Lack of evidence for direct ligand-gated ion channel activity of GluD receptors.

Delta receptors (GluD1 and GluD2), members of the large ionotropic glutamate receptor (iGluR) family, play a central role in numerous neurodevelopmental and psychiatric disorders. The amino-terminal domain (ATD) of GluD orchestrates synapse formation and maturation processes through its interaction with the Cbln family of synaptic organizers and neurexin (Nrxn). The transsynaptic triad of Nrxn-Cbln-GluD also serves as a potent regulator of synaptic plasticity, at both excitatory and inhibitory synapses. Despite these recognized functions, there is still debate as to whether GluD functions as a "canonical" ion channel, similar to other iGluRs. A recent report proposes that the ATD of GluD2 imposes conformational constraints on channel activity; removal of this constraint by binding to Cbln1 and Nrxn, or removal of the ATD, reveals channel activity in GluD2 upon administration of glycine (Gly) and d-serine (d-Ser), two GluD ligands. We were able to reproduce currents when Gly or d-Ser was administered to clusters of heterologous human embryonic kidney 293 (HEK293) cells expressing Cbln1, GluD2 (or GluD1), and Nrxn. However, Gly or d-Ser, but also l-glutamate (l-Glu), evoked similar currents in naive (i.e., untransfected) HEK293 cells and in GluD2-null Purkinje neurons. Furthermore, no current was detected in isolated HEK293 cells expressing GluD2 lacking the ATD upon administration of Gly. Taken together, these results cast doubt on the previously proposed hypothesis that extracellular ligands directly gate wild-type GluD channels.

Impairment of serine transport across the blood-brain barrier by deletion of Slc38a5 causes developmental delay and motor dysfunction.

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. Slc38a5-KO pups exhibit motor impairments that are affected by the administration of L-serine at concentrations that replenish the serine pool in the brain. Our results highlight a critical role of Slc38a5 in supplying L-serine via the BBB for proper brain development.

d-Serine Inhibits Non-ionotropic NMDA Receptor Signaling.

NMDA-type glutamate receptors (NMDARs) are widely recognized as master regulators of synaptic plasticity, most notably for driving long-term changes in synapse size and strength that support learning. NMDARs are unique among neurotransmitter receptors in that they require binding of both neurotransmitter (glutamate) and co-agonist (e.g., d-serine) to open the receptor channel, which leads to the influx of calcium ions that drive synaptic plasticity. Over the past decade, evidence has accumulated that NMDARs also support synaptic plasticity via ion flux-independent (non-ionotropic) signaling upon the binding of glutamate in the absence of co-agonist, although conflicting results have led to significant controversy. Here, we hypothesized that a major source of contradictory results might be attributed to variable occupancy of the co-agonist binding site under different experimental conditions. To test this hypothesis, we manipulated co-agonist availability in acute hippocampal slices from mice of both sexes. We found that enzymatic scavenging of endogenous co-agonists enhanced the magnitude of long-term depression (LTD) induced by non-ionotropic NMDAR signaling in the presence of the NMDAR pore blocker MK801. Conversely, a saturating concentration of d-serine completely inhibited LTD and spine shrinkage induced by glutamate binding in the presence of MK801 or Mg2+ Using a Förster resonance energy transfer (FRET)-based assay in cultured neurons, we further found that d-serine completely blocked NMDA-induced conformational movements of the GluN1 cytoplasmic domains in the presence of MK801. Our results support a model in which d-serine availability serves to modulate NMDAR signaling and synaptic plasticity even when the NMDAR is blocked by magnesium.

A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.

Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum, and microcephaly in children. SLC1A4 catalyzes obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models, including a constitutive Slc1a4-KO mouse, a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E), and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fide L-serine transporter at the BBB and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids in the brain, neurodegeneration, synaptic and mitochondrial abnormalities, and behavioral impairments. Prenatal and early postnatal oral administration of L-serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioral changes. Administration of L-serine till the second postnatal week also normalized brain weight in Slc1a4-E256 K mice. Our observations suggest that the transport of "non-essential" amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We proposed that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB required for optimal brain growth and leads to a metabolic microcephaly, which may be amenable to treatment with L-serine.

Blood D-serine levels correlate with aging and dopaminergic treatment in Parkinson's disease.

We recently described increased D- and L-serine concentrations in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, the post-mortem caudate-putamen of human Parkinson's disease (PD) brains and the cerebrospinal fluid (CSF) of de novo living PD patients. However, data regarding blood D- and L-serine levels in PD are scarce. Here, we investigated whether the serum profile of D- and L-serine, as well as the other glutamate N-methyl-D-aspartate ionotropic receptor (NMDAR)-related amino acids, (i) differs between PD patients and healthy controls (HC) and (ii) correlates with clinical-demographic features and levodopa equivalent daily dose (LEDD) in PD. Eighty-three consecutive PD patients and forty-one HC were enrolled. PD cohort underwent an extensive clinical characterization. Serum levels of D- and L-serine, L-glutamate, L-glutamine, L-aspartate, L-asparagine and glycine were determined using High Performance Liquid Chromatography. In age- and sex-adjusted analyses, no differences emerged in the serum levels of D-serine, L-serine and other NMDAR-related amino acids between PD and HC. However, we found that D-serine and D-/Total serine ratio positively correlated with age in PD but not in HC, and also with PD age at onset. Moreover, we found that higher LEDD correlated with lower levels of D-serine and the other excitatory amino acids. Following these results, the addition of LEDD as covariate in the analyses disclosed a selective significant increase of D-serine in PD compared to HC (Δ ≈ 38%). Overall, these findings suggest that serum D-serine and D-/Total serine may represent a valuable biochemical signature of PD.

D-Amino acids differentially trigger an inflammatory environment in vitro.

Studies in vivo have demonstrated that the accumulation of D-amino acids (D-AAs) is associated with age-related diseases and increased immune activation. However, the underlying mechanism(s) of these observations are not well defined. The metabolism of D-AAs by D-amino oxidase (DAO) produces hydrogen peroxide (H2O2), a reactive oxygen species involved in several physiological processes including immune response, cell differentiation, and proliferation. Excessive levels of H2O2 contribute to oxidative stress and eventual cell death, a characteristic of age-related pathology. Here, we explored the molecular mechanisms of D-serine (D-Ser) and D-alanine (D-Ala) in human liver cancer cells, HepG2, with a focus on the production of H2O2 the downstream secretion of pro-inflammatory cytokine and chemokine, and subsequent cell death. In HepG2 cells, we demonstrated that D-Ser decreased H2O2 production and induced concentration-dependent depolarization of mitochondrial membrane potential (MMP). This was associated with the upregulation of activated NF-кB, pro-inflammatory cytokine, TNF-α, and chemokine, IL-8 secretion, and subsequent apoptosis. Conversely, D-Ala-treated cells induced H2O2 production, and were also accompanied by the upregulation of activated NF-кB, TNF-α, and IL-8, but did not cause significant apoptosis. The present study confirms the role of both D-Ser and D-Ala in inducing inflammatory responses, but each via unique activation pathways. This response was associated with apoptotic cell death only with D-Ser. Further research is required to gain a better understanding of the mechanisms underlying D-AA-induced inflammation and its downstream consequences, especially in the context of aging given the wide detection of these entities in systemic circulation.

Impact of Serine Racemase Deletion on Nicotine Discrimination.

INTRODUCTION: The high comorbidity between schizophrenia and cigarette smoking points to a possible shared heritable factor predisposing individuals with schizophrenia to nicotine addiction. The N-methyl-D-aspartate (NMDA) receptor has been highly implicated in both schizophrenia and nicotine addiction. METHODS: In the present study, we used mice with a null mutation on the serine racemase gene (srr), an established risk gene for schizophrenia, which encodes the enzyme to produce the NMDA receptor co-agonist D-serine, to model the pathology of schizophrenia and to determine whether NMDA receptor hypofunction reduced the ability of srr-/- mice to identify nicotine's subjective effects. Established nicotine discrimination procedures were used to train srr-/- and wild-type (WT) mice to discriminate 0.4 mg/kg nicotine under a 10-response fixed-ratio (FR10) schedule of food reinforcement. RESULTS: Results show that WT mice reliably acquired 0.4 mg/kg nicotine discrimination in about 54 training session, whereas srr-/- mice failed to acquire robust 0.4 mg/kg nicotine discrimination even after extended (>70) training sessions. These results show that NDMA receptor hypofunction in srr-/- mice decreased sensitivity to the interoceptive effects of nicotine. CONCLUSIONS: Projected to humans, NMDA receptor hypofunction caused by mutations to the serine racemase gene in schizophrenia may reduce sensitivity to nicotine's subjective effects leading to increased nicotine consumption to produce the same effects as those unaffected by schizophrenia. IMPLICATIONS: There is high comorbidity between schizophrenia and nicotine dependence as well as possible shared genetic risk factors between the two. The serine racemase knockout mouse (srr-/-) with NMDA receptor hypofunction has been developed a model for schizophrenia. We found that srr-/- mice were unable to acquire 0.4 mg/kg nicotine discrimination, whilst wild-type mice readily discriminated nicotine. These results show that decreased NMDA receptor function present in srr-/- mice and patients with schizophrenia may result in reduced sensitivity to nicotine's interoceptive effects, leading to increased nicotine consumption to produce the same subjective effects as those unaffected by schizophrenia.

Biosynthesis and Degradation of Free D-Amino Acids and Their Physiological Roles in the Periphery and Endocrine Glands.

It was long believed that D-amino acids were either unnatural isomers or laboratory artifacts, and that the important functions of amino acids were exerted only by L-amino acids. However, recent investigations have revealed a variety of D-amino acids in mammals that play important roles in physiological functions, including free D-serine and D-aspartate that are crucial in the central nervous system. The functions of several D-amino acids in the periphery and endocrine glands are also receiving increasing attention. Here, we present an overview of recent advances in elucidating the physiological roles of D-amino acids, especially in the periphery and endocrine glands.

Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine.

Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine-glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D1 and D3 receptors. Using in vivo microdialysis, we show that D1 and D3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d-serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d-serine is required for the potentiation of cognition by D3R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d-serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine-glutamate cross-talk.

Gut Symptoms, Gut Dysbiosis and Gut-Derived Toxins in ALS.

Many pathogenetic mechanisms have been proposed for amyotrophic lateral sclerosis (ALS). Recently, there have been emerging suggestions of a possible role for the gut microbiota. Gut microbiota have a range of functions and could influence ALS by several mechanisms. Here, we review the possible role of gut-derived neurotoxins/excitotoxins. We review the evidence of gut symptoms and gut dysbiosis in ALS. We then examine a possible role for gut-derived toxins by reviewing the evidence that these molecules are toxic to the central nervous system, evidence of their association with ALS, the existence of biochemical pathways by which these molecules could be produced by the gut microbiota and existence of mechanisms of transport from the gut to the blood and brain. We then present evidence that there are increased levels of these toxins in the blood of some ALS patients. We review the effects of therapies that attempt to alter the gut microbiota or ameliorate the biochemical effects of gut toxins. It is possible that gut dysbiosis contributes to elevated levels of toxins and that these could potentially contribute to ALS pathogenesis, but more work is required.

Selective Ablation of Sod2 in Astrocytes Induces Sex-Specific Effects on Cognitive Function, d-Serine Availability, and Astrogliosis.

Cognitive decline is a debilitating aspect of aging and neurodegenerative diseases such as Alzheimer's disease are closely associated with mitochondrial dysfunction, increased reactive oxygen species, neuroinflammation, and astrogliosis. This study investigated the effects of decreased mitochondrial antioxidant response specifically in astrocytes on cognitive performance and neuronal function in C57BL/6J mice using a tamoxifen-inducible astrocyte-specific knockout of manganese superoxide dismutase (aSOD2-KO), a mitochondrial matrix antioxidant that detoxifies superoxide generated during mitochondrial respiration. We reduced astrocyte SOD2 levels in male and female mice at 11-12 months of age and tested in an automated home cage (PhenoTyper) apparatus for diurnal patterns, spatial learning, and memory function at 15 months of age. aSOD2-KO impaired hippocampal-dependent spatial working memory and decreased cognitive flexibility in the reversal phase of the testing paradigm in males. Female aSOD2-KO showed no learning and memory deficits compared with age-matched controls despite significant reduction in hippocampal SOD2 expression. aSOD2-KO males further showed decreased hippocampal long-term potentiation, but paired-pulse facilitation was unaffected. Levels of d-serine, an NMDA receptor coagonist, were also reduced in aSOD2-KO mice, but female knockouts showed a compensatory increase in serine racemase expression. Furthermore, aSOD2-KO mice demonstrated increased density of astrocytes, indicative of astrogliosis, in the hippocampus compared with age-matched controls. These data demonstrate that reduction in mitochondrial antioxidant stress response in astrocytes recapitulates age-related deficits in cognitive function, d-serine availability, and astrogliosis. Therefore, improving astrocyte mitochondrial homeostasis may provide a therapeutic target for intervention for cognitive impairment in aging.SIGNIFICANCE STATEMENT Diminished antioxidant response is associated with increased astrogliosis in aging and in Alzheimer's disease. Manganese superoxide dismutase (SOD2) is an antioxidant in the mitochondrial matrix that detoxifies superoxide and maintains mitochondrial homeostasis. We show that astrocytic ablation of SOD2 impairs hippocampal-dependent plasticity in spatial working memory, reduces long-term potentiation of hippocampal neurons and levels of the neuromodulator d-serine, and increases astrogliosis, consistent with defects in advanced aging and Alzheimer's disease. Our data provide strong evidence for sex-specific effects of astrocytic SOD2 functions in age-related cognitive dysfunction.

Astroglial cannabinoid signaling and behavior.

In neuroscience, the explosion of innovative and advanced technical accomplishments is fundamental to understanding brain functioning. For example, the possibility to distinguish glial and neuronal activities at the synaptic level and/or the appearance of new genetic tools to specifically monitor and manipulate astroglial functions revealed that astrocytes are involved in several facets of behavioral control. In this sense, the discovery of functional presence of type-1 cannabinoid receptors in astrocytes has led to identify important behavioral responses mediated by this specific pool of cannabinoid receptors. Thus, astroglial type-1 cannabinoid receptors are in the perfect place to play a role in a complex scenario in which astrocytes sense neuronal activity, release gliotransmitters and modulate the activity of other neurons, ultimately controlling behavioral responses. In this review, we will describe the known behavioral implications of astroglial cannabinoid signaling and highlight exciting unexplored research avenues on how astroglial cannabinoid signaling could affect behavior.

Endogenous d-serine exists in the mammalian brain independent of synthesis by serine racemase.

Activation of N-methyl-d-aspartate receptors (NMDARs) requires binding of a co-agonist in addition to l-glutamate. d-serine binds to the co-agonist site on GluN1 subunits of NMDARs and modulates glutamatergic neurotransmission. While loss of GluN1 subunits in mice results in neonatal death due to respiratory failure, animals that lack a d-serine synthetic enzyme, serine racemase (SR), show grossly normal growth. However, SR-independent origins of d-serine in the brain remain unclarified. In the present study, we investigated the origin of brain d-serine in mice. Loss of SR significantly reduced d-serine in the cerebral cortex, but a portion of d-serine remained in both neonates and adults. Although d-serine was also produced by intestinal bacteria, germ-free experiments did not influence d-serine levels in the cerebral cortex. In addition, treatment of SR-knockout mice with antibiotics showed a significant reduction of intestinal d-serine, but no reduction in the brain. On the other hand, restriction of dietary intake reduced systemic circulation of d-serine and resulted in a slight decrease of d-serine in the cerebral cortex, but did not account for brain d-serine found in the SR-knockout mice. Therefore, our findings show that endogenous d-serine of non-SR origin exists in the brain. Such previously unrecognized, SR-independent, endogenous d-serine may contribute baseline activity of NMDARs, especially in developing brain, which has minimal SR expression.

Alterations of serine racemase expression determine proliferation and differentiation of neuroblastoma cells.

Although the role of serine racemase (SR) in neuropsychiatric disorders has been extensively studied, its role in cell proliferation and differentiation remains unclear. Deletion of Srr, the encoding gene for SR, has been shown to reduce dendritic arborization and dendritic spine density in the brains of adult mice, whereas increased SR levels have been associated with differentiation in cell cultures. Previously, we demonstrated that valproic acid induces differentiation in the N2A neuroblastoma cell line, and that this differentiation is associated with increased SR expression. These observations suggest that SR may have a role in cell proliferation and differentiation. We herein found that both valproic acid and all-trans retinoic acid induced N2A differentiation. In contrast, knockdown of SR reduced levels of differentiation, increased N2A proliferation, promoted cell cycle entry, and modulated expression of cell cycle-related proteins. To further evaluate the effects of SR expression on cell proliferation and differentiation, we used an in vivo model of neuroblastoma in nude mice. N2A cells stably expressing scramble shRNA (Srrwt -N2A) or specific Srr shRNA (Srrkd -N2A) were subcutaneously injected into nude mice. The weights and volumes of Srrwt -N2A-derived tumors were lower than Srrkd -N2A-derived tumors. Furthermore, Srrwt -N2A-derived tumors were significantly mitigated by intraperitoneal injection of valproic acid, whereas Srrkd -N2A-derived tumors were unaffected. Taken together, our findings demonstrate for the first time that alterations in SR expression determine the transition between proliferation and differentiation in neural progenitor cells. Thus, in addition to its well-established roles in neuropsychiatric disorders, our study has highlighted a novel role for SR in cell proliferation and differentiation.

Astroglial gliotransmitters released via Cx43 hemichannels regulate NMDAR-dependent transmission and short-term fear memory in the basolateral amygdala.

Astrocytes release gliotransmitters via connexin 43 (Cx43) hemichannels into neighboring synapses, which can modulate synaptic activity and are necessary for fear memory consolidation. However, the gliotransmitters released, and their mechanisms of action remain elusive. Here, we report that fear conditioning training elevated Cx43 hemichannel activity in astrocytes from the basolateral amygdala (BLA). The selective blockade of Cx43 hemichannels by microinfusion of TAT-Cx43L2 peptide into the BLA induced memory deficits 1 and 24 h after training, without affecting learning. The memory impairments were prevented by the co-injection of glutamate and D-serine, but not by the injection of either alone, suggesting a role for NMDA receptors (NMDAR). The incubation with TAT-Cx43L2 decreased NMDAR-mediated currents in BLA slices, effect that was also prevented by the addition of glutamate and D-serine. NMDARs in primary neuronal cultures were unaffected by TAT-Cx43L2, ruling out direct effects of the peptide on NMDARs. Finally, we show that D-serine permeates through purified Cx43 hemichannels reconstituted in liposomes. We propose that the release of glutamate and D-serine from astrocytes through Cx43 hemichannels is necessary for the activation of post-synaptic NMDARs during training, to allow for the formation of short-term and subsequent long-term memory, but not for learning per se.

Cross species review of the physiological role of D-serine in translationally relevant behaviors.

Bridging the gap between preclinical models of neurological and psychiatric disorders with their human manifestations is necessary to understand their underlying mechanisms, identify biomarkers, and develop novel therapeutics. Cognitive and social impairments underlie multiple neuropsychiatric and neurological disorders and are often comorbid with sleep disturbances, which can exacerbate poor outcomes. Importantly, many symptoms are conserved between vertebrates and invertebrates, although they may have subtle differences. Therefore, it is essential to determine the molecular mechanisms underlying these behaviors across different species and their translatability to humans. Genome-wide association studies have indicated an association between glutamatergic gene variants and both the risk and frequency of psychiatric disorders such as schizophrenia, bipolar disorder, and autism spectrum disorder. For example, changes in glutamatergic neurotransmission, such as glutamate receptor subtype N-methyl-D-aspartate receptor (NMDAR) hypofunction, have been shown to contribute to the pathophysiology of schizophrenia. Furthermore, in neurological disorders, such as traumatic brain injury and Alzheimer's disease, hyperactivation of NMDARs leads to synaptic damage. In addition to glutamate binding, NMDARs require the binding of a co-agonist D-serine or glycine to the GluN1 subunit to open. D-serine, which is racemized from L-serine by the neuronal enzyme serine racemase (SRR), and both SRR and D-serine are enriched in cortico-limbic brain regions. D-serine is critical for complex behaviors, such as cognition and social behavior, where dysregulation of its synthesis and release has been implicated in many pathological conditions. In this review, we explore the role of D-serine in behaviors that are translationally relevant to multiple psychiatric and neurological disorders in different models across species.

Determination of D-serine and D-alanine Tissue Levels in the Prefrontal Cortex and Hippocampus of Rats After a Single Dose of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, with Potential Antipsychotic and Antidepressant Properties.

The effects of the N-methyl-D-aspartate receptor activators D-serine, D-alanine, and sarcosine against schizophrenia and depression are promising. Nevertheless, high doses of D-serine and sarcosine are associated with undesirable nephrotoxicity or worsened prostatic cancer. Thus, alternatives are needed. DAAO inhibition can increase D-serine as well as D-alanine and protect against D-serine-induced nephrotoxicity. Although several DAAO inhibitors improve the symptoms of schizophrenia and depression, they can increase the plasma levels but not brain levels of D-serine. The mechanism of action of DAAO inhibitors remains unclear. We investigated the effects of the DAAO inhibitor sodium benzoate on the prefrontal cortex and hippocampal level of D-alanine as known another substrate with antipsychotic and antidepressant properties and other NMDAR-related amino acids, such as, L-alanine, D-serine, L-serine, D-glutamate, L-glutamate, and glycine levels. Our results indicate that sodium benzoate exerts antipsychotic and antidepressant-like effects without changing the D-serine levels in the brain prefrontal cortex (PFC) and hippocampus. Moreover, D-alanine levels in the PFC and hippocampus did not change. Despite these negative findings regarding the effects of D-amino acids in the PFC and hippocampus, sodium benzoate exhibited antipsychotic and antidepressant-like effects. Thus, the therapeutic effects of sodium benzoate are independent of D-serine or D-alanine levels. In conclusion, sodium benzoate may be effective among patients with schizophrenia or depression; however, the mechanisms of actions remain to be elucidated.

Mammalian D-Cysteine: A new addition to the growing family of biologically relevant D-amino acids.

Mammalian D-Cysteine is racemized from L-cysteine by serine racemase, a pyridoxal phosphate (PLP)-dependent enzyme. Endogenous D-Cysteine plays a role in neural development by inhibiting proliferation of neural progenitor cells (NPCs) via protein kinase B (AKT) signaling mediated by the FoxO family of transcription factors. D-Cysteine binds to Myristoylated Alanine Rich C Kinase Substrate (MARCKS) and alters phosphorylation at Ser 159/163 and its translocation from the membrane. By racemizing serine and cysteine, mammalian serine racemase may play important roles in neural development highlighting its importance in psychiatric disorders.

D-Serine as a sensor and effector of the kidney.

D-Serine, a rare enantiomer of serine, is a biomarker of kidney disease and function. The level of D-serine in the human body is precisely regulated through the urinary clearance of the kidney, and its clearance serves as a new measure of glomerular filtration rate with a lower bias than creatinine clearance. D-Serine also has a direct effect on the kidneys and mediates the cellular proliferation of tubular cells via mTOR signaling and induces kidney remodeling as a compensatory reaction to the loss of kidney mass. In living kidney donors, the removal of the kidney results in an increase in blood D-serine level, which in turn accelerates kidney remodeling and augments kidney clearance, thus reducing blood levels of D-serine. This feedback system strictly controls D-serine levels in the body. The function of D-serine as a biomarker and modulator of kidney function will be the basis of precision medicine for kidney diseases.

Predictive value of serum d-serine level for hearing impairment in uremic patients.

OBJECTIVE: To investigate the predictive value of serum d-serine level for hearing impairment (HI) in uremic patients. METHODS: In this study, 30 uremic patients with HI and 30 with normal hearing were selected. The basic conditions, biochemical indicators, and serum serine levels of the two groups were compared to analyze the influencing factors of HI. RESULTS: The age and d-serine levels were higher in the HI group, while the l-serine level was lower than uremia in the normal hearing group. Logistic regression analysis showed that d-serine level ≥10 µM and older age increased the risk of HI. The area of the receiver operating characteristic (ROC) curve drawn by the prediction probability of HI was 0.838, indicating that age, d-serine, and l-serine had predictive diagnostic values for HI (p < .001). Among these, the ROC curve area of d-serine in predicting HI in uremic patients was 0.822 (p < .001). CONCLUSIONS: Increased d-serine and age are two risk factors for HI, while l-serine is a protective factor. d-Serine level has a predictive value for HI in uremic patients. Uremic patients are recommended hearing assessment, estimation of d-serine levels, and early intervention.