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Objective: To test the application of fully automated telephone screening using computerized digital voice recordings and touch-tone responses to assess symptoms of depression.Design: A cross-sectional study of a 2-week-long telephone survey.Setting: Toll-free telephone calls placed from home, work, or school to a central telephone/computer system at a telecommunications company in the Boston, Mass, area.Participants: A total of 1812 participants called the system. Of these, 278 were students and faculty at a large midwestern state university, 725 were employees of a large northeastern high-technology firm, and 809 did not identify which site they were calling from.Main Outcome Measures: The 20-question multiple-choice Zung Depression Scale was used to screen for depressive symptoms, and additional questions gathered demographic and caller satisfaction information.Results: No technical problems were encountered during the trial. Of 1812 callers, 1597 (88.1%) completed all questions. Of these, 412 callers (25.8%) met criteria for "moderate or marked" depression and another 194 (12.1%) met criteria for "severe or extreme" depression. The majority of callers scoring positive for depression had received no previous treatment for depression. Of callers who completed the screening questionnaire, 74.6% reported the call to have been at least "moderately" helpful.Conclusion: Readily available low-cost technology provides a fully automated, widely accessible, and confidential method of screening for a common mental illness. [ABSTRACT FROM AUTHOR]

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 sessions, 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 as a model for schizophrenia. We found that srr-/- mice were unable to acquire 0.4 mg/kg nicotine discrimination, while WT 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

For nearly fifty years, the dopamine hypothesis has dominated our understanding of the pathophysiology of schizophrenia and provided the lone target for drug development. However, with the exception of clozapine, the dopamine D2 receptor antagonizing anti-psychotic drugs have little impact on the negative symptoms and cognitive deficits, aspects of the disorder that robustly predict outcome. Pathologic studies reveal cortical atrophy and wide-spread loss of glutamatergic synaptic spines, unexplained by dopaminergic malfunction. Recent genome-wide association studies indicate that at least thirty risk genes for schizophrenia encode proteins localized to the glutamatergic synapse and inhibit glutamate neurotransmission, especially at the NMDA receptor. To function, the NMDA receptor requires the binding of glycine (primarily in the cerebellum and brainstem) or D-serine (in forebrain) to the NR1 channel subunit of the NMDA receptor. Genetically silencing the gene (srr) encoding serine racemase, the biosynthetic enzyme for D-serine, results in forebrain NMDA receptor hypofunction. The srr-/- mice have 90 % loss of endogenous D-serine and approximately 70 % decrease in NMDA receptor function. Several animal models of schizophrenia are based on behavioral and pharmacologic strategies, which have negligible validity with regard to the fundamental etiology of schizophrenia. We summarize here the results of a mouse model, in which srr, one of the two dozen or more risk gene for schizophrenia that affect NMDA receptor function, has been inactivated. The srr-/- mice exhibit striking similarities to schizophrenia including cortical atrophy, loss of cortico-limbic glutamatergic synapses, increased sub-cortical dopamine release, EEG abnormalities, and cognitive impairments. The limited efficacy of drugs targeting the glutamatergic synapse on DSM-5 diagnosed criteria for schizophrenia used in clinical trials may reflect the fact that only 30 % of the patients have impaired glutamatergic neurotransmission, resulting from the genetic heterogeneity of the disorder., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Glycine is an obligatory co-agonist at excitatory NMDA receptors in the brain, especially in the dentate gyrus, which has been postulated to be crucial for the development of psychotic associations and memories with psychotic content. Drugs modulating glycine levels are in clinical development for improving cognition in schizophrenia. However, the functional relevance of the regulation of glycine metabolism by endogenous enzymes is unclear. Using a chromosome-engineered allelic series in mice, we report that a triplication of the gene encoding the glycine-catabolizing enzyme glycine decarboxylase (GLDC) - as found on a small supernumerary marker chromosome in patients with psychosis - reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) and suppresses long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduces the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displays deficits in schizophrenia-like behaviors which are in part known to be dependent on the activity of the dentate gyrus, e.g., prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference. Our results demonstrate that Gldc negatively regulates long-term synaptic plasticity in the dentate gyrus in mice, suggesting that an increase in GLDC copy number possibly contributes to the development of psychosis in humans., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Remarkable advances have been made in schizophrenia (SCZ) GWAS, but gleaning biological insight from these loci is challenging. Genetic influences on gene expression (e.g., eQTLs) are cell type-specific, but most studies that attempt to clarify GWAS loci's influence on gene expression have employed tissues with mixed cell compositions that can obscure cell-specific effects. Furthermore, enriched SCZ heritability in the fetal brain underscores the need to study the impact of SCZ risk loci in specific developing neurons. MGE-derived cortical interneurons (cINs) are consistently affected in SCZ brains and show enriched SCZ heritability in human fetal brains. We identified SCZ GWAS risk genes that are dysregulated in iPSC-derived homogeneous populations of developing SCZ cINs. These SCZ GWAS loci differential expression (DE) genes converge on the PKC pathway. Their disruption results in PKC hyperactivity in developing cINs, leading to arborization deficits. We show that the fine-mapped GWAS locus in the ATP2A2 gene of the PKC pathway harbors enhancer marks by ATACseq and ChIPseq, and regulates ATP2A2 expression. We also generated developing glutamatergic neurons (GNs), another population with enriched SCZ heritability, and confirmed their functionality after transplantation into the mouse brain. Then, we identified SCZ GWAS risk genes that are dysregulated in developing SCZ GNs. GN-specific SCZ GWAS loci DE genes converge on the ion transporter pathway, distinct from those for cINs. Disruption of the pathway gene CACNA1D resulted in deficits of Ca 2+ currents in developing GNs, suggesting compromised neuronal function by GWAS loci pathway deficits during development. This study allows us to identify cell type-specific and developmental stage-specific mechanisms of SCZ risk gene function, and may aid in identifying mechanism-based novel therapeutic targets., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

D-serine is synthesized by serine racemase (SR) and is a co-agonist at forebrain N-methyl-D-aspartate receptors (NMDARs). D-serine and SR are expressed primarily in neurons, but not in quiescent astrocytes. In this study, we examined the localization of D-serine and SR in the mouse striatum and the effects of genetically silencing SR expression in GABAergic interneurons (iSR-/-). iSR-/- mice had substantially reduced SR expression almost exclusively in striatum, but only exhibited marginal D-serine reduction. SR positive cells in the striatum showed strong co-localization with dopamine- and cyclic AMP-regulated neuronal phosphoprotein (DARPP32) in wild type mice. Transgenic fluorescent reporter mice for either the D1 or D2 dopamine receptors exhibited a 65:35 ratio for co-localization with D1and D2 receptor positive cells, respectively. These results indicate that GABAergic medium spiny neurons receiving dopaminergic inputs in striatum robustly and uniformly express SR. In behavioral tests, iSR-/- mice showed a blunted response to the hedonic and stimulant effects of cocaine, without affecting anxiety-related behaviors. Because the cocaine effects have been shown in the constitutive SR-/- mice, the restriction of the blunted response to cocaine to iSR-/- mice reinforces the conclusion that D-serine in striatal GABAergic neurons plays an important role in mediating dopaminergic stimulant effects. Results in this study suggest that SR in striatal GABAergic neurons is synthesizing D-serine, not as a glutamatergic co-transmitter, but rather as an autocrine whereby the GABAergic neurons control the excitability of their NMDARs by determining the availability of the co-agonist, D-serine., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

There are no validated biomarkers for schizophrenia (SCZ), a disorder linked to neural network dysfunction. We demonstrate that collapsin response mediator protein-2 (CRMP2), a master regulator of cytoskeleton and, hence, neural circuitry, may form the basis for a biomarker because its activity is uniquely imbalanced in SCZ patients. CRMP2's activity depends upon its phosphorylation state. While an equilibrium between inactive (phosphorylated) and active (nonphosphorylated) CRMP2 is present in unaffected individuals, we show that SCZ patients are characterized by excess active CRMP2. We examined CRMP2 levels first in postmortem brains (correlated with neuronal morphometrics) and then, because CRMP2 is expressed in lymphocytes as well, in the peripheral blood of SCZ patients versus age-matched unaffected controls. In the brains and, more starkly, in the lymphocytes of SCZ patients <40 y old, we observed that nonphosphorylated CRMP2 was higher than in controls, while phosphorylated CRMP2 remained unchanged from control. In the brain, these changes were associated with dendritic structural abnormalities. The abundance of active CRMP2 with insufficient opposing inactive p-CRMP2 yielded a unique lowering of the p-CRMP2:CRMP2 ratio in SCZ patients, implying a disruption in the normal equilibrium between active and inactive CRMP2. These clinical data suggest that measuring CRMP2 and p-CRMP2 in peripheral blood might reflect intracerebral processes and suggest a rapid, minimally invasive, sensitive, and specific adjunctive diagnostic aid for early SCZ: increased CRMP2 or a decreased p-CRMP2:CRMP2 ratio may help cinch the diagnosis in a newly presenting young patient suspected of SCZ (versus such mimics as mania in bipolar disorder, where the ratio is high)., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

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 D 1 and D 3 receptors. Using in vivo microdialysis, we show that D 1 and D 3 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 D 3 R 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., Competing Interests: Competing interest statement: M.J.M. and J.-M.R., respectively, were and are full-time employees of Institut de Recherche Servier and have no other interests to declare. S. Schmidt and J.K. are employees of Pronexus Analytical AB but declare no conflicts of interests.

Abnormalities in electroencephalographic (EEG) biomarkers occur in patients with schizophrenia and those clinically at high risk for transition to psychosis and are associated with cognitive impairment. Converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role in the pathophysiology of schizophrenia and likely contributes to biomarker impairments. Thus, characterizing these biomarkers is of significant interest for early diagnosis of schizophrenia and development of novel treatments. We utilized in vivo EEG recordings and behavioral analyses to perform a battery of electrophysiological biomarkers in an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice, and their wild-type littermates. SRKO mice displayed impairments in investigation-elicited gamma power that corresponded with reduced short-term social recognition and enhanced background (pre-investigation) gamma activity. Additionally, SRKO mice exhibited sensory gating impairments in both evoked-gamma power and event-related potential amplitude. However, other biomarkers including the auditory steady-state response, sleep spindles, and state-specific power spectral density were generally neurotypical. In conclusion, SRKO mice demonstrate how chronic NMDAR hypofunction contributes to deficits in certain translationally-relevant EEG biomarkers altered in schizophrenia. Importantly, our gamma band findings suggest an aberrant signal-to-noise ratio impairing cognition that occurs with NMDAR hypofunction, potentially tied to impaired task-dependent alteration in functional connectivity.

d-Serine plays an important role in modulating N-methyl-d-aspartate receptor (NMDAR) neurotransmission in the mammalian brain by binding to the receptor's glycine modulatory site (GMS). The cytosolic enzyme serine racemase (SR) converts L-serine to d-serine, while the peroxisomal enzyme d-amino acid oxidase (DAAO) catalyzes the breakdown of d-serine. Although it is important to understand how the activities of SR and DAAO regulate d-serine levels, very little is known about the mechanisms that regulate the expression of SR and DAAO. In this study, we investigated whether the different centrally active drugs affect the expression of SR and DAAO in adult mouse brain. We found that the NMDAR antagonist, MK801, and cocaine, psychotropic drugs that both augment glutamate release, reduce the expression of SR and DAAO. This regulation is brain region selective, and in the case of cocaine, is reversed in part byα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). However, d-serine and antipsychotics do not regulate SR and DAAO protein levels. In a genetic model of SR disruption, we found that DAAO expression was unaltered in SR conditional knockout mice, in which tissue d-serine content remains fairly stable despite marked reduction in SR expression. This study reveals a new mechanism by which AMPAR activity could regulate NMDAR function via d-serine availability., (Copyright © 2020 Elsevier B.V. All rights reserved.)

d-serine is the primary NMDAR coagonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic d-serine remains limited. Though early studies suggested d-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and d-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons. In addition, using a single-neuron genetic approach in SR conditional KO mice from both sexes, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at 1 month of age, which could be rescued by exogenous d-serine. Interestingly, there was a restoration of LTP by 2 months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of d-serine action. SIGNIFICANCE STATEMENT NMDARs are key regulators of neurodevelopment and synaptic plasticity and are unique in their requirement for binding of a coagonist, which is d-serine at most forebrain synapses. However, our understanding of the mechanisms regulating synaptic d-serine availability remains limited. d-serine is synthesized in the brain by the neuronal enzyme serine racemase (SR). Here, we show dendritic and postsynaptic localization of SR and d-serine in CA1 pyramidal neurons. In addition, using single-neuron genetic deletion of SR, we establish a role of postsynaptic SR in regulating NMDAR function. These results support an autocrine mode of d-serine action at synapses., (Copyright © 2020 the authors.)

The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-L-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors.

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains. These abnormalities may explain altered gamma oscillation and cognitive function in patients with SCZ. Of note, currently used antipsychotic drugs ameliorate psychosis, but they are not very effective in reversing cognitive deficits. Characterizing mechanisms of SCZ pathogenesis, especially related to cognitive deficits, may lead to improved treatments. We generated homogeneous populations of developing cINs from 15 healthy control (HC) iPSC lines and 15 SCZ iPSC lines. SCZ cINs, but not SCZ glutamatergic neurons, show dysregulated Oxidative Phosphorylation (OxPhos) related gene expression, accompanied by compromised mitochondrial function. The OxPhos deficit in cINs could be reversed by Alpha Lipoic Acid/Acetyl-L-Carnitine (ALA/ALC) but not by other chemicals previously identified as increasing mitochondrial function. The restoration of mitochondrial function by ALA/ALC was accompanied by a reversal of arborization deficits in SCZ cINs. OxPhos abnormality, even in the absence of any circuit environment with other neuronal subtypes, appears to be an intrinsic deficit in SCZ cINs.

The neurotoxic action of glutamic acid was first described by Lucas and Newhouse, who demonstrated neural degeneration in the inner layers of the neonatal mouse retina after systemic treatment with L-glutamate. Olney extended these findings by showing that neuronal degeneration affected other brain structures including neurons within the arcuate nucleus of the hypothalamus and the area postrema, that the lesion spared axons passing through these areas, and that the neurotoxic potency of glutamate analogs correlated with their excitatory potency, resulting in the designation "excitotoxins." As this method affected only a small number of brain regions, it was not suitable for targeted brain lesions. The Coyle laboratory showed that direct injection of the potent glutamate receptor agonist, kainic acid, into the rat striatum caused a rapid degeneration of intrinsic neurons while sparing axons of passage or termination including the unmyelinated dopaminergic terminals. Kainic acid also exhibited this perikaryal-specific and axon-sparing profile when injected into the cerebellum, hippocampus and eye. However, neuronal vulnerability was highly variable, with hippocampal CA3, pyriform cortex and amygdala neurons exhibiting great sensitivity due to kainate's high convulsive activity. In a comparison study, ibotenic acid, a potent glutamatergic agonist isolated from the amanita muscaria mushroom, was found to have excitotoxic potency comparable to kainate but was far less epileptogenic. Ibotenate produced spherical, perikaryal-specific lesions regardless of the site of injection, and experiments with specific glutamate receptor antagonists showed that its effects were mediated by the N-methyl-D-aspartate receptor. Because of this uniform neurotoxicity and near ubiquitous efficacy, ibotenic acid became the excitotoxic lesioning agent of choice. The discovery of the excitotoxic properties of the tryptophan metabolite quinolinic acid and of the anti-excitotoxic, neuroprotective effects of the related metabolite kynurenic acid in the Schwarcz laboratory then gave rise to the concept that these endogenous compounds may play causative roles in the neuropathology of a wide range of neurological and psychiatric disorders., (Copyright © 2020 Coyle and Schwarcz.)

Shape-shifting, a phenomenon wide-spread in folklore, refers to the ability to physically change from one identity to another, typically from an innocuous entity to a destructive one. The amino acid D-serine over the last 25 years has "shape-shifted" into several identities: a purported glial transmitter activating N-methyl-D-aspartate receptors (NMDARs), a co-transmitter concentrated in excitatory glutamatergic neurons, an autocrine that is released at dendritic spines to prime their post-synaptic NMDARs for an instantaneous response to glutamate and an excitotoxic moiety released from inflammatory (A1) astrocytes. This article will review evidence in support of these scenarios and the artifacts that misled investigators of the true identity of D-serine.

Purpose: Mesopic flash electroretinography (fERG) as a tool to identify N-methyl-d-aspartate receptor (NMDAR) hypofunction in subjects with schizophrenia shows great potential. We report the first fERG study in a genetic mouse model of schizophrenia characterized by NMDAR hypofunction from gene silencing of serine racemase (SR) expression (SR-/-), an established risk gene for schizophrenia. We analyzed fERG parameters under various background light adaptations to determine the most significant variables to allow for early identification of people at risk for schizophrenia, prior to onset of psychosis. SR is a risk gene for schizophrenia, and negative and cognitive symptoms antedate the onset of psychosis that is required for diagnosis., Methods: The scotopic, photopic, and mesopic fERGs were analyzed in male and female mice in both SR-/- and wild-type (WT) mice and also analyzed for sex differences. Amplitude and implicit time of the a- and b-wave components, b-/a-wave ratio, and Fourier transform analysis were analyzed., Results: Mesopic a- and b-wave implicit times were significantly delayed, and b-wave amplitudes, b/a ratios, and Fourier transform were significantly decreased in the male SR-/- mice compared to WT, but not in female SR-/- mice. No significant differences were observed in photopic or scotopic fERGs between genotype., Conclusions: The fERG prognostic capability may be improved by examination of background light adaptation, a larger array of light intensities, considering sex as a variable, and performing Fourier transform analyses of all waveforms. This should improve the ability to differentiate between controls and subjects with schizophrenia characterized by NMDAR hypofunction.

Although β-amyloid plaques are a well-recognized hallmark of Alzheimer's disease (AD) neuropathology, no drugs reducing amyloid burden have shown efficacy in clinical trials, suggesting that once AD symptoms emerge, disease progression becomes independent of Aβ production. Reactive astrocytes are another neuropathological feature of AD, where there is an emergence of neurotoxic (A1) reactive astrocytes. We find that serine racemase (SR), the neuronal enzyme that produces the N-methyl-d-aspartate receptor (NMDAR) co-agonist d-serine, is robustly expressed in A1-reactive neurotoxic astrocytes in the hippocampus and entorhinal cortex of AD subjects and an AD rat model. Furthermore, we observe intracellular signaling changes consistent with increased extra-synaptic NMDAR activation, excitotoxicity and decreased neuronal survival. Thus, reducing neurotoxic d-serine release from A1 inflammatory astrocytes could have therapeutic benefit for mild to advanced AD, when anti-amyloid strategies are ineffective., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder., Methods: We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one., Results: Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials., Conclusions: These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The last two decades have witnessed remarkable advance in our understanding the role of d-amino acids in the mammalian nervous system: from the unknown, to known molecules with unknown functions, to potential central players in health and disease. d-Amino acids have emerged as an important class of signaling molecules. In particular, the exploration of the roles of d-serine in brain physiopathology is a vibrant field that is growing at an accelerating pace. However, disentangling the functions of a chiral molecule in a complex chemical matrice as the brain requires specific measurement and detection methods but is also a challenging task as many molecular tools and models investigators are using can lead to confounded observations. Thus, study of d-amino acids demands accurate methodologies and specific controls, and these have often been lacking. Here we outline best practices for d-amino acid research, with a special emphasis on d-serine. We hope these concepts help move the field to greater rigor and reproducibility, allowing the field to advance., (© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Schizophrenia is a chronic and severe psychiatric disorder that has profound impact on an individual's life and on society. Thus, developing more effective therapeutic interventions is essential. Over the past quarter-century, an abundance of evidence from pharmacologic challenges, post-mortem studies, brain imaging, and genetic studies supports the role of glutamatergic dysregulation in the pathophysiology of schizophrenia, and the results of recent randomized clinical trials based on this evidence have yielded promising results. In this article, we review the evidence that alterations in glutamatergic neurotransmission, especially focusing on the N-methyl-d-aspartate receptor (NMDAR) function, may be a critical causative feature of schizophrenia, how this contributes to pathologic circuit function in the brain, and how these insights are revealing whole new avenues for treatment development that could reduce treatment-resistant symptoms, which account for persistent disability., (© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology.)

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.

Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability. Moreover, N-methyl-d-aspartate receptors (NMDARs) have been implicated in the pathophysiology of both SZ and SA. We hypothesize that the high prevalence of comorbid SA in SZ is due to dysfunction of NMDARs caused by shared risk genes. We used transgenic mice with a null mutation of the gene encoding serine racemase (SR), the enzyme that synthesizes the NMDAR co-agonist d-serine and an established risk gene for SZ, to recreate the pathology of SZ. We determined the effect of NMDAR hypofunction resulting from the absence of d-serine on motivated behavior by using intracranial self-stimulation and neurotransmitter release in the nucleus accumbens by using in vivo microdialysis. Compared with wild-type mice, SR-/- mice exhibited similar baseline intracranial self-stimulation thresholds but were less sensitive to the threshold-lowering (rewarding) and the performance-elevating (stimulant) effects of cocaine. While basal dopamine (DA) and glutamate release were elevated in the nucleus accumbens of SR-/- mice, cocaine-induced increases in DA and glutamate release were blunted. γ-Amino-butyric acid efflux was unaffected in the SR-/- mice. Together, these findings suggest that the impaired NMDAR function and a consequent decrease in sensitivity to cocaine effects on behavior are mediated by blunted DA and glutamate responses normally triggered by the drug. Projected to humans, NMDAR hypofunction due to mutations in SR or other genes impacting glutamatergic function in SZ may render abused substances less potent and effective, thus requiring higher doses to achieve a hedonic response, resulting in elevated drug exposure and increased dependence/addiction., (© 2017 Society for the Study of Addiction.)