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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

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.

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.

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.

IntroductionAbnormalities 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. While the pathophysiology of schizophrenia remains poorly understood, converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role and likely contributes to biomarker impairments. Thus, the characterization of such biomarkers is of significant interest for both the early diagnosis of schizophrenia and the development of novel treatments.MethodsWe utilized an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice. In vivo EEG recording and behavioral analyses were performed on adult male and female SRKO mice and wild-type littermates to determine the impact of chronic NMDAR hypofunction on a battery of translationally-relevant electrophysiological biomarkers.ResultsSRKO mice displayed impairments in investigation-elicited gamma power that corresponded with reduced short-term social recognition. This impairment was associated with enhanced background (pre-investigation) broadband gamma activity that only appeared during social task performance. Additionally, SRKO mice exhibited sensory gating impairments, in both gamma power and event-related potential amplitude. However, other biomarkers such as the auditory steady-state response, sleep spindles, and state-specific power spectral density were generally neurotypical.ConclusionsSRKO mice provide a useful model to understand how chronic NMDAR hypofunction contributes to deficits in a subset of translationally-relevant EEG biomarkers that are altered in schizophrenia. Importantly, our gamma band findings support the hypothesis that an aberrant signal-to-noise ratio impairing cognition occurs with NMDAR hypofunction, which may be tied to impaired taskdependent alteration in functional connectivity.

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 synapticd-serine remains limited. Though early studies suggestedd-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 andd-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 exogenousd-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 ofd-serine action.SIGNIFICANCE STATEMENTNMDARs are key regulators of neurodevelopment and synaptic plasticity and are unique in their requirement for binding of a coagonist, which isd-serine at most forebrain synapses. However, our understanding of the mechanisms regulating synapticd-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 andd-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 ofd-serine action at synapses.

D-serine is the primary NMDA receptor (NMDAR) co-agonist 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, as well as the presence of SR in human hippocampal synaptosomes. In addition, using a single-neuron genetic approach in SR conditional knockout mice, 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 one month of age. Interestingly, there was a restoration of LTP by two 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.

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.

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.

Deep layer III pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) from subjects with schizophrenia and bipolar disorder previously were shown to exhibit dendritic arbor pathology. This study sought to determine whether MARCKS, its regulatory protein dysbindin-1, and two proteins, identified using microarray data, CDC42BPA and ARHGEF6, were associated with dendritic arbor pathology in the DLPFC from schizophrenia and bipolar disorder subjects. Using western blotting, relative protein expression was assessed in the DLPFC (BA 46) grey matter from subjects with schizophrenia (n = 19), bipolar disorder (n = 17) and unaffected control subjects (n = 19). Protein expression data were then correlated with dendritic parameter data obtained previously. MARCKS and dysbindin-1a expression levels did not differ among the three groups. Dysbindin-1b expression was 26% higher in schizophrenia subjects (p = 0.01) and correlated inversely with basilar dendrite length (r = -0.31, p = 0.048) and the number of spines per basilar dendrite (r = -0.31, p = 0.048), but not with dendritic spine density (r = -0.16, p = 0.32). The protein expression of CDC42BPA was 33% higher in schizophrenia subjects (p = 0.03) but, did not correlate with any dendritic parameter (p > 0.05). ARHGEF6 87 kDa isoform expression did not differ among the groups. CDC42BPA expression was not altered in frontal cortex from rats chronically administered haloperidol or clozapine. Dysbindin-1b appears to play a role in dendritic arbor pathology observed previously in the DLPFC in schizophrenia.

Background The amygdala is a central component of the neural circuitry that underlies fear learning. N-methyl-D-aspartate receptor–dependent plasticity in the amygdala is required for pavlovian fear conditioning and extinction. N-methyl-D-aspartate receptor activation requires the binding of a coagonist, D-serine, which is synthesized from L-serine by the neuronal enzyme serine racemase (SR). However, little is known about SR and D-serine function in the amygdala. Methods We used immunohistochemical methods to characterize the cellular localization of SR and D-serine in the mouse and human amygdala. Using biochemical and molecular techniques, we determined whether trace fear conditioning and extinction engages the SR/D-serine system in the brain. D-serine was administered systemically to mice to evaluate its effect on fear extinction. Finally, we investigated whether the functional single nucleotide polymorphism rs4523957, which is an expression quantitative trait locus of the human serine racemase (SRR) gene, was associated with fear-related phenotypes in a highly traumatized human cohort. Results We demonstrate that approximately half of the neurons in the amygdala express SR, including both excitatory and inhibitory neurons. We find that the acquisition and extinction of fear memory engages the SR/D-serine system in the mouse amygdala and that D-serine administration facilitates fear extinction. We also demonstrate that the SRR single nucleotide polymorphism, rs4523957, is associated with posttraumatic stress disorder in humans, consistent with the facilitatory effect of D-serine on fear extinction. Conclusions These new findings have important implications for understanding D-serine–mediated N-methyl-D-aspartate receptor plasticity in the amygdala and how this system could contribute to disorders with maladaptive fear circuitry.

cAMP-response-element-binding protein (CREB) is a transcription factor ubiquitously expressed in the brain that regulates neuroplasticity by modulating gene expression. The influx of calcium through N-methyl-d-aspartate receptors (NMDARs) is a well-defined mechanism that leads to the increased expression of CREB-dependent genes, including brain derived neurotrophic factor (BDNF), microRNA-132, and activity-regulated cytoskeleton-associated protein (Arc). These molecules are implicated in the pathophysiology of schizophrenia. We previously demonstrated that serine racemase knockout (SR-/-) mice, which exhibit NMDAR hypofunction due to a lack of the forebrain NMDAR co-agonist d-serine, also have reduced expression of CREB-dependent genes in the hippocampus. Using chromatin immunoprecipitation, we show here that, in SR-/- mice, there is less CREB bound to the promoter regions of BDNF, microRNA-132, and Arc. These data suggest that NMDAR hypofunction in SR-/- mice leads to reduced CREB binding on known activity-dependent genes, in turn contributing to their reduced expression.

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.

Recent studies describe distinct DNA methylomes among phenotypic subclasses of neurons in the human brain, but variation in DNA methylation between common neuronal phenotypes distinguished by their function within distinct neural circuits remains an unexplored concept. Studies able to resolve epigenetic profiles at the level of microcircuits are needed to illuminate chromatin dynamics in the regulation of specific neuronal populations and circuits mediating normal and abnormal behaviors. The Illumina HumanMethylation450 BeadChip was used to assess genome-wide DNA methylation in stratum oriens GABAergic interneurons sampled by laser-microdissection from two discrete microcircuits along the trisynaptic pathway in postmortem human hippocampus from eight control, eight schizophrenia, and eight bipolar disorder subjects. Data were analysed using the minfi Bioconductor package in R software version 3.3.2. We identified 11 highly significant differentially methylated regions associated with a group of genes with high construct-validity, including multiple zinc finger of the cerebellum gene family members and WNT signaling factors. Genomic locations of differentially methylated regions were highly similar between diagnostic categories, with a greater number of differentially methylated individual cytosine residues between circuit locations in bipolar disorder cases than in schizophrenia or control (42, 7, and 7 differentially methylated positions, respectively). These findings identify distinct DNA methylomes among phenotypically similar populations of GABAergic interneurons functioning within separate hippocampal subfields. These data compliment recent studies describing diverse epigenotypes among separate neuronal subclasses, extending this concept to distinct epigenotypes within similar neuronal phenotypes from separate microcircuits within the human brain.

Schizophrenia is a chronic disabling mental disorder that affects about 1% population world-wide, for which there is a desperate need to develop more effective treatments. In this minireview, we summarize the findings from recent studies using induced pluripotent stem cells to model the developmental pathogenesis of schizophrenia and discuss what we have learned from these studies. We also discuss what are the important next steps and key issues to be addressed to move the field forward.

Traumatic brain injury (TBI), ranging from mild concussion to severe penetrating wounds, can involve brain regions that contain damaged or lost synapses in the absence of neuronal death. These affected regions significantly contribute to sensory, motor and/or cognitive deficits. Thus, studying the mechanisms responsible for synaptic instability and dysfunction is important for protecting the nervous system from the consequences of progressive TBI. Our controlled cortical impact (CCI) injury produces ~20% loss of synapses and mild changes in synaptic protein levels in the CA3-CA1 hippocampus without neuronal losses. These synaptic changes are associated with functional deficits, indicated by >50% loss in synaptic plasticity and impaired learning behavior. We show that the receptor tyrosine kinase EphB3 participates in CCI injury-induced synaptic damage, where EphB3−/− mice show preserved long-term potentiation and hippocampal-dependent learning behavior as compared with wild type (WT) injured mice. Improved synaptic function in the absence of EphB3 results from attenuation in CCI injury-induced synaptic losses and reduced d-serine levels compared with WT injured mice. Together, these findings suggest that EphB3 signaling plays a deleterious role in synaptic stability and plasticity after TBI.

Nearly 60 years ago Seymour Kety proposed that research on genetics and brain pathology, but not on neurochemistry, would ultimately lead to an understanding of the pathophysiology of schizophrenia. This article will demonstrate the prescience of Kety's proposal; advances in our knowledge of brain structure and genetics have shaped our current understanding of the pathophysiology of schizophrenia. Brain-imaging techniques have shown that schizophrenia is associated with cortical atrophy and ventricular enlargement, which progresses for at least a decade after the onset of psychotic symptoms. Cortical atrophy correlates with negative symptoms and cognitive impairment, but not with psychotic symptoms, in schizophrenia. Studies with the Golgi-staining technique that illuminates the entire neuron indicate that cortical atrophy is due to reduced synaptic connectivity on the pyramidal neurons and not due to actual loss of neurons. Results of recent genetic studies indicate that several risk genes for schizophrenia are within two degrees of separation from the N-methy-D-aspartate receptor (NMDAR), a subtype of glutamate receptor that is critical to synapse formation and synaptic plasticity. Inactivation of one of these risk genes that encodes serine racemase, which synthesizes D-serine, an NMDAR co-agonist, reproduces the synaptic pathology of schizophrenia. Thus, widespread loss of cortical synaptic connectivity appears to be the primary pathology in schizophrenia that is driven by multiple risk genes that adversely affect synaptogenesis and synapse maintenance, as hypothesized by Kety.

Recent developments in precision gene editing have led to the emergence of the marmoset as an experimental subject of considerable interest and translational value. A better understanding of behavioral phenotypes of the common marmoset will inform the extent to which forthcoming transgenic mutants are cognitively intact. Therefore, additional information regarding their learning, inhibitory control, and motivational abilities is needed. The present studies used touchscreen-based repeated acquisition and discrimination reversal tasks to examine basic dimensions of learning and response inhibition. Marmosets were trained daily to respond to one of the two simultaneously presented novel stimuli. Subjects learned to discriminate the two stimuli (acquisition) and, subsequently, with the contingencies switched (reversal). In addition, progressive ratio performance was used to measure the effort expended to obtain a highly palatable reinforcer varying in magnitude and, thereby, provide an index of relative motivational value. Results indicate that rates of both acquisition and reversal of novel discriminations increased across successive sessions, but that rate of reversal learning remained slower than acquisition learning, i.e., more trials were needed for mastery. A positive correlation was observed between progressive ratio break point and reinforcement magnitude. These results closely replicate previous findings with squirrel monkeys, thus providing evidence of similarity in learning processes across nonhuman primate species. Moreover, these data provide key information about the normative phenotype of wild-type marmosets using three relevant behavioral endpoints.

There is substantial evidence that NMDA receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia (SCZ). A recent large-scale genome-wide association study identified serine racemase (SR), the enzyme that produces the NMDAR co-agonist D-serine, as a risk gene for SCZ. Serine racemase knockout (SR-/-) mice, which lack D-serine, exhibit many of the neurochemical and behavioral abnormalities observed in SCZ. Metabotropic glutamate receptor 5 (mGlu5)-positive allosteric modulators (PAMs) are currently being developed to treat cognitive dysfunction. We used in vitro electrophysiology to determine whether the mGlu5 PAM VU0409551 directly enhances NMDAR function in hippocampal slices from adult male SR-/- mice. We administered VU0409551 systemically for 5 days to adult male wild-type C57BL/6 animals to determine the optimal dose to test in SR-/- mice. We used western blot analyses and trace-fear conditioning to determine whether 5 days of VU0409551 treatment could reverse the neuroplasticity and learning deficits, respectively, in SR-/- mice. We show that VU0409551 enhances NMDAR function and rescues long-term potentiation in hippocampal slices obtained from SR-/- mice. Systemic treatment with VU0409551 (10 and 30 mg/kg) to wild-type mice causes a dose-dependent increase in the Akt/GS3Kα/β signaling pathway, which is reduced in SR-/- mice and in SCZ. Furthermore, the administration of VU0409551 to SR-/- mice reverses their deficits in several neuroplasticity signaling pathways and improves their contextual fear memory. These results support positive allosteric modulation of mGlu5, particularly with VU0409551, as a viable mechanism to reverse the deficits in NMDAR function, synaptic plasticity, and memory that are known to be impaired in SCZ.

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.

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.

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.

Increasing injection of heroin and prescription opioids have led to increases in the incidence of hepatitis C virus (HCV) infections in US young adults since the early 2000s. How best to interrupt transmission and decrease HCV prevalence in young people who inject drugs (PWID) is uncertain.We developed an age-stratified ordinary differential equation HCV transmission model of PWID aged 15–64, which we fit to Michigan HCV surveillance data among young PWID aged 15–29. We used Latin hypercube sampling to fit to data under 10,000 plausible model parameterizations. We used the best-fitting 10% of simulations to predict the potential impact of primary (reducing injection initiation), secondary (increasing cessation, reducing injection partners, or reducing injection drug use relapse), and tertiary (HCV treatment) interventions (over the period 2017–2030) on acute and chronic HCV cases by the year 2030.Treating 3 per 100 current and former PWID per year could reduce chronic HCV by 27.3% (range: 18.7–30.3%) and acute HCV by 23.6% (range: 6.7–29.5%) by 2030 among PWID aged 15–29 if 90% are cured (i.e. achieved sustained virologic response [SVR] to treatment). Reducing the number of syringe sharing partners per year by 10% was predicted to reduce chronic HCV by 15.7% (range: 9.4–23.8%) and acute cases by 21.4% (range: 14.2–32.3%) among PWID aged 15–29 by 2030. In simulations of combinations of interventions, reducing injection initiation, syringe sharing, and relapse rates each by 10% while increasing cessation rates by 10% predicted a 27.7% (range: 18.0–39.7%) reduction in chronic HCV and a 38.4% (range: 28.3–53.3%) reduction in acute HCV.Our results highlight the need for HCV treatment among both current and former PWID and the scale up of both primary and secondary interventions to concurrently reduce HCV prevalence and incidence in Michigan. Keywords: Hepatitis C virus, Injection drug use, Systems modeling

The N-methyl-D-aspartate receptor (NMDAR) is unique in requiring two agonists to bind simultaneously to open its cation channel: the neurotransmitter, glutamate, and the coagonists, glycine, or D-serine. The Snyder laboratory was the first to clone serine racemase (SR), the enzyme that synthesizes D-serine, and to localize it immunocytochemically. Our laboratory has focused on the role of D-serine in brain disorders. Silencing the expression of SR, a risk gene for schizophrenia (SCZ), in mice (SR−/−), results in a phenotype that closely resembles SCZ including: cortical atrophy, reduced dendritic spine density and complexity, downregulation of parvalbumin-positive cortical GABAergic neurons, and cognitive impairments. This pathology can be reversed by treatment of SR−/− mice with D-serine in adulthood. SR−/− mice also exhibit abnormal response toward abusable substances, such as stimulants. They show reduced behavioral sensitization to D-amphetamine, but fail to extinguish it. Place preference to cocaine is altered, and the hedonic response to it is profoundly impaired as assessed by intracranial self-stimulation. D-cycloserine, a partial agonist at the NMDAR glycine modulatory site, shows therapeutic benefit for treating pathologic anxiety in combination with behavioral therapies. Studies in vitro with cortical culture and in vivo with middle cerebral artery occlusion show that silencing SR provides substantial protection against ischemic neuronal death. Finally, the switch of SR expression from neurons to reactive astrocytes after closed head trauma accounts for the reduced in vivo neuro-plasticity, electroencephalogram abnormalities, and cognitive impairments.

In the hippocampus of mice lacking the gene for serine racemase (SR), a D-serine synthesizing enzyme, in the CaMKIIα-expressing neurons, we observed a significant decrease in the extracellular concentration of D-serine, a coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDAR), and NMDAR hypofunction as revealed by diminished extracellular taurine concentrations after an intra-hippocampal NMDA infusion when compared to the wild type controls. Therefore, the neuronal SR could regulate the extracellular D-serine signaling responsible for NMDAR activation in the hippocampus.

d-Serine is a co-agonist at forebrain N-methyl-d-aspartate receptors (NMDAR) and is synthesized by serine racemase (SR). Although d-serine and SR were originally reported to be localized to glia, recent studies have provided compelling evidence that under healthy physiologic conditions both are localized primarily in neurons. However, in pathologic conditions, reactive astrocytes can also express SR and synthesize d-serine. Since cultured astrocytes exhibit features of reactive astrocytes, we have characterized d-serine synthesis and the expression of enzymes involved in its disposition in primary glial cultures. The levels of SR were quite low early in culture and increased markedly in all astrocytes with the duration in vitro. The concentration of d-serine in the culture medium increased in parallel with SR expression in the astrocytes. Microglia, identified by robust expression of Iba1, did not express SR. While the levels of glial fibrillary acidic protein (GFAP), glycine decarboxylase (GLDC) and phosphoglycerate dehydrogenase (PHGDH), the initial enzyme in the pathway converting glycine to l-serine, remained constant in culture, the expression of lipocalin-2, a marker for pan-reactive astrocytes, increased several-fold. The cultured astrocytes also expressed Complement-3a, a marker for a subpopulation of reactive astrocytes (A1). Astrocytes grown from mice with a copy number variant associated with psychosis, which have four copies of the GLDC gene, showed a more rapid production of d-serine and a reduction in glycine in the culture medium. These results substantiate the conclusion that A1 reactive astrocytes express SR and release d-serine under pathologic conditions, which may contribute to their neurotoxic effects by activating extra-synaptic NMDARs.

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.

Purpose Intravenous opioid use is a major contributor to the increases in hepatitis C virus (HCV) incidence observed among young adults during the past decade. HCV is a bloodborne virus; because transmission occurs through sharing syringes or other injection equipment, persons who inject drugs (PWID) are the primary group at risk for new HCV infection. Long-term HCV infection can cause cirrhosis or hepatocellular carcinoma. HCV is curable, but treatment is expensive and often unavailable to PWID. We used an HCV transmission model to predict the potential impact of primary (reducing injection initiation), secondary (reducing injection drug use relapse or effective contacts and increasing cessation), and tertiary (HCV treatment) interventions on incident and prevalent HCV cases in Michigan. Methods We fit an ordinary differential equation HCV transmission model with preferential age mixing to newly reported chronic HCV cases aged 15–30 years reported to the Michigan Department of Health and Human Services. After adjusting for under-reporting and incorporating parameter uncertainty using Latin hypercube sampling, we simulated the potential impact of several interventions. Results Reducing injection initiation and HCV treatment interventions among former PWID predicted reductions in HCV prevalence; however, only injection initiation interventions predicted incidence reductions. For example, reducing initiation by 10% or treating 10% of former PWID per year predicted a 20% reduction in prevalence, on average. Treatment had no predicted impact on incidence while reducing injection initiation predicted a reduction of 15%. Conclusion Results supported that while several strategies could reduce prevalence, decreasing injection initiation is more likely to reduce HCV incidence than HCV treatment. Significance PWID are at high risk of acquiring HCV, and if untreated, of developing liver-related injury and transmitting HCV to others. Incorporating HCV surveillance data into simulation models provides a new opportunity to evaluate HCV intervention strategies among young PWID.

Schizophrenia is a chronic severe mental disorder characterized by psychosis, cognitive impairments, and social and motivational deficits. It is associated with a progressive loss of cortical volume after onset of psychosis; nevertheless, cortical atrophy correlates with the cognitive impairments and the negative symptoms but not with the psychosis. The cortical atrophy is not primarily due to neuronal degeneration but rather to neuronal atrophy and loss of glutamatergic synapses. A downregulation of the presynaptic markers for the parvalbumin-expressing GABAergic interneurons that provide recurrent inhibition to cortical pyramidal neurons is another consistent pathologic feature. Antipsychotic drugs continue after 50 years to be the mainstay of treatment although these drugs, with the possible exception of clozapine, have negligible effects on cognition and negative symptoms. Pharmacologic challenge studies, postmortem analyses and a recent sufficiently powered genome-wide association study and copy number variant studies provide compelling evidence that NMDA receptor hypofunction is an important pathophsysiologic feature of schizophrenia. Silencing the gene encoding serine racemase, the enzyme that synthesizes the cortical-limbic NMDA receptor co-agonist, D-serine, replicates the dendritic and GABAergic pathology and cognitive deficits of schizophrenia in mice. Pharmacologic strategies to overcome NMDA receptor hypofunction hold promise of treating the disabling cognitive and negative symptoms.

d-Serine modulates N-methyl d-aspartate receptors (NMDARs) and regulates synaptic plasticity, neurodevelopment, and learning and memory. However, the primary site of d-serine synthesis and release remains controversial, with some arguing that it is a gliotransmitter and others defining it as a neuronal cotransmitter. Results from several laboratories using different strategies now show that the biosynthetic enzyme of d-serine, serine racemase (SR), is expressed almost entirely by neurons, with few astrocytes appearing to contain d-serine. Cell-selective suppression of SR expression demonstrates that neuronal, rather than astrocytic d-serine, modulates synaptic plasticity. Here, we propose an alternative conceptualization whereby astrocytes affect d-serine levels by synthesizing l-serine that shuttles to neurons to fuel the neuronal synthesis of d-serine.

Background Accumulating evidence suggests the involvement of abnormal glutamateric neurotransmission and N-methyl-D-aspartate receptor hypofunction in the pathophysiology of psychotic disorders. The purpose of this study was to quantify in vivo glutamate (Glu) and glycine (Gly) levels in patients with first-episode psychosis as well as age-matched healthy control subjects with magnetic resonance spectroscopy (MRS). Methods The subjects were 46 patients with first-episode psychosis (20 with a schizophrenia spectrum disorder, 26 with bipolar disorder) and 50 age-matched healthy control subjects. Glu and Gly levels were measured in vivo in the anterior cingulate cortex and posterior cingulate cortex of the subjects by using the echo time–averaged proton MRS technique at 4T (i.e., modified point resolved spectroscopy sequence: 24 echo time steps with 20-ms increments). Metabolite levels were quantified using LCModel with simulated basis sets. Results Significantly higher Glu and Gly levels were found in both the anterior cingulate cortex and posterior cingulate cortex of patients with first-episode psychosis as compared with healthy control subjects. Glu and Gly levels were positively correlated in patients. Patients with a schizophrenia spectrum disorder and bipolar disorder showed similar abnormalities. Conclusions Our findings demonstrate abnormally elevated brain Glu and Gly levels in patients with first-episode psychosis by means of echo time–averaged proton MRS at 4T. The findings implicate dysfunction of N-methyl-D-aspartate receptor and glutamatergic neurotransmission in the pathophysiology of the acute early phase of psychotic illnesses.

Schizophrenia is a chronic severe mental disorder characterized by psychosis, cognitive impairments, and social and motivational deficits. It is associated with a progressive loss of cortical volume after onset of psychosis; nevertheless, cortical atrophy correlates with the cognitive impairments and the negative symptoms but not with the psychosis. The cortical atrophy is not primarily due to neuronal degeneration but rather to neuronal atrophy and loss of glutamatergic synapses. A downregulation of the presynaptic markers for the parvalbumin-expressing GABAergic interneurons that provide recurrent inhibition to cortical pyramidal neurons is another consistent pathologic feature. Antipsychotic drugs continue after 50 years to be the mainstay of treatment although these drugs, with the possible exception of clozapine, have negligible effects on cognition and negative symptoms. Pharmacologic challenge studies, postmortem analyses and a recent sufficiently powered genome-wide association study and copy number variant studies provide compelling evidence that NMDA receptor hypofunction is an important pathophsysiologic feature of schizophrenia. Silencing the gene encoding serine racemase, the enzyme that synthesizes the cortical-limbic NMDA receptor co-agonist, d-serine, replicates the dendritic and GABAergic pathology and cognitive deficits of schizophrenia in mice. Pharmacologic strategies to overcome NMDA receptor hypofunction hold promise of treating the disabling cognitive and negative symptoms.

Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly correlates to 5-HT2AR activation and is absent in 5-HT2AR knockout mice. The precise mechanism of this response remains unclear, but both an intrinsic cortico-cortical pathway and a thalamo-cortical pathway involving glutamate release have been proposed. Here, we used a genetic model of NMDAR hypofunction, a serine racemase knockout (SRKO) mouse, to explore the role of glutamatergic transmission in regulating the 5-HT2AR-mediated cellular and behavioral responses. SRKO mice treated with the 5-HT2AR agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished HTR and lower induction of c-fos mRNA. These altered functional responses in SRKO mice were not associated with changes in cortical or hippocampal 5-HT levels or in 5-HT2AR and metabotropic glutamate-2 receptor (mGluR2) mRNA and protein expression. Together, these findings suggest that D-serine-dependent NMDAR activity is involved in mediating the cellular and behavioral effects of 5-HT2AR activation.

d-Serine, a co-agonist at the NMDA receptor (NMDAR), is synthesized from l-serine by the enzyme serine racemase (SR), which is heavily expressed in the forebrain. Although SR was originally reported to be localized exclusively to astrocytes, recent conditional knock out results demonstrate that little SR is expressed in forebrain astrocytes. As a consequence, the cellular location of its product, d-serine, in the brain is also uncertain. Immunocytochemistry now indicates that SR is expressed primarily in forebrain glutamatergic neurons with the remainder in GABAergic interneurons. We utilized SR deficient (SR–/–) mice, which have

Background Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. Based on our previous publications and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. Methods Using immunohistochemistry technique and confocal imaging analysis, we assessed the relationship between oxidative stress (as revealed by 8-oxo-DG immunolabeling) and PVI and their perineuronal net (PNN) in twelve established animal models relevant to autism (i.e., the fmr1 KO and CNV 15q13.3) and schizophrenia (CNV: 22q11, 15q13.3, 1q21, serine racemase (SR) KO, GRIN2A KO, Gclm KO) with or without additional insult (e.g., environmental: Gclm KO + GBR12909, GRIN2A KO + GBR12909, neonatal ventral hippocampal lesion (NVHL), methylazoxymethanol acetate developmental rodent model (MAM) and poly:IC). Results When PVI deficits in the anterior cingulate cortex were found in these animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders, oxidative stress was always present. Specifically, oxidative stress was negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune, and antioxidant signaling. As convergent endpoint, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models (e.g., Gclm KO, NVHL rats, GRIN2A KO and SR KO mice). D-serine, an allosteric modulator of brain NMDA receptor also protected PVIs and PNN against oxidative stress in SR KO mice. Discussion In view of the fact that the established pathophysiological processes dopamine excess, immune dysregulation and NMDA receptor hypofunction could all induce oxidative stress and are potentiated by additional oxidative insults, this mechanism could be central to damage of the highly metabolically active PVIs and the PNN surrounding them. Antioxidant systems are therefore potential therapeutic targets, assuming that redox regulators could be applied early, during environmental impacts, long before the clinical emergence of the disease.

Schizophrenia is a severe, persistent, and fairly common mental illness. Haloperidol is widely used and is effective against the symptoms of psychosis seen in schizophrenia. Chronic oral haloperidol administration decreased the number of astrocytes in the parietal cortex of macaque monkeys (Konopaske et al., Biol Psych 63:759-765, 2008). Since astrocytes play a key role in glutamate metabolism, chronic haloperidol administration was hypothesized to modulate astrocyte metabolic function and glutamate homeostasis.This study investigated the effects of chronic haloperidol administration on astrocyte metabolic activity and glutamate, glutamine, and GABA homeostasis.We used ex vivo ¹³C magnetic resonance spectroscopy along with high-performance liquid chromatography after [1-¹³C]glucose and [1,2-¹³C]acetate administration to analyze forebrain tissue from rats administered oral haloperidol for 1 or 6 months.Administration of haloperidol for 1 month produced no changes in ¹³C labeling of glutamate, glutamine, or GABA, or in their total levels. However, a 6-month haloperidol administration increased ¹³C labeling of glutamine by [1,2-¹³C]acetate. Moreover, total GABA levels were also increased. Haloperidol administration also increased the acetate/glucose utilization ratio for glutamine in the 6-month cohort.Chronic haloperidol administration in rats appears to increase forebrain GABA production along with astrocyte metabolic activity. Studies exploring these processes in subjects with schizophrenia should take into account the potential confounding effects of antipsychotic medication treatment.

After traumatic brain injury (TBI), glial cells have both beneficial and deleterious roles in injury progression and recovery. However, few studies have examined the influence of reactive astrocytes in the tripartite synapse following TBI. Here, we have demonstrated that hippocampal synaptic damage caused by controlled cortical impact (CCI) injury in mice results in a switch from neuronal to astrocytic d-serine release. Under nonpathological conditions, d-serine functions as a neurotransmitter and coagonist for NMDA receptors and is involved in mediating synaptic plasticity. The phasic release of neuronal d-serine is important in maintaining synaptic function, and deficiencies lead to reductions in synaptic function and plasticity. Following CCI injury, hippocampal neurons downregulated d-serine levels, while astrocytes enhanced production and release of d-serine. We further determined that this switch in the cellular source of d-serine, together with the release of basal levels of glutamate, contributes to synaptic damage and dysfunction. Astrocyte-specific elimination of the astrocytic d-serine-synthesizing enzyme serine racemase after CCI injury improved synaptic plasticity, brain oscillations, and learning behavior. We conclude that the enhanced tonic release of d-serine from astrocytes after TBI underlies much of the synaptic damage associated with brain injury.

Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.

Schizophrenia is a chronic, disabling psychiatric disorder characterized by psychosis, cognitive impairments, and negative symptoms such as social withdrawal and anhedonia. Pathologic changes in the brain include cortical atrophy, loss of pyramidal cell dendritic complexity and spine density, ventricular enlargement, and reduction in intracellular mediators of neuronal plasticity. Acute blockade of N-methyl-d-aspartate receptors (NMDARs) with ketamine reproduces the full range of symptoms of schizophrenia in normal volunteers. A recent genome-wide association study revealed that many of the risk genes for schizophrenia interact directly with the NMDAR such as serine racemase (SR), which synthesizes its co-agonist, d-serine, or downstream mediators of NMDAR activity. Consistent with the genetic findings, alterations in the levels of SR, d-serine, and d-amino acid oxidase have been found in schizophrenia. Genetically silencing the SR gene (SR−/−) in mice causes an 85 % reduction of d-serine in the brain and reproduces the synaptic neuropathology of schizophrenia as well as the cognitive deficits and anhedonia. Treatment of adult SR−/− mice with d-serine to restore brain levels reverses most of the neuropathology and the cognitive deficits. Placebo-controlled clinical trials in schizophrenic patients on antipsychotic drugs with d-serine or agents that act at its site on the NMDAR have shown significant reductions in symptoms including psychosis. These findings support the hypothesis that drugs that enhance NMDAR function might be effective treatments for schizophrenia, especially the cognitive and negative symptoms, which are unaffected by current treatments.