(b)

Figure 5: Effect of NMDAR-glycine-site agonists on dyskinesia symptoms as reflected in Abnormal Involuntary Movement Scale (AIMS) score. Data are from studies of glycine [61, 64] and D-serine [62, 65]. Across all studies, D-serine treatment led to a highly significant ( = 4.86, d.f. = 192, , d = 0.83) improvement in AIMS scores. (Reproduced from [66]).

This hypothesis accords well with current theories on the role of NMDAR in modulation of brain dopaminergic systems relevant to PD [99]. NMDARs are divided into subtypes based upon the presence of specific modulatory subunits. In adults, NMDARs are primarily of types NR2A and NR2B and research in PD has focused predominantly upon development of NR2B antagonists based upon the observation that dopaminergic denervation leads to specific upregulation of striatal NR2B versus NR2A receptors [100]. Significantly, in animal models, NR2B selective antagonists have proven more effective than nonselective drugs, such as MK-801, that target both NR2A and NR2B receptors [101], indicating that NR2A blockade, in fact, may be deleterious, but that NR2A stimulation might be beneficial. NMDAR subtypes show differing sensitivity to GMS agonists such that NR2B receptors are saturated under physiological conditions, whereas NR2A are not [102]. Thus, GMS agonists may function in vivo as selective NR2A agonists. Consequently, activation of NR2A versus NR2B receptors may restore the balance between NR2A- and NR2B-containing NMDARs similarly to the effects of NR2B antagonists.

We recently addressed the hypothesis that GMS agonists might be beneficial for motor and negative-like symptoms in PD in a 6-week controlled adjuvant treatment trial of DSR (30 mg/day) versus placebo in advanced PD patients (age, years; disease duration, years; Hoehn & Yahr staging II–IV) [67]. The ~2 g/day DSR regimen was well tolerated and resulted in significant reductions in Unified Parkinson’s Disease Rating Scale (UPDRS) and Simpson-Angus Scale for Extrapyramidal Symptoms (SAS) total scores. Five of 10 completers had >20% improvement in total UPDRS scores during DSR treatment versus 1 of 10 subjects during placebo administration ( = 4.07, ). For SAS scores, 7 subjects had >20% improvement during DSR treatment versus 2 during placebo administration ( = 5.3, ) (Figure 6). Significant benefits relative to placebo were also observed in the Positive and Negative Syndrome Scale (PANSS) and in both the motor (III) and mental (I) UPDRS subscales. In view of these novel concepts and findings, additional larger-scale studies are presently warranted to further determine whether motor and nonmotor PD components are significantly affected by GMS modulators.

Figure 6: Subject-by-subject change scores in Simpson Angus Scale for Extrapyramidal Symptoms (SAS) and Unified Parkinson’s Disease Rating Scale (UPDRS) by treatment group. Squares show group means. Data are from pilot trial with D-serine in Parkinson’s disease [67]. (Reproduced from [63]).

3.3. Depression and Anxiety

The antidepressant potential of NMDAR antagonism has been unambiguously established during the last decade. Already in the early 1990s, preclinical studies indicated that several types of NMDAR antagonists exert antidepressant-like effects in animal models of depression [103–105]. Subsequently, a series of animal studies demonstrated that long-term antidepressant treatment produces adaptive changes in the binding profile of NMDARs [106]. The translational confirmation of these findings was achieved by the demonstration of a robust, rapid, and long-lasting antidepressant effect of ketamine in, usually treatment-resistant, unipolar or bipolar depression patients (rev. in [107, 108]). Furthermore, in addition to ketamine which acts as a noncompetitive antagonist at the intra-NMDAR channel PCP site, similar effects seem achievable with mechanistically diverse NMDAR antagonists. Recently, we reported that treatment with high-dose DCS, potentially having a net antagonistic effect at the GMS, also improves major depression symptomatology in treatment-resistant patients [109].

Nevertheless, an apparently contradictory body of data advocates in favor of NMDAR agonists efficacy as antidepressants. GLY and DSR adjuvant treatment results in alleviation of depressive symptoms in schizophrenia patients [91, 92], and SSR504734, a reversible GLY-transporter inhibitor, as well as DSR, has been shown to have antidepressant/anxiolytic effects in depression/anxiety models [110, 111]. Moreover, expression of NMDAR 1 and 2A subunit is decreased in postmortem brains of patients with major depression [112], and NMDAR binding is also reduced in suicide victims [113]. Taken together, these findings imply that NMDAR hypofunction may contribute to the pathophysiology of depression. Moreover, this hypothesis is supported by recent clinical data, although systematic investigation of antidepressant effects of NMDAR enhancement is still in an early phase. Acute administration of 2.1 g DSR to 35 healthy university students was reported to reduce, in a placebo-controlled challenge paradigm study, subjective feelings of depression and anxiety as measured by Visual Analog Scales [114]. The GLY-transporter-1 (GLYT1) inhibitor sarcosine [115] and the DAAO inhibitor sodium benzoate [116] were reported to be beneficial in depressed patients who were drug-naïve for at least 3 months and had no history of treatment-resistance.

Present explanations for the discordant observations of antidepressant effect of both NMDAR agonists and antagonists include, theoretically, common -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated mechanisms [117] and similar net effects achieved by differential action at synaptic versus extrasynaptic NMDARs [29, 32]. A stratified model of psychiatric phenomenology, as function of suboptimal/decreased versus overactive/increased NMDAR function, may also contribute to the conceptualization of available data by taking into account the vast heterogeneity underlying the overinclusive concept of depression. While schizophrenia is a typical NMDAR hypofunction disorder, responsive to treatment with NMDAR agonists, the opposite may be characteristic of treatment-resistant depression. Nevertheless, milder, nonrefractory forms of depression may represent predominately suboptimal NMDAR functioning and could be responsive to GMS agonism. Interestingly, depression feelings are improved in both schizophrenia [91, 92] and normal subjects [114] by DSR and in schizophrenia [92] and nonrefractory depression [115] by sarcosine. On the other hand, ketamine characteristically exacerbates schizophrenia manifestations [118], while it has antidepressant, mood stabilizing and procognitive effects in treatment-resistant depression [119].

Anxiety disorders represent an additional domain in which treatment aiming at augmentation of DSR synaptic levels may prove beneficial. Brain regions extensively implicated in the mediation of fear and anxiety (i.e., amygdala, hippocampus, and prefrontal cortex) are characterized by high NMDAR levels [120] and may show morphological changes as a result of stress-related disorders [121, 122]. NMDARs play a central role in stress response [123] and are critically involved in learning and memory formation which may be impaired in anxiety disorder (e.g., post-traumatic stress disorder, PTSD) [124].

Following a series of studies indicating that extinction learning is NMDAR- dependent, Davis and colleagues first demonstrated that DCS can enhance retention of fear extinction in rats and subsequently showed that DCS enhances the outcome of extinction-based therapy (i.e., virtual reality exposure therapy) for height phobia [125, 126]. These findings were replicated and are cardinal for the concept that DCS may enhance the outcomes of exposure-based cognitive behavioral therapy (CBT). Furthermore, clinical trials accumulated across a range of anxiety-related disorders including specific phobia, social phobia, panic disorders, obsessive-compulsive disorder, and PTSD confirm that single dose (25–500 mg) DCS acutely administered prior to the psychotherapeutic sessions shows promise in augmenting the effects of exposure-based therapy (rev. in [127]). However, the efficacy of DCS has been variable across studies, with several evidencing strong augmentative effects and several showing either relatively weak or no effects [128].

The potential of acute DSR administration in conjunction with CBT interventions has not yet been explored, although it may hold several advantages. DCS is a partial agonist at the GMS of NMDARs bearing the GluN2A and GluN2B subunits (previously NR2A and NR2B subunits) and a full agonist of NMDARs containing the GluN2C and GluN2D subunits [69, 129]. Furthermore, its net effect is affected by the concentration of endogenous GMS modulators (e.g., GLY, DSR, and kynurenic acid), which may be differentially altered in pathophysiological states. In contrast, DSR acts as a specific and potent full agonist at GMS and DSR-induced improvements in cognition parameters have been reported in healthy subjects [114] and schizophrenia patients [65]. Furthermore, Horio et al. [130] recently proposed that DCS may act as a prodrug for DSR in the brain. In an in vivo microdialysis study using free-moving mice, these researchers reported significantly increased extracellular DSR levels in mouse hippocampus following oral or intracerebroventricular (ICV) administration of DCS. Therefore, it was proposed that the DSR produced in the brain after DCS treatment may play at least a partial role in the therapeutic effects of DCS seen in patients with anxiety disorders [130].

While chronic use of DCS for facilitation of exposure sessions is known to lead to negative effects [131, 132], the use of DSR as continuous pharmacology unrelated to CBT interventions may prove rewarding. In long-standing PTSD, in which learning deficits may impair normal extinction of aversive memories, NMDAR agonists may hold a therapeutic potential [133–135]. Accordingly, the demonstrated efficacy of DSR against negative and cognitive symptoms of chronic treatment-resistant schizophrenia patients [91, 92] may also be of relevance to PTSD therapeutics, since PTSD impairments include cognitive dysfunction and features such as affective numbing, anhedonia, and withdrawal from social/vocational activities. Consequently, we have conducted a 6-week controlled proof-of-concept trial that examined the effects of 30 mg/kg/day DSR used as mono- or add-on pharmacotherapy with twenty-two chronic PTSD patients [136]. Compared with placebo administration, DSR treatment resulted in significantly reduced Hamilton Rating Scale for Depression (HAM-D) () and Mississippi Scale for Combat-Related PTSD-civilian version (MISS-PTSD-CV) () scores and a trend towards improved Clinician-Administered PTSD Scale (CAPS) total scores. These preliminary findings suggest that GMS-based pharmacotherapy may be effective in PTSD and warrant larger-sized clinical trials with optimized DSR dosages.

Obsessive-compulsive disorder (OCD) represents an additional clinical entity for which enhancement of GMS-mediated neurotransmission via continuous pharmacological treatment is presently assessed [137]. A case report of a young adult male patient who was disabled with OCD and body dysmorphic disorder illustrates the use of high-dose GLY (0.8 mg/kg), with gradual improvement of clinical status [138]. In a placebo-controlled double-blind trial including 24 adult outpatients with OCD, who were treated with adjunctive GLY 60 g/day for 12 weeks, 14 patients completed the study and two patients in the GLY group were considered responders [139]. The Hoffmann-LaRoche GLYT1 inhibitor bitopertin is presently assessed as add-on treatment in conjunction with selective serotonin reuptake inhibitors in OCD in a Phase II multicenter study [140]. The use of DSR or indirect elevation of DSR levels in OCD has not yet been reported.

3.4. Cognitive Impairment and Dementia

Cognitive impairment is a cardinal feature of dementia and NMDAR dysfunction is hypothesized to play a cardinal role in AD which is the most common type of dementia [141]. NMDAR overactivation by GLU leads to cell death mediated by calcium overload [31, 32]. This process, known as excitotoxicity, is one of the accepted neurochemical models of AD. Furthermore, there are mutual interactions between NMDAR and Amyloid-β peptide (Aβ) which is a hallmark of AD pathogenesis [142]. Aβ increases NMDAR activity [143, 144] and induces inwards current and neurotoxicity [145]. Reciprocally, NMDAR activation stimulates Aβ production [146–148] and Aβ associated synaptic loss may be NMDAR-dependent [149].

On the contrary, NMDAR signaling pathways in the cerebral cortex and hippocampus are impaired in the aging brain [150]. NMDAR neurotransmission is crucial to neuronal survival and NMDAR hypofunction is known to lead to apoptosis [29, 30]. Blockade of NMDAR function by gene deletion or using NMDAR antagonists increases apoptotic cell death [151, 152]. This type of NMDAR hypoactivity-induced neurodegeneration is postulated to contribute to AD pathogenesis [153, 154]. Furthermore, NMDAR hypofunction may also be involved in the progression of the aging brain from mild cognitive impairment (MCI) to AD (rev. in [155]). Individuals with AD or MCI have fewer NMDARs in the frontal cortex and hippocampus [156, 157]. In the genetic mouse model of AD, expression of surface NMDARs in neurons is decreased [158] and NMDAR-mediated response is impaired progressively with age [159, 160]. In addition to reduced number of NMDARs, disrupted glutamatergic neurotransmission [146], decreased CSF concentrations of excitatory amino acids [161], decreased serum levels of DSR [162], and reduced D-aspartate uptake [163] are also noted in AD.

Thus, balanced NMDAR activity is required for optimal cognitive performance and both over- or underfunction of NMDAR neurotransmission may contribute to cognitive dysfunction or neurotoxicity. This NMDAR function paradox may be related to different composition of NR subunits and receptor localization [164, 165]. Accordingly, normalizing NMDAR dysfunction by selectively enhancing NR1/NR2B NMDARs, while avoiding excitotoxicity mediated at NR1/NR2B receptors, could be a better therapeutic approach than nonselective NMDAR antagonism which may actually impair cognitive functioning (rev. in [155]).

During the 1990s, we have witnessed the development of NMDAR antagonists as neuroprotective agents for AD. However, with the exception of memantine, this type of compounds failed to show neuroprotective effects in large scale Phase II/III studies. Memantine is a weak uncompetitive NMDAR partial antagonist of low affinity, which hypothetically can block NMDAR overactivation by preventing excessive influx of calcium without affecting physiological NMDAR activity [166, 167]. Consistently, therapeutically relevant plasma concentrations of memantine produce only 30% NMDAR occupancy [168]. Pharmacological intervention at GMS may represent an additional therapeutic mechanism for AD. NMDAR function enhancement via GMS may avoid the excitotoxicity mediated through the GLU site. Furthermore, in mouse models, the learning deficits caused by NMDAR hypofunction in mice with point mutations in GMS can be rescued by administration of DSR [169, 170]. Supporting neurotrophic/cognitive effects, DCS can improve cognitive functions in animal studies [171, 172] and is used clinically in conjunction with CBT interventions [127]. However, cognition-enhancing effects of DCS in AD have not been conclusively demonstrated [173–175].

The potential efficacy of DSR for the treatment of cognitive impairments has not yet been assessed. Nevertheless, in preliminary investigations, DSR was shown to improve recognition and working memory parameters in mice [176] and cognitive tasks performance in healthy subjects [114]. Thus, DSR may improve cognitive parameters, while NMDAR antagonists (e.g., ketamine) may worsen them in the healthy human organism. Furthermore, it was recently reported that sodium benzoate administration, which hypothetically results in increased synaptic DSR levels is beneficial in patients with MCI or mild AD [177]. In contrast, memantine is approved for use in moderate to severe AD [178], but its efficacy in MCI or mild AD is questionable [179].

3.5. Amyotrophic Lateral Sclerosis

Recent data suggest that DSR is involved in the neurodegenerative processes associated with amyotrophic lateral sclerosis (ALS). This neurodegenerative disease targets motor neurons in the spinal cord, brain stem, and cerebral cortex, leading to death within a few years of onset [180, 181]. In ALS, DSR may mediate motoneuron cell death caused by excessive NMDAR stimulation [182]. A missense mutation that inactivates DAAO results in increased DSR in the spinal cord of patients and causes a familial form of ALS. The affected patients with the DAAO mutation exhibit much lower DAAO activity in spinal cord and significantly increased DSR levels [183]. Furthermore, in sporadic ALS cases elevated DSR may also arise from induction of SR, the DSR synthetic enzyme, caused by cell stress and inflammation [181]. Thus, both anabolic and catabolic DSR-related abnormalities may lead to increased synaptic DSR levels and contribute to disease pathogenesis. Pharmacological interventions aiming at inhibiting DSR synthesis or release may represent an innovative treatment strategy in ALS and potentially other neurodegenerative disorders characterized by NMDAR overactivation.

4. Indirect Augmentation of DSR Function

Regulation of GMS function via pharmacological manipulation of GLYT1 and DAAO represents presently an important research and development target. Although DSR may be effective for treatment of various psychiatric symptom domains, DSR is substantially neutralized by DAAO, diminishing its oral bioavailability and necessitating the administration of high doses. Moreover, a concern with high doses may be potential nephrotoxicity, although no significant adverse events have yet been observed at DSR doses of ≤4 g/day [65, 91, 92].

High levels of DAAO expression and enzyme activity are found in the mammalian liver, kidney, and brain although the expression pattern can vary between species. Humans express DAAO in both liver and kidney, whereas mice, for example, express DAAO in the kidney but not the liver [184]. The physiological role of DAAO in the kidney and liver is detoxification of accumulated D-amino acids [185]. Collectively, the limited preclinical experience with a small number of structurally diverse DAAO inhibitors indicates that extensive inhibition of peripheral and central DAAO has a limited effect on brain or extracellular DSR concentration. Furthermore, in contrast to the fairly robust effects reported with DSR administration in animal models, the reported behavioral effects of DAAO inhibitors are fairly modest and inconsistent (rev. in [186]).

Given the moderate efficacy of DAAO inhibitors on brain DSR and behavior, several authors have investigated the effects of coadministering DAAO inhibitors in conjunction with DSR. Ferraris et al. [187] showed that the 6-chloro analog (CBIO) had quite pronounced effects on brain and plasma DSR when coadministered with 30 mg/kg DSR, relative to either CBIO or DSR administered alone. Hashimoto et al. [188] extended this finding by showing effects on cortical DSR and also demonstrated that coadministration of DSR (30 mg/kg) and CBIO reversed an MK-801-induced deficit in prepulse inhibition (PPI), whereas the 30 mg/kg dose of DSR had no effect on its own. Smith et al. [186] showed that coadministration of compound 4 in conjunction with DSR elevates CSF and cortical DSR levels to a greater extent than administration of DSR alone in male rats. Overall, these findings suggest that DAAO inhibitors could be useful clinically for reducing the dose of DSR necessary for symptom improvement. Moreover, the coadministration of DAAO inhibitors with DSR could ameliorate potential side effects associated with the administration of high DSR doses, for example, nephrotoxicity [189].

Recently, the first results of clinical research with sodium benzoate have been reported. Benzoic acid and its salts, including sodium benzoate, exist in many plants and are widely used as food preservatives [190]. Sodium benzoate also acts as a DAAO inhibitor and has favorable effects in NMDAR-based models such as pain relief [191, 192] and glial cell death [193]. The potential molecular mechanisms of action of sodium benzoate remain to be determined. Since DAAO activity is high in the adult brain cerebellum, it is possible that DSR cerebellar levels may be increased following sodium benzoate administration. Furthermore, recent findings suggest that sodium benzoate may upregulate brain-derived neurotrophic factor (BDNF) via protein kinase A- (PKA-)mediated activation of cAMP response element binding (CREB) protein [194].

In two controlled trials, the administration of up to 1 g/day sodium benzoate proved beneficial for schizophrenia [195] and MCI or mild AD [177] patients. Furthermore, partial remission within 6 weeks was reported with a major depressive disorder patient treated with 500 g/day sodium benzoate [116]. These preliminary findings show promise for DAAO inhibition as a novel treatment approach. Nevertheless, at present, the therapeutic potential of DAAO inhibitors is still relatively unexplored and preclinical studies have primarily addressed the relevance of these compounds mainly for schizophrenia. Further research is warranted given that the few published studies characterizing novel DAAO inhibitors have yielded conflicting results.

5. Conclusions and Future Directions

The scientific view about DSR has changed drastically during the last decade. Converging data strongly suggest a complex and unique neurotransmitter function of DSR which is likely to include an important role in glia-synapse interactions. Furthermore, the demonstration of a DSR modulatory role in cardinal NMDAR-dependent processes has been a driving force for the conceptualization of novel treatment strategies involving the direct or indirect manipulation of DSR signaling. These concepts are likely to undergo further integration and development in the context of the need for strictly balanced NMDAR functioning, with either over- or under-NMDAR function potentially involved in the pathogenesis of neuropsychiatric dysfunctions. A first generation of proof-of-concept animal and clinical studies indicate beneficial DSR effects in refractory schizophrenia, movement, depression, and anxiety disorders and for the improvement of cognitive performance. An additional presently developing strategy is the indirect modulation of DSR synaptic levels by use of compounds that alter the function of main enzymes responsible for DSR production and degradation.

Future research on DSR is likely to further develop along three main axes: (1) characterization of the DSR neurotransmitter system and its role throughout lifespan; (2) the implication of DSR in pathological states characterized by either hypo- or hyper- NMDAR function; and (3) direct or indirect pharmacological manipulation of DSR signaling. The accumulated data suggest that, during the next decade, we will witness important advances in DSR research that will further contribute to elucidate the causes of neuropsychiatric disorders and will be instrumental in the development of innovative treatments.

Conflict of Interests

Dr. Heresco-Levy is inventor in patents for the use of NMDAR-glycine site modulators in movement disorders and in patent applications for the use of NMDAR-glycine site modulators in depression and autoimmune-induced NMDAR dysfunctions. Dr. Durrant reports no conflict of interests.

Acknowledgments

Part of the work reviewed in this paper has been supported by research Grants to Dr. Heresco-Levy from The Stanley Medical Research Institute (SMRI), USA, The Brain and Behavior Research Foundation (formerly National Alliance for Research on Schizophrenia and Depression (NARSAD)), USA, and The Israel Science Foundation (ISF), Israel.

References

H. A. Krebs, “Metabolism of amino-acids: deamination of amino-acids,” Biochemical Journal, vol. 29, no. 7, pp. 1620–1644, 1935.

A. Hashimoto, T. Nishikawa, T. Hayashi et al., “The presence of free D-serine in rat brain,” FEBS Letters, vol. 296, no. 1, pp. 33–36, 1992.

A. Hashimoto, T. Nishikawa, T. Oka, and K. Takahashi, “Endogenous D-serine in rat brain: N-methyl-D-aspartate receptor-related distribution and aging,” Journal of Neurochemistry, vol. 60, no. 2, pp. 783–786, 1993.

J. P. Crow, J. C. Marecki, and M. Thompson, “D-Serine production, degradation, and transport in ALS: critical role of methodology,” Neurology Research International, vol. 2012, Article ID 625245, 8 pages, 2012.

Y. Nagata, K. Horiike, and T. Maeda, “Distribution of free D-serine in vertebrate brains,” Brain Research, vol. 634, no. 2, pp. 291–295, 1994.

N. Rebola, B. N. Srikumar, and C. Mulle, “Activity-dependent synaptic plasticity of NMDA receptors,” Journal of Physiology, vol. 588, no. 1, pp. 93–99, 2010.

R. C. Malenka and M. F. Bear, “LTP and LTD: an embarrassment of riches,” Neuron, vol. 44, no. 1, pp. 5–21, 2004.

P. Paoletti and J. Neyton, “NMDA receptor subunits: function and pharmacology,” Current Opinion in Pharmacology, vol. 7, no. 1, pp. 39–47, 2007.

J. W. Johnson and P. Ascher, “Glycine potentiates the NMDA response in cultured mouse brain neurons,” Nature, vol. 325, no. 6104, pp. 529–531, 1987.

A. Hashimoto and T. Oka, “Free D-aspartate and D-serine in the mammalian brain and periphery,” Progress in Neurobiology, vol. 52, no. 4, pp. 325–353, 1997.

L. Pollegioni and S. Sacchi, “Metabolism of the neuromodulator D-serine,” Cellular and Molecular Life Sciences, vol. 67, no. 14, pp. 2387–2404, 2010.

M. Martineau, G. Baux, and J.-P. Mothet, “D-Serine signalling in the brain: friend and foe,” Trends in Neurosciences, vol. 29, no. 8, pp. 481–491, 2006.

H. Wolosker, “NMDA receptor regulation by D-serine: new findings and perspectives,” Molecular Neurobiology, vol. 36, no. 2, pp. 152–164, 2007.

J.-P. Mothet and S. H. Snyder, “Brain D-amino acids: a novel class of neuromodulators,” Amino Acids, vol. 43, no. 5, pp. 1809–1810, 2012.

Y. Yang, W. Ge, Y. Chen et al., “Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 25, pp. 15194–15199, 2003.

A. C. Basu, G. E. Tsai, C.-L. Ma et al., “Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior,” Molecular Psychiatry, vol. 14, no. 7, pp. 719–727, 2009.

Z. Zhang, N. Gong, W. Wang, L. Xu, and T.-L. Xu, “Bell-shaped d-serine actions on hippocampal long-term depression and spatial memory retrieval,” Cerebral Cortex, vol. 18, no. 10, pp. 2391–2401, 2008.

J. P. Mothet, E. Rouaud, P.-M. Sinet et al., “A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory,” Aging Cell, vol. 5, no. 3, pp. 267–274, 2006.

A. Panatier, D. T. Theodosis, J.-P. Mothet et al., “Glia-derived D-serine controls NMDA receptor activity and synaptic memory,” Cell, vol. 125, no. 4, pp. 775–784, 2006.

E. R. Stevens, M. Esguerra, P. M. Kim et al., “D-serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 11, pp. 6789–6794, 2003.

T. L. Kalbaugh, J. Zhang, and J. S. Diamond, “Coagonist release modulates NMDA receptor subtype contributions at synaptic inputs to retinal ganglion cells,” The Journal of Neuroscience, vol. 29, no. 5, pp. 1469–1479, 2009.

J.-P. Mothet, A. T. Parent, H. Wolosker et al., “D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 9, pp. 4926–4931, 2000.

E. Kartvelishvily, M. Shleper, L. Balan, E. Dumin, and H. Wolosker, “Neuron-derived D-serine release provides a novel means to activate N-methyl-D-aspartate receptors,” The Journal of Biological Chemistry, vol. 281, no. 20, pp. 14151–14162, 2006.

M. Shleper, E. Kartvelishvily, and H. Wolosker, “D-serine is the dominant endogenous coagonist for NMDA receptor neurotoxicity in organotypic hippocampal slices,” The Journal of Neuroscience, vol. 25, no. 41, pp. 9413–9417, 2005.

P. M. Kim, H. Aizawa, P. S. Kim et al., “Serine racemase: activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 6, pp. 2105–2110, 2005.

S. A. Lipton and P. A. Rosenberg, “Mechanisms of disease: excitatory amino acids as a final common pathway for neurologic disorders,” The New England Journal of Medicine, vol. 330, no. 9, pp. 613–622, 1994.

D. W. Choi, “Excitotoxic cell death,” Journal of Neurobiology, vol. 23, no. 9, pp. 1261–1276, 1992.

J. A. Kemp and R. M. McKernan, “NMDA receptor pathways as drug targets,” Nature Neuroscience, vol. 5, pp. 1039–1042, 2002.

G. E. Hardingham and H. Bading, “The Yin and Yang of NMDA receptor signalling,” Trends in Neurosciences, vol. 26, no. 2, pp. 81–89, 2003.

C. Ikonomidou, F. Bosch, M. Miksa et al., “Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain,” Science, vol. 283, no. 5398, pp. 70–74, 1999.

B. K. Fiske and P. C. Brunjes, “NMDA receptor regulation of cell death in the rat olfactory bulb,” Journal of Neurobiology, vol. 47, no. 3, pp. 223–232, 2001.

G. E. Hardingham and H. Bading, “Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders,” Nature Reviews Neuroscience, vol. 11, no. 10, pp. 682–696, 2010.

M. J. Schell, M. E. Molliver, and S. H. Snyder, “D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 9, pp. 3948–3952, 1995.

H. Wolosker, “Serine racemase and the serine shuttle between neurons and astrocytes,” Biochimica et Biophysica Acta—Proteins and Proteomics, vol. 1814, no. 11, pp. 1558–1566, 2011.

J.-P. Mothet, L. Pollegioni, G. Ouanounou, M. Martineau, P. Fossier, and G. Baux, “Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 15, pp. 5606–5611, 2005.

E. Yasuda, N. Ma, and R. Semba, “Immunohistochemical evidences for localization and production of D-serine in some neurons in the rat brain,” Neuroscience Letters, vol. 299, no. 1-2, pp. 162–164, 2001.

S. M. Williams, C. M. Diaz, L. T. Macnab, R. K. P. Sullivan, and D. V. Pow, “Immunocytochemical analysis of D-serine distribution in the mammalian brain reveals novel anatomical compartmentalizations in glia and neurons,” GLIA, vol. 53, no. 4, pp. 401–411, 2006.

J. Puyal, M. Martineau, J.-P. Mothet, M.-T. Nicolas, and J. Raymond, “Changes in D-serine levels and localization during postnatal development of the rat vestibular nuclei,” Journal of Comparative Neurology, vol. 497, no. 4, pp. 610–621, 2006.

D. T. Balu and J. T. Coyle, “Neuronal d-serine regulates dendritic architecture in the somatosensory cortex,” Neuroscience Letters, vol. 517, no. 2, pp. 77–81, 2012.

M. A. Benneyworth, Y. Li, A. C. Basu, V. Y. Bolshakov, and J. T. Coyle, “Cell selective conditional null mutations of serine racemase demonstrate a predominate localization in cortical glutamatergic neurons,” Cellular and Molecular Neurobiology, vol. 32, no. 4, pp. 613–624, 2012.

K. Miya, R. Inoue, Y. Takata et al., “Serine racemase is predominantly localized in neurons in mouse brain,” Journal of Comparative Neurology, vol. 510, no. 6, pp. 641–654, 2008.

D. Rosenberg, E. Kartvelishvily, M. Shleper, C. M. C. Klinker, M. T. Bowser, and H. Wolosker, “Neuronal release of D-serine: a physiological pathway controlling extracellular D-serine concentration,” The FASEB Journal, vol. 24, no. 8, pp. 2951–2961, 2010.

D. Rosenberg, S. Artoul, A. C. Segal et al., “Neuronal D-serine and glycine release via the Asc-1 transporter regulates NMDA receptor-dependent synaptic activity,” The Journal of Neuroscience, vol. 33, no. 8, pp. 3533–3544, 2013.

H. Wolosker, “D-serine regulation of NMDA receptor activity,” Science's STKE: Signal Transduction Knowledge Environment, vol. 2006, no. 356, p. pe41, 2006.

N. Kishi and J. D. Macklis, “MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions,” Molecular and Cellular Neuroscience, vol. 27, no. 3, pp. 306–321, 2004.

M. J. Schell, R. O. Brady Jr., M. E. Molliver, and S. H. Snyder, “D-serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors,” The Journal of Neuroscience, vol. 17, no. 5, pp. 1604–1615, 1997.

T. Papouin, L. Ladépêche, J. Ruel et al., “Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists,” Cell, vol. 150, no. 3, pp. 633–646, 2012.

P. Fossat, F. R. Turpin, S. Sacchi et al., “Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex,” Cerebral Cortex, vol. 22, no. 3, pp. 595–606, 2012.

C. Henneberger, T. Papouin, S. H. R. Oliet, and D. A. Rusakov, “Long-term potentiation depends on release of d-serine from astrocytes,” Nature, vol. 463, no. 7278, pp. 232–236, 2010.

L. Liu, T. P. Wong, M. F. Pozza et al., “Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity,” Science, vol. 304, no. 5673, pp. 1021–1024, 2004.

P. V. Massey, B. E. Johnson, P. R. Moult et al., “Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression,” The Journal of Neuroscience, vol. 24, no. 36, pp. 7821–7828, 2004.

W. Morishita, W. Lu, G. B. Smith, R. A. Nicoll, M. F. Bear, and R. C. Malenka, “Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression,” Neuropharmacology, vol. 52, no. 1, pp. 71–76, 2007.

S. Berberich, P. Punnakkal, V. Jensen et al., “Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation,” The Journal of Neuroscience, vol. 25, no. 29, pp. 6907–6910, 2005.

C. Weitlauf, Y. Honse, Y. P. Auberson, M. Mishina, D. M. Lovinger, and D. G. Winder, “Activation of NR2A-containing NMDA receptors is not obligatory for NMDA receptor-dependent long-term potentiation,” The Journal of Neuroscience, vol. 25, no. 37, pp. 8386–8390, 2005.

D. A. Rusakov, A. Scimemi, M. C. Walker, and D. M. Kullmann, “Comment on “Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity”,” Science, vol. 305, no. 5692, p. 1912, 2004.

T. Fellin, O. Pascual, S. Gobbo, T. Pozzan, P. G. Haydon, and G. Carmignoto, “Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors,” Neuron, vol. 43, no. 5, pp. 729–743, 2004.

M. C. Angulo, A. S. Kozlov, S. Charpak, and E. Audinat, “Glutamate released from glial cells synchronizes neuronal activity in the hippocampus,” The Journal of Neuroscience, vol. 24, no. 31, pp. 6920–6927, 2004.

M. Arundine and M. Tymianski, “Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity,” Cell Calcium, vol. 34, no. 4-5, pp. 325–337, 2003.

A. J. Milnerwood, C. M. Gladding, M. A. Pouladi et al., “Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice,” Neuron, vol. 65, no. 2, pp. 178–190, 2010.

K. Bordji, J. Becerril-Ortega, O. Nicole, and A. Buisson, “Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-β production,” The Journal of Neuroscience, vol. 30, no. 47, pp. 15927–15942, 2010.

U. Heresco-Levy, D. C. Javitt, M. Ermilov, C. Mordel, G. Silipo, and M. Lichtenstein, “Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia,” Archives of General Psychiatry, vol. 56, no. 1, pp. 29–36, 1999.

U. Heresco-Levy, D. C. Javitt, R. Ebstein et al., “D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia,” Biological Psychiatry, vol. 57, no. 6, pp. 577–585, 2005.

U. Heresco-Levy, S. Shoham, and D. C. Javitt, “Glycine site agonists of the N-methyl-d-aspartate receptor and Parkinson's disease: a hypothesis,” Movement Disorders, vol. 28, no. 4, pp. 419–424, 2013.

U. Heresco-Levy, M. Ermilov, P. Lichtenberg, G. Bar, and D. C. Javitt, “High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia,” Biological Psychiatry, vol. 55, no. 2, pp. 165–171, 2004.

J. T. Kantrowitz, A. K. Malhotra, B. Cornblatt et al., “High dose D-serine in the treatment of schizophrenia,” Schizophrenia Research, vol. 121, no. 1–3, pp. 125–130, 2010.

D. C. Javitt, S. R. Zukin, U. Heresco-Levy, and D. Umbricht, “Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia,” Schizophrenia Bulletin, vol. 38, no. 5, pp. 958–966, 2012.

E. Gelfin, Y. Kaufman, I. Korn-Lubetzki et al., “D-serine adjuvant treatment alleviates behavioural and motor symptoms in Parkinson's disease,” International Journal of Neuropsychopharmacology, vol. 15, no. 4, pp. 543–549, 2012.

J. T. Coyle and P. Puttfarcken, “Oxidative stress, glutamate, and neurodegenerative disorders,” Science, vol. 262, no. 5134, pp. 689–695, 1993.

S. M. Dravid, P. B. Burger, A. Prakash et al., “Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors,” The Journal of Neuroscience, vol. 30, no. 7, pp. 2741–2754, 2010.

T.-A. Matsui, M. Sekiguchi, A. Hashimoto, U. Tomita, T. Nishikawa, and K. Wada, “Functional comparison of D-serine and glycine in rodents: the effect on cloned NMDA receptors and the extracellular concentration,” Journal of Neurochemistry, vol. 65, no. 1, pp. 454–458, 1995.

U. Heresco-Levy, “Glutamatergic neurotransmission modulators as emerging new drugs for schizophrenia,” Expert Opinion on Emerging Drugs, vol. 10, no. 4, pp. 827–844, 2005.

C. A. Ross, R. L. Margolis, S. A. J. Reading, M. Pletnikov, and J. T. Coyle, “Neurobiology of Schizophrenia,” Neuron, vol. 52, no. 1, pp. 139–153, 2006.

L. Verrall, M. Walker, N. Rawlings et al., “D-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia,” European Journal of Neuroscience, vol. 26, no. 6, pp. 1657–1669, 2007.

V. Labrie, R. Fukumura, A. Rastogi et al., “Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model,” Human Molecular Genetics, vol. 18, no. 17, pp. 3227–3243, 2009.

S. Sacchi, M. Bernasconi, M. Martineau et al., “pLG72 modulates intracellular D-serine levels through its interaction with D-amino acid oxidase: effect on schizophrenia susceptibility,” The Journal of Biological Chemistry, vol. 283, no. 32, pp. 22244–22256, 2008.

J. Schumacher, R. Abon Jamra, J. Freudenberg et al., “Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder,” Molecular Psychiatry, vol. 9, no. 2, pp. 203–207, 2004.

S. D. Detera-Wadleigh and F. J. McMahon, “G72/G30 in Schizophrenia and bipolar disorder: review and meta-analysis,” Biological Psychiatry, vol. 60, no. 2, pp. 106–114, 2006.

A. M. Addington, M. Gornick, A. L. Sporn et al., “Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified,” Biological Psychiatry, vol. 55, no. 10, pp. 976–980, 2004.

S. L. Almond, R. L. Fradley, E. J. Armstrong et al., “Behavioral and biochemical characterization of a mutant mouse strain lacking d-amino acid oxidase activity and its implications for schizophrenia,” Molecular and Cellular Neuroscience, vol. 32, no. 4, pp. 324–334, 2006.

V. Labrie, W. Wang, S. W. Barger, G. B. Baker, and J. C. Roder, “Genetic loss of D-amino acid oxidase activity reverses schizophrenia-like phenotypes in mice,” Genes, Brain and Behavior, vol. 9, no. 1, pp. 11–25, 2010.

K. Hashimoto, T. Fukushima, E. Shimizu et al., “Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia,” Archives of General Psychiatry, vol. 60, no. 6, pp. 572–576, 2003.

K. Hashimoto, G. Engberg, E. Shimizu, C. Nordin, L. H. Lindström, and M. Iyo, “Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 29, no. 5, pp. 767–769, 2005.

M. A. Calcia, C. Madeira, F. V. Alheira et al., “Plasma levels of D-serine in Brazilian individuals with schizophrenia,” Schizophrenia Research, vol. 142, no. 1–3, pp. 83–87, 2012.

K. Yamada, T. Ohnishi, K. Hashimoto et al., “Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and D-serine levels,” Biological Psychiatry, vol. 57, no. 12, pp. 1493–1503, 2005.

I. Bendikov, C. Nadri, S. Amar et al., “A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia,” Schizophrenia Research, vol. 90, no. 1–3, pp. 41–51, 2007.

Y. Tanii, T. Nishikawa, A. Hashimoto, and K. Takahashi, “Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactivity, stereotypy and ataxia in the rat,” Journal of Pharmacology and Experimental Therapeutics, vol. 269, no. 3, pp. 1040–1048, 1994.

P. C. Contreras, “D-serine antagonized phencyclidine- and MK-801-induced stereotyped behavior and ataxia,” Neuropharmacology, vol. 29, no. 3, pp. 291–293, 1990.

G. Tsai, P. Yang, L.-C. Chung, N. Lange, and J. T. Coyle, “D-serine added to antipsychotics for the treatment of schizophrenia,” Biological Psychiatry, vol. 44, no. 11, pp. 1081–1089, 1998.

H.-Y. Lane, Y.-C. Chang, Y.-C. Liu, C.-C. Chiu, and G. E. Tsai, “Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study,” Archives of General Psychiatry, vol. 62, no. 11, pp. 1196–1204, 2005.

M. Weiser, U. Heresco-Levy, M. Davidson et al., “A multicenter, add-on randomized controlled trial of low-dose D-serine for negative and cognitive symptoms of schizophrenia,” Journal of Clinical Psychiatry, vol. 73, no. 6, pp. e728–e734, 2012.

S. P. Singh and V. Singh, “Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia,” CNS Drugs, vol. 25, no. 10, pp. 859–885, 2011.

G. E. Tsai and P.-Y. Lin, “Strategies to enhance N-Methyl-D-Aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis,” Current Pharmaceutical Design, vol. 16, no. 5, pp. 522–537, 2010.

M. Ermilov, E. Gelfin, R. Levin et al., “A pilot double-blind comparison of d-serine and high-dose olanzapine in treatment-resistant patients with schizophrenia,” Schizophrenia Research, vol. 150, no. 2-3, pp. 604–605, 2013.

J. P. Kaltenbach, C. E. Ganote, and F. A. Carone, “Renal tubular necrosis induced by compounds structurally related to D-serine,” Experimental and Molecular Pathology, vol. 30, no. 2, pp. 209–214, 1979.

F. A. Carone, S. Nakamura, and B. Goldman, “Urinary loss of glucose, phosphate, and protein by diffusion into proximal straight tubules injured by D-serine and maleic acid,” Laboratory Investigation, vol. 52, no. 6, pp. 605–610, 1985.

G. E. Tsai, H.-Y. Lane, C. M. Vandenberg, Y.-C. Liu, P. Tsai, and M. W. Jann, “Disposition of D-serine in healthy adults,” Journal of Clinical Pharmacology, vol. 48, no. 4, pp. 524–527, 2008.

K. A. Johnson, P. J. Conn, and C. M. Niswender, “Glutamate receptors as therapeutic targets for Parkinson's disease,” CNS and Neurological Disorders—Drug Targets, vol. 8, no. 6, pp. 475–491, 2009.

R. S. Marin, “Apathy: a neuropsychiatric syndrome,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 3, no. 3, pp. 243–254, 1991.

M. S. Starr, “Glutamate/dopamine D1/D2 balance in the basal ganglia and its relevance to Parkinson's disease,” Synapse, vol. 19, no. 4, pp. 264–293, 1995.

S. S. Nikam and L. T. Meltzer, “NR2B selective NMDA receptor antagonists,” Current Pharmaceutical Design, vol. 8, no. 10, pp. 845–855, 2002.

P. J. Blanchet, S. Konitsiotis, E. R. Whittemore, Z. L. Zhou, R. M. Woodward, and T. N. Chase, “Differing effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys,” Journal of Pharmacology and Experimental Therapeutics, vol. 290, no. 3, pp. 1034–1040, 1999.

J. N. C. Kew, J. G. Richards, V. Mutel, and J. A. Kemp, “Developmental changes in NMDA receptor glycine affinity and ifenprodil sensitivity reveal three distinct populations of NMDA receptors in individual rat cortical neurons,” The Journal of Neuroscience, vol. 18, no. 6, pp. 1935–1943, 1998.

R. Trullas and P. Skolnick, “Functional antagonists at the NMDA receptor complex exhibit antidepressant actions,” European Journal of Pharmacology, vol. 185, no. 1, pp. 1–10, 1990.

R. Trullas, T. Folio, A. Young, R. Miller, K. Boje, and P. Skolnick, “1-Aminocyclopropanecarboxylates exhibit antidepressant and anxiolytic actions in animal models,” European Journal of Pharmacology, vol. 203, no. 3, pp. 379–385, 1991.

R. T. Layer, P. Popik, T. Olds, and P. Skolnick, “Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82.0715),” Pharmacology Biochemistry and Behavior, vol. 52, no. 3, pp. 621–627, 1995.

P. Skolnick, P. Popik, and R. Trullas, “Glutamate-based antidepressants: 20 years on,” Trends in Pharmacological Sciences, vol. 30, no. 11, pp. 563–569, 2009.

J. H. Krystal, G. Sanacora, and R. S. Duman, “Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond,” Biological Psychiatry, vol. 73, no. 12, pp. 1133–1141, 2013.

A. J. Rush, “Ketamine for treatment-resistant depression: ready or not for clinical use?” The American Journal of Psychiatry, vol. 170, no. 10, pp. 1079–1081, 2013.

U. Heresco-Levy, G. Gelfin, B. Bloch et al., “A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression,” International Journal of Neuropsychopharmacology, vol. 16, no. 3, pp. 501–506, 2013.

R. Depoortère, G. Dargazanli, G. Estenne-Bouhtou et al., “Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic,” Neuropsychopharmacology, vol. 30, no. 11, pp. 1963–1985, 2005.

O. Malkesman, D. R. Austin, T. Tragon et al., “Acute d-serine treatment produces antidepressant-like effects in rodents,” International Journal of Neuropsychopharmacology, vol. 15, no. 8, pp. 1135–1148, 2012.

M. Beneyto and J. H. Meador-Woodruff, “Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder,” Neuropsychopharmacology, vol. 33, no. 9, pp. 2175–2186, 2008.

G. Nowak, G. A. Ordway, and I. A. Paul, “Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims,” Brain Research, vol. 675, no. 1-2, pp. 157–164, 1995.

U. Heresco-Levy, “D-serine effects in healthy volunteers and neuropsychiatric disorders,” in Proceedings of the CINP Thematic Meeting: Pharmacogenomics and Personalized Medicine, Jerusalem, Israel, April 2013.

C. C. Huang, I. H. Wei, C. L. Huang et al., “Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression,” Biological Psychiatry, vol. 74, no. 10, pp. 734–741, 2013.

C.-H. Lai, H.-Y. Lane, and G. E. Tsai, “Clinical and cerebral volumetric effects of sodium benzoate, a d-amino acid oxidase inhibitor, in a drug-nave patient with major depression,” Biological Psychiatry, vol. 71, no. 4, pp. e9–e10, 2012.

S. Maeng, C. A. Zarate Jr., J. Du et al., “Cellular mechanisms underlying the antidepressant effects of ketamine: Role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors,” Biological Psychiatry, vol. 63, no. 4, pp. 349–352, 2008.

A. C. Lahti, B. Koffel, D. LaPorte, and C. A. Tamminga, “Subanesthetic doses of ketamine stimulate psychosis in schizophrenia,” Neuropsychopharmacology, vol. 13, no. 1, pp. 9–19, 1995.

D. R. Lara, L. W. Bisol, and L. R. Munari, “Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression,” International Journal of Neuropsychopharmacology, vol. 16, no. 9, pp. 2111–2117, 2013.

A. J. McDonald, “Glutamate and aspartate immunoreactive neurons of the rat basolateral amygdala: colocalization of excitatory amino acids and projections to the limbic circuit,” Journal of Comparative Neurology, vol. 365, no. 3, pp. 367–379, 1996.

B. S. McEwen, “Plasticity of the hippocampus: adaptation to chronic stress and allostatic load,” Annals of the New York Academy of Sciences, vol. 933, pp. 265–277, 2001.

B. H. Harvey, F. Oosthuizen, L. Brand, G. Wegener, and D. J. Stein, “Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus,” Psychopharmacology, vol. 175, no. 4, pp. 494–502, 2004.

B. S. McEwen, “Gonadal and adrenal steroids regulate neurochemical and structural plasticity of the hippocampus via cellular mechanisms involving NMDA receptors,” Cellular and Molecular Neurobiology, vol. 16, no. 2, pp. 103–116, 1996.

M. D. Horner and M. B. Hamner, “Neurocognitive functioning in posttraumatic stress disorder,” Neuropsychology Review, vol. 12, no. 1, pp. 15–30, 2002.

M. Davis and K. M. Myers, “The role of glutamate and gamma-aminobutyric acid in fear extinction: clinical implications for exposure therapy,” Biological Psychiatry, vol. 52, no. 10, pp. 998–1007, 2002.

M. Davis, K. Ressler, B. O. Rothbaum, and R. Richardson, “Effects of D-cycloserine on extinction: translation from preclinical to clinical work,” Biological Psychiatry, vol. 60, no. 4, pp. 369–375, 2006.

M. M. Norberg, J. H. Krystal, and D. F. Tolin, “A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy,” Biological Psychiatry, vol. 63, no. 12, pp. 1118–1126, 2008.

J. A. J. Smits, D. Rosenfield, M. W. Otto et al., “D-cycloserine enhancement of exposure therapy for social anxiety disorder depends on the success of exposure sessions,” Journal of Psychiatric Research, vol. 47, no. 10, pp. 1455–1461, 2013.

A. Sheinin, S. Shavit, and M. Benveniste, “Subunit specificity and mechanism of action of NMDA partial agonist D-cycloserine,” Neuropharmacology, vol. 41, no. 2, pp. 151–158, 2001.

M. Horio, H. Mori, and K. Hashimoto, “Is D-cycloserine a prodrug for D-serine in the brain?” Biological Psychiatry, vol. 73, no. 12, pp. e33–e34, 2013.

R. Richardson, L. Ledgerwood, and J. Cranney, “Facilitation of fear extinction by D-cycloserine: theoretical and clinical implications,” Learning and Memory, vol. 11, no. 5, pp. 510–516, 2004.

K. J. Ressler, B. O. Rothbaum, L. Tannenbaum et al., “Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear,” Archives of General Psychiatry, vol. 61, no. 11, pp. 1136–1144, 2004.

M. J. Friedman, “What might the psychobiology of posttraumatic stress disorder teach us about future approaches to pharmacotherapy?” Journal of Clinical Psychiatry, vol. 61, no. 7, pp. 44–51, 2000.

A. Garakani, S. J. Mathew, and D. S. Charney, “Neurobiology of anxiety disorders and implications for treatment,” Mount Sinai Journal of Medicine, vol. 73, no. 7, pp. 941–949, 2006.

D. J. Nutt, “The psychobiology of posttraumatic stress disorder,” Journal of Clinical Psychiatry, vol. 61, no. 5, pp. 24–32, 2000.

U. Heresco-Levy, A. Vass, B. Bloch et al., “Pilot controlled trial of d-serine for the treatment of post-traumatic stress disorder,” International Journal of Neuropsychopharmacology, vol. 12, no. 9, pp. 1275–1282, 2009.

M. A. Grados, M. W. Specht, H. M. Sung, and D. Fortune, “Glutamate drugs and pharmacogenetics of OCD: a pathway-based exploratory approach,” Expert Opinion on Drug Discovery, vol. 8, no. 12, pp. 1515–1527, 2013.

W. L. Cleveland, R. L. DeLaPaz, R. A. Fawwaz, and R. S. Challop, “High-dose glycine treatment of refractory obsessive-compulsive disorder and body dysmorphic disorder in a 5-year period,” Neural Plasticity, vol. 2009, Article ID 768398, 25 pages, 2009.

W. M. Greenberg, M. M. Benedict, J. Doerfer et al., “Adjunctive glycine in the treatment of obsessive-compulsive disorder in adults,” Journal of Psychiatric Research, vol. 43, no. 6, pp. 664–670, 2009.

Hoffmann-La Roche, “A study of bitopertin (RO4917838) in combination with selective serotonin reuptake inhibitors in patients with obsessive-compulsive disorder,” National Library of Medicine (US), Bethesda, Md, USA, 2013, NLM Identifier: NCT01674361, http://clinicaltrials.gov/show/NCT01674361

N. B. Farber, J. W. Newcomer, and J. W. Olney, “The glutamate synapse in neuropsychiatric disorders: focus on schizophrenia and Alzheimer's disease,” Progress in Brain Research, vol. 116, pp. 421–437, 1998.

H. W. Querfurth and F. M. LaFerla, “Alzheimer's disease,” The New England Journal of Medicine, vol. 362, no. 4, pp. 329–344, 2010.

C. G. Parsons, A. Stöffler, and W. Danysz, “Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system—too little activation is bad, too much is even worse,” Neuropharmacology, vol. 53, no. 6, pp. 699–723, 2007.

G. J. Uhász, B. Barkóczi, G. Vass et al., “Fibrillar Aβ1-42 enhances NMDA receptor sensitivity via the integrin signaling pathway,” Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1055–1067, 2010.

E. Alberdi, M. V. Sánchez-Gómez, F. Cavaliere et al., “Amyloid β oligomers induce Ca²⁺ dysregulation and neuronal death through activation of ionotropic glutamate receptors,” Cell Calcium, vol. 47, no. 3, pp. 264–272, 2010.

D. A. Butterfield and C. B. Pocernich, “The glutamatergic system and Alzheimer's disease: therapeutic implications,” CNS Drugs, vol. 17, no. 9, pp. 641–652, 2003.

S. Lesné, C. Ali, C. Gabriel et al., “NMDA receptor activation inhibits α-secretase and promotes neuronal amyloid-β production,” The Journal of Neuroscience, vol. 25, no. 41, pp. 9367–9377, 2005.

W. Gordon-Krajcer, E. Salińska, and J. W. Łazarewicz, “N-methyl-d-aspartate receptor-mediated processing of β-amyloid precursor protein in rat hippocampal slices: in vitro-superfusion study,” Folia Neuropathologica, vol. 40, no. 1, pp. 13–17, 2002.

K. Ando, K. Uemura, A. Kuzuya et al., “N-cadherin regulates p38 MAPK signaling via association with JNK-associated leucine zipper protein: implications for neurodegeneration in Alzheimer disease,” The Journal of Biological Chemistry, vol. 286, no. 9, pp. 7619–7628, 2011.

K. Yamada and T. Nabeshima, “Changes in NMDA receptor/nitric oxide signaling pathway in the brain with aging,” Microscopy Research and Technique, vol. 43, no. 1, pp. 68–74, 1998.

C. Ikonomidou, V. Stefovska, and L. Turski, “Neuronal death enhanced by N-methyl-D-aspartate antagonists,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 23, pp. 12885–12890, 2000.

S. M. Adams, J. C. De Rivero Vaccari, and R. A. Corriveau, “Pronounced cell death in the absence of NMDA receptors in the developing somatosensory thalamus,” The Journal of Neuroscience, vol. 24, no. 42, pp. 9441–9450, 2004.

J. W. Olney, D. F. Wozniak, and N. B. Farber, “Excitotoxic neurodegeneration in Alzheimer disease: new hypothesis and new therapeutic strategies,” Archives of Neurology, vol. 54, no. 10, pp. 1234–1240, 1997.

D. F. Wozniak, K. Dikranian, M. J. Ishimaru et al., “Disseminated corticolimbic neuronal degeneration induced in rat brain by MK-801: potential relevance to Alzheimer's disease,” Neurobiology of Disease, vol. 5, no. 5, pp. 305–322, 1998.

Y.-J. Huang, C.-H. Lin, H.-Y. Lane, and G. E. Tsai, “NMDA neurotransmission dysfunction in behavioral and psychological symptoms of Alzheimer's disease,” Current Neuropharmacology, vol. 10, no. 3, pp. 272–285, 2012.

A. W. Procter, E. H. F. Wong, G. C. Stratmann, S. L. Lowe, and D. M. Bowen, “Reduced glycine stimulation of [3H]MK-801 binding in Alzheimer's disease,” Journal of Neurochemistry, vol. 53, no. 3, pp. 698–704, 1989.

E. L. Schaeffer and W. F. Gattaz, “Cholinergic and glutamatergic alterations beginning at the early stages of Alzheimer disease: participation of the phospholipase A2 enzyme,” Psychopharmacology, vol. 198, no. 1, pp. 1–27, 2008.

E. M. Snyder, Y. Nong, C. G. Almeida et al., “Regulation of NMDA receptor trafficking by amyloid-β,” Nature Neuroscience, vol. 8, no. 8, pp. 1051–1058, 2005.

A. Auffret, V. Gautheron, M. Repici et al., “Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease,” The Journal of Neuroscience, vol. 29, no. 32, pp. 10144–10152, 2009.

A. Auffret, V. Gautheron, M. P. Mattson, J. Mariani, and C. Rovira, “Progressive age-related impairment of the late long-term potentiation in Alzheimer's disease presenilin-1 mutant knock-in mice,” Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1021–1033, 2010.

M. Martinez, A. Frank, E. Diez-Tejedor, and A. Hernanz, “Amino acid concentrations in cerebrospinal fluid and serum in Alzheimer's disease and vascular dementia,” Journal of Neural Transmission—Parkinson's Disease and Dementia Section, vol. 6, no. 1, pp. 1–9, 1993.

K. Hashimoto, T. Fukushima, E. Shimizu et al., “Possible role of D-serine in the pathophysiology of Alzheimer's disease,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 28, no. 2, pp. 385–388, 2004.

S. L. Lowe and D. M. Bowen, “Glutamic acid concentration in brains of patients with Alzheimer's disease,” Biochemical Society Transactions, vol. 18, no. 3, pp. 443–444, 1990.

X. Ye and T. J. Carew, “Small G protein signaling in neuronal plasticity and memory formation: the specific role of ras family proteins,” Neuron, vol. 68, no. 3, pp. 340–361, 2010.

L. V. Kalia, S. K. Kalia, and M. W. Salter, “NMDA receptors in clinical neurology: excitatory times ahead,” The Lancet Neurology, vol. 7, no. 8, pp. 742–755, 2008.

E. Scarpini, P. Scheltens, and H. Feldman, “Treatment of Alzheimer's disease: current status and new perspectives,” Lancet Neurology, vol. 2, no. 9, pp. 539–547, 2003.

F. Gardoni and M. Di Luca, “New targets for pharmacological intervention in the glutamatergic synapse,” European Journal of Pharmacology, vol. 545, no. 1, pp. 2–10, 2006.

L. Morè, A. Gravius, J. Nagel, B. Valastro, S. Greco, and W. Danysz, “Therapeutically relevant plasma concentrations of memantine produce significant L-N-methyl-D-aspartate receptor occupation and do not impair learning in rats,” Behavioural Pharmacology, vol. 19, no. 7, pp. 724–734, 2008.

T. M. Ballard, M. Pauly-Evers, G. A. Higgins et al., “Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity,” The Journal of Neuroscience, vol. 22, no. 15, pp. 6713–6723, 2002.

J. N. C. Kew, A. Koester, J.-L. Moreau et al., “Functional consequences of reduction in NMDA receptor glycine affinity in mice carrying targeted point mutations in the glycine binding site,” The Journal of Neuroscience, vol. 20, no. 11, pp. 4037–4049, 2000.

J. F. Flood, J. E. Morley, and T. H. Lanthorn, “Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycine receptor,” European Journal of Pharmacology, vol. 221, no. 2-3, pp. 249–254, 1992.

G. M. Schuster and W. J. Schmidt, “D-Cycloserine reverses the working memory impairment of hippocampal-lesioned rats in a spatial learning task,” European Journal of Pharmacology, vol. 224, no. 1, pp. 97–98, 1992.

C. Randolph, J. W. Roberts, M. C. Tierney, D. Bravi, M. M. Mouradian, and T. N. Chase, “D-Cycloserine treatment of Alzheimer disease,” Alzheimer Disease and Associated Disorders, vol. 8, no. 3, pp. 198–205, 1994.

G. E. Tsai, W. E. Falk, and J. Gunther, “A preliminary study of D-cycloserine treatment in Alzheimer's disease,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 10, no. 2, pp. 224–226, 1998.

T. D. Fakouhi, S. S. Jhee, J. J. Sramek et al., “Evaluation of cycloserine in the treatment of Alzheimer's disease,” Journal of Geriatric Psychiatry and Neurology, vol. 8, no. 4, pp. 226–230, 1995.

P. Bado, C. Madeira, C. Vargas-Lopes et al., “Effects of low-dose d-serine on recognition and working memory in mice,” Psychopharmacology, vol. 218, no. 3, pp. 461–470, 2011.

C. H. Lin, P. K. Chen, Y. C. Chang et al., “Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial,” Biological Psychiatry, vol. 75, no. 9, pp. 678–685, 2014.

B. Reisberg, R. Doody, A. Stöffler, F. Schmitt, S. Ferris, and H. J. Möbius, “Memantine in moderate-to-severe Alzheimer's disease,” The New England Journal of Medicine, vol. 348, no. 14, pp. 1333–1341, 2003.

L. S. Schneider, K. S. Dagerman, J. P. T. Higgins, and R. McShane, “Lack of evidence for the efficacy of memantine in mild Alzheimer disease,” Archives of Neurology, vol. 68, no. 8, pp. 991–998, 2011.

A. C. Ludolph, J. Brettschneider, and J. H. Weishaupt, “Amyotrophic lateral sclerosis,” Current Opinion in Neurology, vol. 25, no. 5, pp. 530–535, 2012.

P. Paul and J. De Belleroche, “The role of D-amino acids in amyotrophic lateral sclerosis pathogenesis: a review,” Amino Acids, vol. 43, no. 5, pp. 1823–1831, 2012.

J. Sasabe, Y. Miyoshi, M. Suzuki et al., “D-Amino acid oxidase controls motoneuron degeneration through D-serine,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 2, pp. 627–632, 2012.

J. Mitchell, P. Paul, H.-J. Chen et al., “Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 16, pp. 7556–7561, 2010.

V. I. Tishkov and S. V. Khoronenkova, “D-Amino acid oxidase: structure, catalytic mechanism, and practical application,” Biochemistry, vol. 70, no. 1, pp. 40–54, 2005.

H. Hasegawa, T. Matsukawa, Y. Shinohara, R. Konno, and T. Hashimoto, “Role of renal D-amino-acid oxidase in pharmacokinetics of D-leucine,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 287, no. 1, pp. E160–E165, 2004.

S. M. Smith, J. M. Uslaner, and P. H. Hutson, “The therapeutic potential of D-amino acid oxidase (DAAO) inhibitors,” Open Medicinal Chemistry Journal, vol. 4, no. 1, pp. 3–9, 2010.

D. Ferraris, B. Duvall, Y.-S. Ko et al., “Synthesis and biological evaluation of D-amino acid oxidase inhibitors,” Journal of Medicinal Chemistry, vol. 51, no. 12, pp. 3357–3359, 2008.

K. Hashimoto, Y. Fujita, M. Horio et al., “Co-administration of a D-amino acid oxidase inhibitor potentiates the efficacy of D-serine in attenuating prepulse inhibition deficits after administration of dizocilpine,” Biological Psychiatry, vol. 65, no. 12, pp. 1103–1106, 2009.

A. W. Krug, K. Völker, W. H. Dantzler, and S. Silbernagl, “Why is D-serine nephrotoxic and α-aminoisobutyric acid protective?” The American Journal of Physiology—Renal Physiology, vol. 293, no. 1, pp. F382–F390, 2007.

World Health Organization, “Concise International Chemical Assessment, Document 26. Benzoic Acid and Sodium Benzoate,” World Health Organization, Geneva, Switzerland, 2000, http://www.who.int/ipcs/publications/cicad/cicad26_rev_1.pdf

W.-J. Zhao, Z.-Y. Gao, H. Wei et al., “Spinal D-amino acid oxidase contributes to neuropathic pain in rats,” Journal of Pharmacology and Experimental Therapeutics, vol. 332, no. 1, pp. 248–254, 2010.

N. Gong, Z.-Y. Gao, Y.-C. Wang et al., “A series of d-amino acid oxidase inhibitors specifically prevents and reverses formalin-induced tonic pain in rats,” Journal of Pharmacology and Experimental Therapeutics, vol. 336, no. 1, pp. 282–293, 2011.

H. K. Park, Y. Shishido, S. Ichise-Shishido et al., “Potential role for astroglial D-amino acid oxidase in extracellular D-serine metabolism and cytotoxicity,” Journal of Biochemistry, vol. 139, no. 2, pp. 295–304, 2006.

A. Jana, K. K. Modi, A. Roy, J. A. Anderson, R. B. Van Breemen, and K. Pahan, “Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: therapeutic implications for neurodegenerative disorders,” Journal of Neuroimmune Pharmacology, vol. 8, no. 3, pp. 739–755, 2013.

H. Y. Lane, C. H. Lin, M. F. Green et al., “Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor,” JAMA Psychiatry, vol. 70, no. 12, pp. 1267–1275, 2013.